bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–09–07
ninety-one papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial Quality Control.
  2. Sestrin2 alleviates sepsis-induced immunosuppression of dendritic cells by regulating mitochondrial dynamics.
  3. Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions.
  4. PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
  5. [Effects and mechanisms of the kidney-reinforcing and blood circulation-activating and collateral dredging decoction metabolites on the proliferation of multiple myeloma KM3 cells].
  6. Melatonin attenuates intervertebral disc degeneration by restoring mitochondrial homeostasis through PGC-1α signaling pathway.
  7. ROS and Drp1-mediated mitochondrial fission contributes to the hyposalivation caused by Sjögren's disease.
  8. Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy.
  9. Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
  10. Natural lignan justicidin A-induced mitophagy as a targetable niche in bladder cancer.
  11. SRT1720 ameliorates LPS-induced depressive-like behaviors in mice and activates Parkin-mediated mitophagy.
  12. Targeting Drp1 in Cerebral Ischemia-Reperfusion Injury: Mechanisms and Therapeutic Implications.
  13. Knockdown of TFB2M induces ferroptosis in lung adenocarcinoma via mitophagy-mediated GPX4 degradation.
  14. The Juvenile Parkinson's Disease Mutation C212Y Impairs Mitochondrial Homeostasis in a Caenorhabditis elegans Model.
  15. Rhapontigenin attenuates neurodegeneration in a parkinson's disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy.
  16. Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
  17. Molecular mechanisms of mitochondrial quality control.
  18. RNAi of mitochondrial sirtuin, sir-2.2 reduces alpha-synuclein clearance and impairs energy homeostasis in C. elegans.
  19. GLP-1/GIP dual agonist tirzepatide alleviates mice model of Parkinson's disease by promoting mitochondrial homeostasis.
  20. Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
  21. ER stress disrupts MFN2-related mitophagy via HRD1-PINK1/ parkin axis in bovine embryos.
  22. Running exercise alleviates depressive-like behaviors through the activation of PINK1-Parkin mediated mitophagy in mice exposed to chronic social defeat stress.
  23. Capsaicin regulated lipid metabolism in HepG2 via mitochondrial autophagy PINK1/Parkin pathway.
  24. Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
  25. MicroRNA-15b promotes Myofascial pain syndrome by targeting NFS1 to regulate mitophagy.
  26. Astaxanthin mitigates cardiac toxicity induced via doxorubicin by alleviating mitochondrial fission and autophagy in rats.
  27. A Mediterranean Diet-Based Food Mix Ameliorates Diabetes- and Obesity-Associated Liver Alterations Through Mitochondrial and Metabolic Reprogramming.
  28. PRKN/PINK1 Mutations in a Chinese Patient With Early-Onset Parkinson's Disease.
  29. Mitochondrial Biogenesis in Skeletal Muscle.
  30. [Caffeoylquinic acids from Erigeron breviscapus ameliorates cognitive impairment and mitochondrial dysfunction in AD by activating PINK1/Parkin-mediated mitophagy].
  31. MitoTraP: mitochondrial protection for cellular proteostasis.
  32. Histone deacetylase 7 mediates lipopolysaccharide-inducible mitochondrial fission in macrophages.
  33. Methylene Blue Protects Spatial Working Memory after Traumatic Brain Injury in Mice by Affecting Mitochondrial Quality Control System.
  34. Mitophagy in kidney transplantation ischemia-reperfusion injury.
  35. Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity.
  36. A novel cardioprotective mechanism of rosuvastatin: restoring PINK1/parkin-mediated mitophagy via SIRT1/FOXO1 activation in doxorubicin-induced cardiotoxicity.
  37. PRDX3 promotes nasopharyngeal carcinoma tumor growth by regulating PINK1/Parkin pathway-dependent lipid peroxidation and mitochondrial dysfunction.
  38. Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review).
  39. Conformational Rearrangement of Fission DSPs.
  40. Prognostic impact of excessive mitochondrial fission in patients with heart failure and evaluation of mitochondrial dynamics-related miRNAs in heart failure.
  41. Detyrosinated α-tubulin mediates mitochondrial dysfunction and diastolic impairment in heart failure with preserved ejection fraction.
  42. CircRERE promotes myocardial ischemia/reperfusion injury by increasing UHRF1 mRNA decay through targeting PUM2 to reduce Drp1 promoter methylation.
  43. Traditional wisdom meets modern science: The protective role of sanhuang shu'ai decoction in ulcerative colitis models.
  44. Identification of the prognostic effect of mitophagy-related genes in acute myeloid leukemia.
  45. Dingxin Recipe III Ameliorates Endothelial Cell Senescence in Atherosclerosis by Activating the FOXO3a/Pink1/Parkin Axis.
  46. Super-Resolution Imaging Captures Mitophagy Dynamics: Tricolor Fluorescence Labels Mitochondria, Autophagosomes, and Lysosomes.
  47. Therapeutic potential of alpha-lipoic acid on mitochondrial dynamics, oxidative/nitrosative stress, and histopathological changes in rat ulcerative colitis model.
  48. Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies.
  49. Melittin-induced modulation of mitochondrial physiology: Beyond the antitumoral actions.
  50. Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
  51. Niujiaodihuang Detoxify Decoction Inhibits D-GalN/LPS-induced Hepatocyte Ferroptosis by Maintaining Mitochondrial Homeostasis Via OMA1-OPA1 Pathway.
  52. Reconstitution of autophagic-like membrane tethering reveals that Atg11 can bind and cluster vesicles on cargo mimetics.
  53. Maidong Dishao Decoction can inhibit the activation of the cGAS-STING signaling pathway of Sjögren's syndrome by reducing oxidative stress in salivary gland epithelial cells.
  54. Loss of SETD8 Impairs Mitochondrial Homeostasis to Suppress Leukemia Stem Cell Function in t(8;21) Acute Myeloid Leukemia.
  55. FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
  56. Corrigendum to "High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway" [Cell Signal, 135 (2025), 112027].
  57. Understanding the Changes in Mitochondrial Morphology through Dynamic and Three-dimensional Fluorescence Micrographs.
  58. Sex-specific programming of the gastric and duodenal mitochondrial biogenesis by early-life stress.
  59. Dnm1 Is Required for the Focal Clustering of Fis1 on the Mitochondrial Outer Membrane.
  60. Therapeutic restoration of mitochondria-endoplasmic reticulum cross talk for osteoarthritis.
  61. Correction: TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancer.
  62. Propionibacterium acnes evades microbicidal phagocytosis by inhibiting the mitochondrial biogenesis of nucleus pulposus cells.
  63. [Effect of 40 Hz pulsed magnetic field on mitochondrial dynamics and heart rate variability in dementia mice].
  64. Genetically engineered MSC-derived hybrid cellular vesicles for ROS-scavenging and mitochondrial homeostasis in hepatic ischemia-reperfusion injury.
  65. PLEKHF1 Induces Mitochondrial Dysfunction to Inhibit Osteosarcoma Growth and Metastasis.
  66. Temporal transcriptional regulation of mitochondrial morphology primes activity-dependent circuit connectivity.
  67. Paraquat Induced Neuro-immunotoxicity: Dysregulated Microglial Antigen Processing and Mitochondrial Activated Mechanisms.
  68. Comparative Analysis of Septin Modifiers, Forchlorfenuron and UR214-9, on Mitochondrial Fragmentation and Lytic Cell Death.
  69. FGF5 alleviates ferroptosis in renal tubular epithelial cells by inducing mitophagy under in vitro ischemia-reperfusion-like injury.
  70. Failure of efficient cardiac proteostatic adaptations to chronic cAMP-stress is associated with accelerated heart aging.
  71. Targeting mitochondrial proteases CLPP and LONP1 via disruption of mitochondrial redox homeostasis induces proteotoxic stress and suppresses tumor progression.
  72. Dynamic TOM-TIM23 supercomplex directs mitochondrial protein translocation and sorting.
  73. [Effects and mechanisms of total flavones of Abelmoschus manihot combined with empagliflozin in attenuating diabetic tubulopathy through multiple targets based on mitochondrial homeostasis and ZBP1-mediated PANoptosis].
  74. Silicon-rhodamine-enabled identification for near-infrared light controlled proximity labeling in vitro and in vivo.
  75. Flubendazole inhibits cervical carcinoma by targeting DHODH to induce ferroptosis and mitophagy.
  76. Tetrabromophthalate bis(2-ethylhexyl) ester (TBPH) exposure induces renal inflammation injury by activating MAVS-IRF3 signaling pathway in vitro and in vivo models.
  77. Replication competition drives the selective mtDNA inheritance in Drosophila ovary.
  78. Crosstalk between mitochondrial dysfunction and benign prostatic hyperplasia: unraveling the intrinsic mechanisms.
  79. TRPM2 knockdown alleviated H9N2 influenza virus infected ferroptosis in mouse pulmonary microvascular endothelial cells.
  80. TRIB1 silencing attenuates epilepsy by restoring mitochondrial homeostasis and suppressing microglia-driven neuroinflammation via MAPK pathway inhibition.
  81. Iron-responsive ZNF185 overexpression drives mitochondrial fission and endoplasmic reticulum stress via cytoskeletal remodeling in granulosa cells.
  82. Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
  83. Reorganization of Mitochondrial Function and Architecture in Response to Plant-Derived Alkaloids: Anatabine, Anabasine, and Nicotine, Investigated in SH-SY5Y Cells and in a Cellular Model of Parkinson's Disease.
  84. Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
  85. SFXN2 contributes mitochondrial dysfunction-induced apoptosis as a substrate of Parkin.
  86. Targeting ROCK2 to Restore Epileptic Synaptic Networks via Mitophagy Activation: Insights from Translational Imaging of SV2A In Vivo.
  87. TRIM2 inhibits apoptosis by ubiquitinating BNIP3 to protect the intestine against ischemia-reperfusion injury in mice.
  88. MFN2 and BAG6 Synergistically Protect Against Cerebral Reperfusion Injury by Regulating ROS Levels and Autophagic Flux.
  89. Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
  90. Trastuzumab cardiotoxicity and drug cardioprotection in healthy and cardiac dysfunction mouse models.
  91. AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming.
  1. Adv Exp Med Biol. 2025 ;1478 51-60
    Mitochondrial Quality Control.
    Yuntian Guan, Zhen Yan.
      Mitochondria, the power plants of cells, are essential for various cellular functions. In skeletal muscle, mitochondria form a network, called mitochondrial reticulum, which fuels muscle contractile and metabolic functions. The high degree of structure-to-function specialization of mitochondria in skeletal muscle implies that it is closely gauged and regulated to maintain energy production capacity to match the functional demands. The processes that regulate the overall structure and function of mitochondrial reticulum are collectively referred to as mitochondrial quality control. Mitochondrial quality control consists of mitochondrial biogenesis, dynamics (i.e., fission and fusion), and selective degradation via proteolysis and mitophagy. In this chapter, we will discuss different aspects of contemporary understanding of mitochondrial quality control, their respective mechanisms, and their adaptability to exercise training.
    Keywords:  Adaptation; Exercise; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial reticulum; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_3
  2. Free Radic Biol Med. 2025 Aug 26. pii: S0891-5849(25)00937-2. [Epub ahead of print]240 583-596
    Sestrin2 alleviates sepsis-induced immunosuppression of dendritic cells by regulating mitochondrial dynamics.
    Bing Sun, Jing-Dong Wang, Meng-Yao Wu, Hua-Yong Chen, Si-Qin Yang, Yi-Min Chen, Yu Fu, Zhao-Hong Chen, Yong-Ming Yao.
       BACKGROUND: Mitochondrial dynamics and mitophagy are key mechanisms maintaining mitochondrial quality and homeostasis in inflammatory diseases, though their activation pathways in inflammatory regulation remain unclear. Sestrin2 (Sesn2), a stress-responsive protein critical for cellular homeostasis, was investigated in this study for its regulatory role in mitochondrial dynamics during sepsis and its potential mechanism in dendritic cell (DC) necroptosis.
    METHODS: This study evaluated Sesn2-regulated mitochondrial dynamics proteins such as dynamin-related protein 1 (DRP1), mitochondrial fission factor (MFF), and mitofusin 2 (MFN2) in DCs during sepsis using Western blotting, laser confocal microscopy, and transmission electron microscopy. Lentiviral-transfected cell lines and Sesn2-knockout mouse models were developed to assess Sesn2 deletion's role in DC necroptosis and its impact on immune response signaling pathways post-septic challenge.
    RESULTS: Both cecal ligation and perforation (CLP)-induced sepsis and lipopolysaccharide (LPS) stimulation elicited significant alterations in mitochondrial dynamics, and Sesn2 expression peaked at 24 h. When Sesn2 was knocked down, necroptosis and mitochondrial fission of DCs were noticeably increased, while mitochondrial fusion was decreased. Conversely, the overexpression of Sesn2 exerted a significant protective impact on DCs. Consistently, the necroptosis and immunosuppression of DCs and 7-days mortality rate in Sesn2 gene-deficient mice were significantly increased compared with those in wild-type (WT) mice. Furthermore, Sesn2-mediated mitochondrial fusion and division on DCs was identified to be closely associated with the necroptosis pathway, and DRP1-ROS-ZBP1 signaling was obviously involved in down-regulating necroptosis of DCs in the setting of sepsis.
    CONCLUSIONS: Sesn2-mediated mitochondrial fusion and division can be significantly activated to alleviate the necroptosis of DCs via the DRP1-ROS-ZBP1 pathway in the context of sepsis. Thus, it is of importance that Sesn2 stabilized mitochondrial dynamics might be beneficial for reversing immunosuppression associated with septic complications.
    Keywords:  Dendritic cells; Immunosuppression; Mitochondrial dynamics; Necroptosis; Sepsis; Sestrin2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.050
  3. J Transl Int Med. 2025 Jun;13(3): 211-240
    Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions.
    Miao Zhang, Tong Zhang, Rongjun Zou, Kunyang He, Ru Huang, Jingrui Feng, Jinlin Hu, Teng Ge, Xiaoping Fan, Hao Zhou, Yang Chen.
      Mitochondrial dysfunction is increasingly recognized as a critical driver in the pathogenesis of cardiovascular diseases. Mitochondrial quality control (MQC) is an ensemble of adaptive mechanisms aimed at maintaining mitochondrial integrity and functionality and is essential for cardiomyocyte viability and optimal cardiac performance under the stress of cardiovascular pathology. The key MQC components include mitochondrial fission, fusion, mitophagy, and mitochondria-dependent cell death, each contributing uniquely to cellular homeostasis. The dynamic interplay among these processes is intricately linked to pathological phenomena, such as redox imbalance, calcium overload, dysregulated energy metabolism, impaired signal transduction, mitochondrial unfolded protein response, and endoplasmic reticulum stress. Aberrant mitochondrial fission is an early marker of mitochondrial injury and cardiomyocyte apoptosis, whereas reduced mitochondrial fusion is frequently observed in stressed cardiomyocytes and is associated with mitochondrial dysfunction and cardiac impairment. Mitophagy is a protective, selective autophagic degradation process that eliminates structurally compromised mitochondria, preserving mitochondrial network integrity. However, dysregulated mitophagy can exacerbate cellular injury, promoting cell death. Beyond their role as the primary energy source of the cell, mitochondria are also central regulators of cardiomyocyte survival, mediating apoptosis and necroptosis in reperfused myocardium. Consequently, MQC impairment may be a determining factor in cardiomyocyte fate. This review consolidates current insights into the regulatory mechanisms and pathological significance of MQC across diverse cardiovascular conditions, highlighting potential therapeutic avenues for the clinical management of heart diseases.
    Keywords:  fusion; mitochondrial death; mitochondrial fission; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1515/jtim-2025-0030
  4. Autophagy. 2025 Aug 27.
    PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
    Soumya Ranjan Mishra, Priyadarshni Mishra, Kewal Kumar Mahapatra, Bishnu Prasad Behera, Gajanan Kendre, Moureq Rashed Alotaibi, Vijay Pandey, Birija Sankar Patro, Daniel J Klionsky, Sujit Kumar Bhutia.
      The inorganic pyrophosphatase PPA2, a matrix-localized protein, maintains mitochondrial function. Here, we identified the role of PPA2 in activating mitochondrial fission signaling. We found that PPA2 overexpression promotes mitochondrial fission by upregulating the mitochondrial translocation of phosphorylated DNM1L S616. Moreover, PPA2 interacts with MTFP1, a mitochondrial inner membrane protein, to induce fission signaling; cells knocked down for MTFP1 and overexpressing PPA2 failed to induce DNM1L activation and subsequent mitochondrial fission. Furthermore, in physiological conditions, PPA2 directed mitochondrial fission at the midzone through MFF-DNM1L, leading to mitochondrial proliferation. Interestingly, during mitochondrial stress following CCCP treatment, PPA2 triggers peripheral fission through FIS1 and DNM1L to segregate parts of damaged mitochondria, which is essential for mitophagy. In addition, PPA2 utilized the C-terminal LC3-interacting region (LIR) of MTFP1 for mitophagy-mediated clearance of damaged mitochondria. In conclusion, PPA2 activates mitochondrial fission signaling through MTFP1-DNM1L and is essential in defining the site of mitochondrial fission, leading to mitochondrial proliferation or mitophagy for maintaining mitochondrial homeostasis.
    Keywords:  MTFP1; Mitochondria; PPA2; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2552900
  5. Zhonghua Xue Ye Xue Za Zhi. 2025 Jul 14. 46(7): 647-654
    [Effects and mechanisms of the kidney-reinforcing and blood circulation-activating and collateral dredging decoction metabolites on the proliferation of multiple myeloma KM3 cells].
    J B Shi, C N Li, W J Wei, J Y Ding, G D Ma, L L Li, Y R Wang, Y T Lu, J Xu, W Zheng, Y Wang, J Y Wang, R R Xu, S Y Cui.
      Objective: To evaluate the effects and underlying mechanisms of metabolites derived from the kidney-reinforcing, blood circulation-activating, and collateral dredging decoction on the proliferation of multiple myeloma (MM) KM3 cells. Methods: MM KM3 cells in the logarithmic growth phase were treated with 3%, 6%, 9%, or 12% metabolites of kidney-reinforcing, blood circulation-activating, and collateral dredging decoction. Cell viability was assessed using the CCK-8 assay. Apoptosis and necrosis were evaluated using flow cytometry and TUNEL staining. Mitochondrial and cellular ultrastructural changes were examined using transmission electron microscopy. mRNA and protein expression levels of dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), mitochondrial fission factor (MFF), PTEN-induced kinase 1 (Pink1), and E3 ubiquitin ligase (Parkin) were determined through quantitative real-time PCR and western blotting. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) combined with network pharmacology, was utilized for reverse verification of the pharmacodynamic mechanisms and therapeutic targets underlying the anti-MM activity of this decoction. Results: The metabolites of the kidney-reinforcing, blood circulation-activating, and collateral dredging decoction inhibited KM3 cell proliferation and induced apoptosis in a dose-dependent manner. Transmission electron microscopy revealed increased mitochondrial fission and autophagic structures, with effects intensifying at higher metabolite concentrations. mRNA and protein expression of Drp1, Fis1, MFF, Pink1, and Parkin were significantly upregulated in treatment groups compared to controls (P<0.05), with the most pronounced effects observed in the 12% metabolite group (P<0.01). HPLC-MS/MS identified 121 bioactive compounds in BHTF, which shared 474 overlapping targets with MM. Enrichment analysis suggested that BHTF exerts antitumor effects primarily through apigenin, palmatine, and other key components by modulating TNF, NF-κB, and mitophagy pathways. Conclusion: The kidney-reinforcing and blood circulation-activating and collateral dredging decoction suppresses the proliferation of MM KM3 cells, potentially through mechanisms involving the regulation of mitochondrial dynamics and induction of autophagy.
    Keywords:  Autophagy; Mitochondrial dynamics; Multiple myeloma; Network pharmacology
    DOI:  https://doi.org/10.3760/cma.j.cn121090-20241209-00547
  6. Cell Mol Life Sci. 2025 Aug 31. 82(1): 330
    Melatonin attenuates intervertebral disc degeneration by restoring mitochondrial homeostasis through PGC-1α signaling pathway.
    Tao Lan, Wenhan Yang, Bin Yan, Weizhuang Guo, Yuantao Zhang.
      Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP) and poses a substantial economic burden worldwide. Mitochondrial dysfunction, associated with oxidative stress and apoptosis, is linked to various degenerative diseases. Melatonin has emerged as a potential therapeutic agent for preventing IVDD because of its capacity to regulate cellular rhythms. The impact of melatonin on mitochondrial dysfunction and its underlying mechanisms is not yet fully understood. Firstly, Cell Counting Kit-8 (CCK-8) assay was used to evaluate nucleus pulposus (NP) cell viability treated with melatonin and advanced oxidation protein products (AOPP). Then, Western blotting, immunofluorescence and tunnel staining were employed to explore the underlying mechanisms in vitro. Next, a needle-punctured rat model followed by radiographic analysis and immunohistochemical staining was used to evaluate the potential effect of melatonin in vivo. This study demonstrated that AOPP triggered oxidative stress, exacerbated mitochondrial injury, and increased NP cell apoptosis. Additionally, melatonin enhanced mitochondrial function and protected NP cells from oxidative injury. Further studies demonstrated that melatonin enhanced mitochondrial biogenesis and modulated mitochondrial dynamics and mitophagy via the Peroxisome proliferator-activated receptorγcoactivator 1α (PGC-1α) signaling pathway, maintaining mitochondrial homeostasis and thereby decreasing excessive apoptosis and extracellular matrix (ECM) degradation. A PGC-1α inhibitor lessened melatonin's effect on the mitochondrial quality system, weakening its protective function in NP cells against oxidative stress. Furthermore, in vivo experiments confirmed that melatonin slowed the progression of IVDD. These findings provide a theoretical basis for treating IVDD by targeting mitochondrial dysfunction and modulating the mitochondrial quality control system. Melatonin could be an effective treatment for IVDD.
    Keywords:  Intervertebral disc degeneration (IVDD); Melatonin; Mitochondrial homeostasis; PGC-1α
    DOI:  https://doi.org/10.1007/s00018-025-05877-5
  7. Chin Med J (Engl). 2025 Sep 04.
    ROS and Drp1-mediated mitochondrial fission contributes to the hyposalivation caused by Sjögren's disease.
    Yu Zhang, Zhihao Du, Shan Zhang, Weixia Chu, Chong Ding, Xiaofeng Shan.
       BACKGROUND: Sjögren's disease (SjD) is an autoimmune disorder characterized by sicca syndrome with undetermined roles of reactive oxygen species (ROS) and mitochondrial dynamics in the damaged glands. This study aimed to clarify the roles of ROS and mitochondrial dynamics in SjD-related hyposalivation and explored the therapeutic effect of targeting mitochondrial fission to treat hyposalivation in murine SjD.
    METHODS: Single-cell sequencing analysis of submandibular glands (SMGs) from mice with SjD was performed. ROS and mitochondrial dynamics and function were evaluated. Mitochondrial division inhibitor-1 (Mdivi-1) was intraductally infused into the SMGs of mice with SjD. The saliva flow rate was measured after intraperitoneal injection of pilocarpine.
    RESULTS: Single-cell sequencing analysis revealed that oxidative stress damage in SMGs might play a critical role in hyposalivation caused by SjD. Intraperitoneal injection of Mito-TEMPO (a mitochondrion-targeted antioxidant) increased the salivary flow rate in murine SjD. In vitro, Mito-TEMPO preincubation alleviated mitochondrial dysfunction. Furthermore, the increased ROS levels promoted mitochondrial fission and decreased fusion in vivo and in vitro. Dynamin-related protein 1 (Drp1) and its Ser616 site mediated mitochondrial dysfunction in glandular epithelial cells induced by interferon-γ. Finally, Mdivi-1 and Drp1 inhibitor intraductal infused into the SMGs promote the saliva flow rate in SjD mice, accompanied by improvements in glandular mitochondrial function and cell survival.
    CONCLUSIONS: The elevated ROS in SGECs participates in hyposalivation in SjD. The excess ROS results in the increased mitochondrial fission via Drp1 and its Ser616 site, further worsening mitochondrial dysfunction in glandular cells. Mdivi-1 intraductal infusion significantly can ameliorate hyposalivation in murine models of SjD.
    Keywords:  Dynamin-related protein 1; Reactive oxygen species; Sjögren’s disease; hyposalivation; mitochondrial dynamics
    DOI:  https://doi.org/10.1097/CM9.0000000000003727
  8. Drug Resist Updat. 2025 Aug 20. pii: S1368-7646(25)00097-4. [Epub ahead of print]83 101294
    Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy.
    Ling Li, Yangyang Feng, Jingbo Zhou, Fangyuan Shao, Yuzhong Peng, Sitian Zang, Josh Haipeng Lei, Heng Sun, Dongyang Tang, Shiqi Lin, Jinghong Chen, Hanghang Li, Xiangpeng Chu, Yunfeng Qiao, Xinyu Guo, Kakun Wu, Xiaoling Xu, Chu-Xia Deng.
      Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome-mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPRmt), followed by increased lysosome biogenesis and PINK1-Parkin independent but ROS-BNIP3-mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.
    Keywords:  MDR; cell death; lysosome membrane permeabilization; mitochondrial protein import; mitophagy; proteasome activity; protein damage
    DOI:  https://doi.org/10.1016/j.drup.2025.101294
  9. Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01005-8. [Epub ahead of print]44(9): 116234
    Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
    Shuang Ma, Jianhua Qin, Yao Zhang, Jing Luan, Na Sun, Guoyuan Hou, Jiyuan He, Yang Xiao, Wei Zhang, Minghui Gao.
      Ferroptosis is a regulated necrosis driven by iron-dependent lipid peroxidation. Mitochondria play vital roles in ferroptosis. Mitochondrial dynamics is critical for the health of mitochondria and cells. But how this process regulates ferroptosis is not fully understood. Here, we found that mitochondrial fission is induced during ferroptosis. Disruption of mitochondrial dynamics by impeding the expression of the central players of mitochondrial dynamics control, dynamin-related protein 1 (DRP1) and Mitofusion1/2, or modifying the expression of optic atrophy 1 (OPA1) inhibits ferroptosis. Mechanistically, a defect in mitochondrial dynamics homeostasis increases the ratio of [AMP+ADP]/[ATP], thus activating AMP-activated protein kinase (AMPK), which further phosphorylates nuclear factor erythroid 2-related factor 2 (NRF2) and promotes NRF2 nuclear translocation. Subsequently, NRF2 triggers ferroptosis suppressor 1 (FSP1) upregulation, which renders the cells resistant to ferroptosis. Importantly, mitochondrial fusion promoter M1 can mitigate the chemotoxicity induced by doxorubicin without compromising its anti-cancer efficacy. Collectively, the results of this study demonstrate the crucial role of mitochondrial dynamics in ferroptosis and indicate a potential therapeutic protective approach for chemotoxicity.
    Keywords:  AMPK; CP: Immunology; CP: Metabolism; FSP1; NRF2; chemotoxicity; ferroptosis; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116234
  10. Chem Biol Interact. 2025 Sep 03. pii: S0009-2797(25)00353-9. [Epub ahead of print] 111723
    Natural lignan justicidin A-induced mitophagy as a targetable niche in bladder cancer.
    Kai-Hsun Chang, Hsin-Chih Chen, Ching-Ying Chen, Shu-Ping Tsai, Man-Yuan Hsu, Pao-Yuan Wang, Shan-Ying Wu, Chun-Li Su.
      Accumulated dysfunctional mitochondria are involved in tumorigenesis, and it is conceivable that mitophagy, a selective form of autophagic degradation of mitochondria, plays a tumor-suppressive role. Our bioinformatics analysis identified lignan justicidin A (JA) as a potential mitophagy inducer. In HRAS-mutant human bladder cancer T24 cells, JA reduced population cell growth, changed mitochondrial membrane potential, and induced autophagy. JA-induced mitophagy was demonstrated by a reduction of mitochondrial puncta by confocal microscopy and co-localization of autophagy marker LC3 and mitochondrial matrix protein HSP60 in the autophagic vesicles by electron microscopy. These phenomena were associated with altered mitochondrial dynamics, increased expressions of HIF-1α and its target gene BNIP3, and induced co-immunoprecipitation of LC3 with BNIP3 homo-dimer. Confocal microscopy further observed co-localizations among puncta of LC3, BNIP3, and HSP60. JA raised BNIP3 expression in T24 but not E7 (HRAS wild-type) and induced stronger autophagy in T24 than in E7 cells, indicating JA preferentially caused BNIP3-mediated mitophagy in urinary tract cells with oncogenic HRAS. Furthermore, JA enhanced cytotoxicity of T24 cells to anti-cancer drugs cisplatin combined with gemcitabine. Analyses of patients' data further showed that, in contrast to other major cancer types, lowered mitophagy in bladder urothelial carcinoma compared with normal tissues and reduced expression of mitochondrial genes in cisplatin-responsive bladder cancer cells compared with non-responsive cells suggest mitophagy acts as a tumor suppressor to avoid cisplatin resistance in bladder cancer. Overall, our data suggest the role of BNIP3 and mitophagy in anti-cancer mechanism of human bladder cancer with HRAS mutation in response to JA.
    Keywords:  BNIP3; bladder cancer; cisplatin; gene database; justicidin A; mitophagy
    DOI:  https://doi.org/10.1016/j.cbi.2025.111723
  11. BMC Neurosci. 2025 Aug 30. 26(1): 56
    SRT1720 ameliorates LPS-induced depressive-like behaviors in mice and activates Parkin-mediated mitophagy.
    Luna Sun, Chaoran Li, Jianli Shi, Wenfeng Zeng, Lingling Wu, Shunlun Wan, Yunxia Wang.
       BACKGROUND: Emerging evidence suggests a connection between mitophagy-a key mitochondrial quality control mechanism-and depression. Furthermore, sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, has been implicated in the pathophysiology of depression, though its precise role remains elusive. This study aimed to investigate how SIRT1 modulates depressive-like behaviors in mice and to determine whether mitophagy mediates this process.
    METHODS: Male BALB/c mice were administered lipopolysaccharide (LPS) to mimic depressive-like behaviors. The treatment group received a pre-administration of SRT1720 (50 mg/kg, i.p.), a specific SIRT1 activator. Depressive-like behaviors were assessed by sucrose preference test (SPT) and forced swimming test (FST). Additionally, hippocampal neuronal and mitochondrial ultrastructure was detected via transmission electron microscopy (TEM), and mitophagy-related protein expression was examined by western blotting.
    RESULTS: Results demonstrated that activation of SIRT1 significantly mitigated LPS-induced depressive-like behaviors in mice. Moreover, it was observed that SIRT1 activation protected against LPS-induced neuronal and mitochondrial damage in the hippocampus. TEM analysis revealed a marked increase in hippocampal autophagosomes following SIRT1 activation, accompanied by significantly elevated expression of LC3II and Parkin, suggesting enhanced mitophagy. In vitro experiment using HT-22 cells provided additional evidence that SIRT1 activation ameliorated LPS-induced mitochondrial dysfunction and promoted mitophagy via Parkin-mediated pathway.
    CONCLUSIONS: These findings suggested that activation of SIRT1 could alleviate depressive-like behaviors in mice following LPS challenge, potentially through a Parkin-dependent mitophagy mechanism.
    Keywords:  Depression; Mitochondria; Mitophagy; Parkin; SIRT1
    DOI:  https://doi.org/10.1186/s12868-025-00968-2
  12. CNS Neurosci Ther. 2025 Aug;31(8): e70590
    Targeting Drp1 in Cerebral Ischemia-Reperfusion Injury: Mechanisms and Therapeutic Implications.
    Mengnan Liu, Zhixue Yin, Binru Li, Ji Qiu, Dechou Zhang, Raoqiong Wang, Xue Bai, Li Chen.
       BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) arises after blood flow restoration in stroke, where reperfusion paradoxically triggers mitochondrial dysfunction, apoptosis, inflammation, and oxidative stress. Dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, amplifies these cascades by promoting apoptosis, inflammatory signaling, and calcium imbalance.
    METHODS: This review synthesizes recent studies on Drp1 in CIRI, focusing on its regulatory roles in mitochondrial dynamics and neuronal injury, and evaluating therapeutic strategies through pharmacological and genetic modulation.
    RESULTS: Evidence shows Drp1 inhibition mitigates CIRI in preclinical models by restoring mitochondrial homeostasis, reducing oxidative stress, and improving neuronal survival. Promising interventions include selective inhibitors and genetic approaches, though challenges remain regarding drug specificity, delivery efficiency, and long-term safety.
    CONCLUSION: Drp1 is central to CIRI pathology and represents a promising therapeutic target. Future work should prioritize advanced delivery systems and safer, more selective Drp1 modulators to enable clinical translation.
    Keywords:  Drp1; cerebral ischemia–reperfusion injury (CIRI); mitochondrial dynamics; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.1111/cns.70590
  13. Expert Rev Anticancer Ther. 2025 Sep 03. 1-10
    Knockdown of TFB2M induces ferroptosis in lung adenocarcinoma via mitophagy-mediated GPX4 degradation.
    Tulei Tian, Tianyu She, Meiling Xie, Xiangkun Qu, Hongbo Zhang, Gengyun Sun.
       BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, with a low survival rate. TFB2M, a mitochondrial transcription factor, maintains normal mitochondrial function. Its role in LUAD is unclear.
    METHODS: We analyzed TFB2M expression in LUAD and normal tissues based on TCGA database. GSEA analyzed pathway enrichment. TFB2M-knockdown LUAD and control groups were constructed. Western blot detected levels of mitophagy- and ferroptosis-related proteins with/without mitophagy inhibitor (Mdivi-1, 10 μM). Malondialdehyde, glutathione, 4-hydroxynonenal, reactive oxygen species, and Fe2+ levels were measured to evaluate ferroptosis. CCK-8, EdU experiments, and flow cytometry evaluated cell survival. Immunofluorescence detected co-localization of glutathione peroxidase 4 and mitochondrial outer membrane transferase 20. Mitochondrial-specific fluorescent probes evaluated mitochondrial changes. A LUAD xenograft mouse model was constructed, with tumor volume and weight (with/without mitophagy inhibitors, 50 mg/kg) measured. IHC detected TFB2M and ki67 expression.
    RESULTS: TFB2M was upregulated (p < 0.05), and enriched in ferroptosis and mitophagy-related pathways. Mitophagy inhibitors reversed the promotion of mitophagy and ferroptosis and the inhibition of cell proliferation conferred by TFB2M knockdown. In animal experiments, they weakened the inhibition of mitophagy and the alleviation of LUAD progression induced by TFB2M knockdown.
    CONCLUSION: TFB2M contributes to ferroptosis resistance in LUAD by suppressing mitophagy.
    Keywords:  Ferroptosis; GPX4; TFB2M; lung adenocarcinoma; mitophagy
    DOI:  https://doi.org/10.1080/14737140.2025.2554642
  14. FASEB J. 2025 Aug 31. 39(16): e70835
    The Juvenile Parkinson's Disease Mutation C212Y Impairs Mitochondrial Homeostasis in a Caenorhabditis elegans Model.
    Eyal Spector, Lirin Michaeli, Anat Nitzan, Hanna Grobe, Gabriel Axel, Ulrike Bening Abu-Shach, Hen Zinger, Cátia A Carvalho, Ronen Zaidel-Bar, Limor Broday.
      Inherited Parkinson's disease (PD) often involves missense mutations in the PRKN2 gene, encoding for Parkin protein. The PDR-1 protein is the C. elegans ortholog of human Parkin. Using a CRISPR/Cas9 genome editing approach, we generated the PDR-1C169Y point mutation on a conserved cysteine residue in the RING0 domain. This mutation in human Parkin, C212Y, has been identified in autosomal recessive juvenile Parkinsonism patients. The PDR-1C169Y homozygous mutant animals exhibited a shorter lifespan and decreased thrashing rate compared with wild-type or heterozygous animals. Unique mitochondrial phenotypes were observed, including an increased mitochondrial area and mitochondrial membrane potential. However, these phenotypes did not activate the mitochondrial unfolded protein response. Pan-neuronal analysis revealed decreased mitophagy. Dopaminergic neurodegeneration in aged animals was not enhanced when compared to WT. Our findings suggest that analysis of the recessive missense point mutations found in early-onset PD using the C. elegans model system has the potential to advance our understanding of the molecular mechanisms that lead to neurodegeneration.
    Keywords:   Parkin C212Y ; PDR‐1C169Y; Parkinson's disease; missense mutations; mitochondria
    DOI:  https://doi.org/10.1096/fj.202402785RRR
  15. Cell Mol Life Sci. 2025 Sep 06. 82(1): 337
    Rhapontigenin attenuates neurodegeneration in a parkinson's disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy.
    Zhongqiang Su, Hui Shu, Xingting Huang, Liuyan Ding, Fengchu Liang, Zongtang Xu, Ziting Zhu, Minshan Chen, Xiaobei Wang, Guihua Li, Huan Xia, Qiannan Cao, Wenlong Zhang, Pingyi Xu, Xinling Yang.
      Microglial activation-induced neuroinflammation and impaired neuronal mitophagy are recognized as pivotal pathogeneses in Parkinson's disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera, exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap's ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.
    Keywords:  CGAS-STING; Microglial mitophagy; Mitochondrial DNA; Neuroinflammation; Parkinson's disease; Rhapontigenin
    DOI:  https://doi.org/10.1007/s00018-025-05873-9
  16. EMBO Rep. 2025 Aug 29.
    Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
    Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.
      Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
    Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing
    DOI:  https://doi.org/10.1038/s44319-025-00536-z
  17. Transl Neurodegener. 2025 Sep 01. 14(1): 45
    Molecular mechanisms of mitochondrial quality control.
    Wensheng Li, Yuran Gui, Cuiping Guo, Yuting Huang, Yi Liu, Xuan Yu, Huiliang Zhang, Jianzhi Wang, Rong Liu, Yacoubou Abdoul Razak Mahaman, Qiuhong Duan, Xiaochuan Wang.
      Mitochondria produce adenosine triphosphate (ATP), the main source of cellular energy. To maintain normal function, cells rely on a complex mitochondrial quality control (MQC) system that regulates mitochondrial homeostasis, including mitochondrial dynamics, mitochondrial dynamic localization, mitochondrial biogenesis, clearance of damaged mitochondria, oxygen radical scavenging, and mitochondrial protein quality control. The MQC system also involves coordination of other organelles, such as the endoplasmic reticulum, lysosomes, and peroxisomes. In this review, we discuss various ways by which the MQC system maintains mitochondrial homeostasis, highlight the relationships between these pathways, and characterize the life cycle of individual mitochondria under the MQC system.
    Keywords:  Evidence-based therapies; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Mitochondrial quality control
    DOI:  https://doi.org/10.1186/s40035-025-00505-5
  18. Dis Model Mech. 2025 Sep 05. pii: dmm.052197. [Epub ahead of print]
    RNAi of mitochondrial sirtuin, sir-2.2 reduces alpha-synuclein clearance and impairs energy homeostasis in C. elegans.
    Anam Naseer, Pranoy Toppo, Mahmood Akbar, Aamir Nazir.
      Mitochondria are the regulators of energy production and play a vital role in modulating ageing and age-associated diseases. We investigated the role of sirtuins, a well-studied class of longevity-associated proteins (NAD+-dependent histone deacetylases), in mitochondrial biology and Parkinson's disease pathology. In particular, we endeavored to study the functional implications of mitochondrial sirtuin, sir-2.2 (ortholog of human SIRT4), in regulating neuroprotection employing Caenorhabditis elegans model. We observed that upon sir-2.2 knockdown, the alpha-synuclein aggregation was increased and expression of dopamine transporter, dat-1, was reduced. Also, the levels of marker proteins for innate immunity, oxidative stress, mitophagy, UPRmt, and autophagy, were decreased, suggesting an important function of sir-2.2 in maintaining mitochondrial homeostasis, regulating protein clearance and ameliorating the disease condition. Because of their crucial role in regulating oxidative stress and mitochondrial quality control, studying mitochondrial sirtuin will provide therapeutic insights into the metabolic regulation of ageing and neurodegeneration.
    Keywords:   Caenorhabditis elegans.; Sir-2.2 ; Mitochondria; Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1242/dmm.052197
  19. Int Immunopharmacol. 2025 Aug 30. pii: S1567-5769(25)01434-1. [Epub ahead of print]165 115443
    GLP-1/GIP dual agonist tirzepatide alleviates mice model of Parkinson's disease by promoting mitochondrial homeostasis.
    Ruixue Tian, Kexin Liu, Hurong Lai, Caifeng Liao, Jian Li, Huaijun Tu.
       BACKGROUND: The prevailing treatment of Parkinson's disease (PD) is not yet satisfactory. The present investigate the neuroprotective effect of the GLP-1/GIP dual agonist tirzepatide and examine the potential mechanisms involved.
    METHODS: Analysis of GLP1 receptor (GLP1R) and GIPR expression alterations in dopaminergic neurons from PD patients in the GSE238129 dataset. The MPTP-induced subacute PD mice was treated with tirzepatide, semaglutide and levodopa. Behavioral tests and brain histopathology of mice were evaluated. The transmission electron microscopy revealed the presence of ultrastructural alterations in the mitochondrial morphology. The ATP level was assessed in substantia nigra. Western blot and immunohistochemical staining were employed to quantify Drp1 and mitophagy proteins. Furthermore, Drp1 inhibitor and mitophagy activator were used to treat MPTP-induced subacute PD mice, and lysosome inhibitor chloroquine (CQ) and the autophagy inhibitor 3-methyladenine (3-MA) were used in SY5Y cells for validation.
    RESULTS: The gene expression levels of both GLP1R and GIPR were significantly downregulated in dopaminergic neurons derived from PD patients. Tirzepatide could significantly ameliorate MPTP-induced the loss of tyrosine hydroxylase (TH) protein in the substantia nigra. There was no statistically difference observed between one-third doses of tirzepatide when compared with semaglutide and levodopa. In addition, tirzepatide not only improved mitochondrial ultrastructure, but also enhanced mitochondrial ATP content. Tirzepatide was found to reduce Drp1 expression and reverse the expressions of mitophagy-related proteins, including Pink1, Parkin, and p62. There was no statistically difference observed between one-third doses of tirzepatide compared with semaglutide in mitochondrial energy control. In addition, we observed that MPTP-induced subacute PD mice treated with a Drp1 inhibitor and mitophagy activator exhibited therapeutic effects. In SY5Y cells, lysosomal and autophagy inhibitors significantly reduced mitochondrial membrane potential, ATP levels, and the NAD+/NADH ratio.
    CONCLUSION: This study demonstrates that the benefits of tirzepatide extend to mitochondrial networks, achieved by means of the inhibition of mitochondrial pathological fission, the promotion of mitophagy, in MPTP-induced subacute PD mice or cells model.
    Keywords:  GIP; GLP1; Mitochondrial homeostasis; Parkinson's disease; Tirzepatide
    DOI:  https://doi.org/10.1016/j.intimp.2025.115443
  20. J Cell Biol. 2025 Oct 06. pii: e202410130. [Epub ahead of print]224(10):
    Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
    Maria Pia Rodriguez Salazar, Sprihaa Kolanukuduru, Valentina Ramirez, Boyu Lyu, Gracie Manigault, Gabrielle Sejourne, Hiromi Sesaki, Guoqiang Yu, Cagla Eroglu.
      Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins such as gap junction protein connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondrial dynamics as a critical step in neurodevelopment.
    DOI:  https://doi.org/10.1083/jcb.202410130
  21. Theriogenology. 2025 Aug 28. pii: S0093-691X(25)00385-1. [Epub ahead of print]249 117659
    ER stress disrupts MFN2-related mitophagy via HRD1-PINK1/ parkin axis in bovine embryos.
    Shu-Ming Shi, Li-Ying Liu, Zhi-Chao Chi, Lin-Yi Qu, Jing-Hang Li, Guan-Lin Jia, Yu-Yan He, Yong-Xun Jin, Ming-Jun Zhang, Xian-Feng Yu.
      The endoplasmic reticulum and mitochondria are interconnected through the MAM structure, and mitochondrial fusion protein 2 (MFN2) is a key regulatory factor. In this study, tunicamycin (TM) was used to induce endoplasmic reticulum stress in bovine embryos to explore its effects on MFN2 expression, mitochondrial function and mitochondrial autophagy. The results showed that TM treatment significantly reduced the blastocyst rate and proliferation capacity of embryos, inhibited the expression of pluripotency genes (SOX2, CDX2, OCT4), and upregulated key proteins of the UPR pathway. The expression of MFN2 and MAM region E3 ubiquitin ligase (HRD1) was significantly increased, PINK1 expression was downregulated, and Parkin localization on the mitochondrial membrane was reduced. Colocalization analysis and the reduction of LC3-II ratio indicated that mitochondrial autophagy was blocked. At the same time, mitochondrial membrane potential, ATP content and functional genes (PGC-1, TFAM) expression were downregulated, OXPHOS key enzymes were inhibited, and glycolysis was compensated. The mitochondrial apoptosis marker cytochrome C was released, Caspase3 was upregulated, and the PI positive rate increased. In summary, ER stress inhibits mitophagy through HRD1 -mediated PINK1 degradation, leading to the accumulation of mitochondrial damage, aggravating energy metabolism disorders and apoptosis, and ultimately inhibiting the in vitro development of bovine embryos.
    Keywords:  Bovine embryo; Endoplasmic reticulum stress; MFN2; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.theriogenology.2025.117659
  22. Psychiatry Res. 2025 Sep 01. pii: S0165-1781(25)00359-2. [Epub ahead of print]352 116714
    Running exercise alleviates depressive-like behaviors through the activation of PINK1-Parkin mediated mitophagy in mice exposed to chronic social defeat stress.
    Luna Sun, Lingling Wu, Zhangyang Xu, Wenfeng Zeng, Yunxia Wang.
       AIMS: Running exercise has demonstrated efficacy in the prevention and treatment of depression, yet the underlying mechanisms remain incompletely elucidated. Mitochondrial dysfunction and impaired mitophagy have been implicated in depression pathogenesis, while SIRT1 has been shown to play a critical role in both depression and mitochondrial regulation. Building on these established associations, this study aimed to investigate the antidepressant mechanisms of running exercise, with particular fucus on mitophagy regulated by SIRT1.
    MATERIALS AND METHODS: Chronic social defeat stress (CSDS) model of depression was established in male BALB/c mice to induce depressive-like phenotypes and a 2-week moderate-intensity running exercise protocol was employed as interventions. Depressive-like behaviors and treatment efficacy were assessed through various behavioral tests. Hippocampal neuronal function and mitophagy activity were evaluated using ultra high performance liquid chromatography-tandem mass spectrometry, transmission electron microscopy and western blotting.
    KEY FINDINGS: Running exercise significantly ameliorated CSDS-induced depressive-like behaviors and improved hippocampal neuronal function and ultrastructure in CSDS mice. Mechanistically, these beneficial effects were associated with the activation of PINK1-Parkin mediated mitophagy. Furthermore, exercise intervention upregulated hippocampal SIRT1 expression, which was downregulated by CSDS exposure. Notably, pharmacological inhibition of SIRT1 not only abolished the antidepressant effects of running exercise, but also induced depressive-like behaviors in mice and impaired hippocampal PINK1-Parkin mitophagy pathway.
    SIGNIFICANCE: The findings demonstrated that running exercise ameliorated CSDS-induced depressive-like behaviors by enhancing hippocampal mitophagy through SIRT1 upregulation and subsequent activation of the PINK1-Parkin pathway. This mechanism promoted the clearance of damaged mitochondria, thereby restoring neuronal function in stressed mice.
    Keywords:  Chronic social defeat stress; Depression; Mitophagy; Running exercise; SIRT1
    DOI:  https://doi.org/10.1016/j.psychres.2025.116714
  23. Gene. 2025 Sep 02. pii: S0378-1119(25)00541-4. [Epub ahead of print] 149752
    Capsaicin regulated lipid metabolism in HepG2 via mitochondrial autophagy PINK1/Parkin pathway.
    Hao Song, Minhao Xie, Hui Xu, Jianhui Liu, AnXiang Su, YiZhou Liu, Ye Wang, Yongjiao Wang, Fei Pei, Wenjian Yang.
      Capsaicin (CAP), a major natural functional component in chili peppers, has garnered considerable attention for its health benefits, including lipid-lowering effects, and its precise mechanisms remain unclear. This study aims to investigate the lipid-reducing effects of CAP on oleic acid (OA)-induced lipid accumulation in HepG2 cells and explore the underlying mechanisms. The results showed that CAP exerted lipid-lowering effects by reducing triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and increasing high-density lipoprotein cholesterol (HDL-C) in OA-induced HepG2 cells. CAP modulated the relative expression levels of lipid metabolism-related genes, including ACC, PPAR-α, PPAR-γ, Fasn, CPT-1, SREBP-1C, and SCD-1 in HepG2 cells. Notably, CAP activated the PINK1/Parkin-mediated mitophagy pathway to alleviatie lipid accumulation. Treatment with the mitophagy inhibitor Mdivi-1 reversed the lipid-lowering effect of CAP, and silencing PINK1 gene using siRNA abolished lipid-lowering effect of CAP in HepG2 cells, confirming the critical involvement of the pathway. In conclusion, CAP targeted the PINK1 gene and activated the PINK1/Parkin signaling pathway to promote mitophagy, restoring cellular energy homeostasis and regulating lipid synthesis and degradation, ultimately reducing lipid accumulation. These findings provided a mechanistic basis for the potential use of CAP in developing novel natural therapies for lipid metabolic disorders and obesity management.
    Keywords:  Capsaicin; Lipid metabolism; Mitochondrial autophagy; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.gene.2025.149752
  24. EMBO Rep. 2025 Aug 29.
    Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
    Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.
      Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.
    Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin
    DOI:  https://doi.org/10.1038/s44319-025-00561-y
  25. Free Radic Biol Med. 2025 Aug 27. pii: S0891-5849(25)00941-4. [Epub ahead of print]
    MicroRNA-15b promotes Myofascial pain syndrome by targeting NFS1 to regulate mitophagy.
    Dawei Han, Molei Liu, Mingwei Sheng, Lili Jia, Yunxia Liu, Ling Liu, Hongxia Li, Yiqi Weng, Xiaofei Song, Yinghui Ren, Wenli Yu.
       BACKGROUND AND AIMS: Myofascial pain syndrome (MPS), driven by dysfunction in myofascial trigger points (MTrPs), remains mechanistically unclear. This study aimed to explore miR-15 b's function in MTrP pathogenesis, focusing on its regulation of iron-sulfur (Fe-S) cluster synthesis and mitophagy.
    METHODS: A rat MTrP model was established using repetitive mechanical injury and eccentric exercise. Skeletal muscle tissues and primary satellite cells were analysed for miR-15b expression, Fe-S cluster-related proteins (NFS1, NDUFS3, and SDH B), and mitophagy markers (FUN14 structural domain-containing protein 1 (FUNDC1) and LC3-II/I). In vitro, tumour necrosis factor-alpha (TNF-α)-induced inflammation and miR-15b modulation (mimics/sponges) and NFS1 modulation (overexpression/knockdown) were used to assess mitochondrial functions. In vivo, the therapeutic effect on normal and MTrP model rats was evaluated by intramuscular injection of transiently transfected complexes of NFS1 plasmid, miR-15b plasmid or sponge constructs.
    RESULTS: MTrP rats exhibited miR-15b, suppressed NFS1, and impaired Fe-S-dependent complexes. Dual luciferase assays verified miR-15b targeting NFS1. Rescue experiments further validated that miR-15b directly inhibits NFS1, increase reactive oxygen species (ROS), lowering mitochondrial membrane potential (MMP), triggering FUNDC1-mediated mitophagy. TNF-α stimulation elevated miR-15b levels, exacerbating mitochondrial dysfunction, whereas miR-15b inhibition restored NFS1 and normalised mitophagy. In normal rats, miR-15b overexpression recapitulated MTrP-like pathology in healthy rats.. Moreover, in the MTrP model rats, miR-15b overexpression exacerbated these manifestations, sponge and NFS1 treatment attenuated or even reversed certain pathological changes.
    CONCLUSIONS: miR-15b drives MTrP progression by suppressing NFS1, disrupting Fe-S homeostasis, and activating FUNDC1-dependent mitophagy. Targeting miR-15b mitigates mitochondrial dysfunction and pain hypersensitivity, underscoring its therapeutic potential in MPS.
    Keywords:  Iron-sulfur clusters; Mitophagy; Myofascial pain syndrome; NFS1; miR-15b
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.054
  26. Sci Rep. 2025 Sep 01. 15(1): 32114
    Astaxanthin mitigates cardiac toxicity induced via doxorubicin by alleviating mitochondrial fission and autophagy in rats.
    Yongjing He, Dan Wu, Qianqian Wu, Sisi Huang, Yuansheng Zhan, Jiaqiang Deng, Jing Yu Chen, Lu Xie, Junhui Zheng.
      
    Keywords:  Astaxanthin; Cardiotoxicity; Doxorubicin; Mitochondria autophagy; Mitochondrial dynamics
    DOI:  https://doi.org/10.1038/s41598-025-17253-1
  27. Mol Nutr Food Res. 2025 Sep 01. e70210
    A Mediterranean Diet-Based Food Mix Ameliorates Diabetes- and Obesity-Associated Liver Alterations Through Mitochondrial and Metabolic Reprogramming.
    Giovanna Mercurio, Antonia Giacco, Antonio Dario Troise, Moira Ledbetter, Sabrina De Pascale, Nicla Scopigno, Michela Vigliotti, Matteo Mazzola, Giuseppe Riccio, Andrea Scaloni, Maria Moreno, Alberto Fiore, Federica Cioffi, Elena Silvestri.
      Metabolic syndrome (MetS)-related diseases, such as type 2 diabetes (T2D) and obesity, are among the leading causes of liver damage, and their prevalence poses an increasing clinical challenge. The Mediterranean diet (MD) has shown promising effects in managing MetS, reducing mortality and morbidity. However, the precise biochemical and molecular mechanisms underlying the MD efficacy remain unclear. This study evaluated the effects of a lab-designed balanced food mix, simulating the 1960s MD, on hepatic metabolic dysfunction in obese and diabetic db/db mice. The MD cocktail, naturally rich in polyphenols, fructose, and monounsaturated fatty acids, prevented hyperlipidemia while not reversing diabetes and obesity. Gene expression, protein representation, and metabolomic analyses of liver tissues from MD-fed db/db mice revealed reduced oxidative damage, preserved mitochondrial quality control, enhanced autophagy markers, and reduced fibrosis markers. The MD cocktail also enhanced liver mitochondrial mass and stimulated the OXPHOS system. It also preserved the hepatic pool of acylated carnitine derivatives and chenodeoxycholic acid, suggesting protective effects on mitochondrial β-oxidation and bile acid biosynthesis, with an overall improvement of metabolite profiles. The experimental MD cocktail exerted significant hepatoprotective effects, mitigating several diabetes- and obesity-induced hepatic disturbances and beneficially affecting metabolic fluxes and tissue texture.
    Keywords:  OXPHOS; autophagy; mitochondrial biogenesis; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1002/mnfr.70210
  28. Brain Behav. 2025 Sep;15(9): e70822
    PRKN/PINK1 Mutations in a Chinese Patient With Early-Onset Parkinson's Disease.
    Zhongjiao Lu, Ye Sun, Liemei Guo, Mei Xin, Yunlan Du, Ruolian Dai, Gang Chen, Hualong Wang, Gang Wang.
       BACKGROUND: PRKN and PINK1 gene mutations have been associated with Parkinson's disease (PD), particularly early-onset PD (EOPD).
    OBJECTIVES: To describe the clinical and molecular features of a Chinese patient with EOPD who had uncommon PRKN and PINK1 mutations.
    METHODS: The patient's clinical history was reviewed, and whole-exome sequencing was performed to identify genetic mutations. An in vitro mitochondrial stress model was created to study the impact of PRKN deletion on the PINK1-PRKN pathway.
    RESULTS: The patient exhibited a 27-year history of tremors and other motor symptoms, with a notable response to levodopa and subthalamic nucleus deep brain stimulation (STN DBS). Genetic testing revealed an unusual double mutation of PRKN/PINK1, while PRKN deletion blocked the activation of the PINK1-PRKN pathway, disrupting the patient's mitophagy pathway.
    CONCLUSIONS: PRKN/PINK1 mutations may be linked to compromised mitophagy pathways. Genetic screening is significant for EOPD patients, especially those with specific symptoms and ethnic backgrounds.
    DOI:  https://doi.org/10.1002/brb3.70822
  29. Adv Exp Med Biol. 2025 ;1478 19-50
    Mitochondrial Biogenesis in Skeletal Muscle.
    David A Hood, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, Sabrina Champsi.
      Mitochondrial biogenesis refers to the synthesis of nuclear- and mitochondrially encoded proteins, along with phospholipids, that aid in the expansion of the mitochondrial network. In skeletal muscle, mitochondria are organized as a reticulum, as this ideal morphology complements the elongated shape of a myofibre. This allows for efficient substrate diffusion and supports the vigorously dynamic metabolic capabilities of this tissue type. Mitochondria are central responders to deviations in metabolic homeostasis and are thus required to support acute or chronic bouts of endurance exercise, cold exposure, starvation, or other externally imposed stimuli. This chapter marks the introduction to skeletal muscle mitochondrial adaptability as we discuss the subcellular events that contribute to mitochondrial biogenesis. Topics range from mitochondrial content and subpopulations in different muscle fibre types to signaling cascades and regulatory elements that support this mechanism. The characterization of mitochondrial biogenesis was made possible through clever models of both exercise and muscle disuse, at times with genetic modifications to important regulators, and is incorporated in this discussion. The chapter concludes with reviews on changes to signaling towards biogenesis with age. Altogether, our review attempts to highlight the vast revelations on the targeting, contribution, and significance of mitochondrial biogenesis in skeletal muscle.
    Keywords:  Aging; Calcium; Exercise signaling; Exercise training; Gene expression; Mitochondria; Mitochondrial dynamics; Muscle disuse; Protein import; ROS
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_2
  30. Zhongguo Zhong Yao Za Zhi. 2025 Jul;50(14): 3969-3979
    [Caffeoylquinic acids from Erigeron breviscapus ameliorates cognitive impairment and mitochondrial dysfunction in AD by activating PINK1/Parkin-mediated mitophagy].
    Yuan-Zhu Pu, Hai-Feng Chen, Xin-Yi Wang, Can Su.
      This study aimed to investigate the effects of caffeoylquinic acids from Erigeron breviscapus(EBCQA) on cognitive impairment and mitochondrial dysfunction in Alzheimer's disease(AD), and to explore its underlying mechanisms. The impacts of EBCQA on paralysis, β-amyloid(Aβ) oligomerization, and mRNA expression of mitophagy-related genes [PTEN-induced putative kinase 1(PINK1) homolog-encoding gene pink-1, Parkin homolog-encoding gene pdr-1, Bcl-2 interacting coiled-coil protein 1(Beclin 1) homolog-encoding gene bec-1, microtubule-associated protein 1 light chain 3(LC3) homolog-encoding gene lgg-1, autophagic adapter protein 62(p62) homolog-encoding gene sqst-1] were examined in the AD Caenorhabditis elegans CL4176 model, along with mitochondrial functions including adenosine triphosphate(ATP) content, enzyme activities of mitochondrial respiratory chain complexes Ⅰ,Ⅲ, and Ⅳ, and mitochondrial membrane potential. Additionally, the effects of EBCQA on the green fluorescent protein(GFP)/red fluorescent protein from Discosoma sp.(DsRed) ratio, the expression of phosphatidylethanolamine-modified and GFP-labeled LGG-1(PE-GFP::LGG-1)/GFP-labeled LGG-1(GFP::LGG-1), and GFP-labeled SQST-1(GFP::SQST-1) proteins were investigated in transgenic C. elegans strains. The effect of EBCQA on paralysis was further evaluated after RNA interference(RNAi)-mediated suppression of the pink-1 and pdr-1 genes in CL4176 strain. An AD rat model was established through intraperitoneal injection of D-galactose and intragastric administration of aluminum trichloride. The effects of β-nicotinamide mononucleotide(NMN) and EBCQA on learning and memory ability, neuronal morphology, mitophagy occurrence, mitophagy-related protein expression(PINK1, Parkin, Beclin 1, LC3-Ⅱ/LC3-Ⅰ, p62), and mitochondrial functions(ATP content; enzyme activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ; mitochondrial membrane potential) were investigated in this AD rat model. The results showed that EBCQA delayed paralysis onset in the CL4176 strain, reduced Aβ oligomer formation, and upregulated the mRNA expression levels of lgg-1, bec-1, pink-1, and pdr-1, while downregulating sqst-1 mRNA expression. EBCQA also enhanced ATP content, mitochondrial membrane potential, and the activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ. Furthermore, EBCQA improved the PE-GFP::LGG-1/GFP::LGG-1 ratio, reduced GFP::SQST-1 expression, and decreased the GFP/DsRed ratio. Notably, the ability of EBCQA to delay paralysis was significantly reduced following RNAi-mediated suppression of pink-1 and pdr-1 in CL4176 strain. In AD rats, the administration of NMN or EBCQA significantly improved learning and memory, restored neuronal morphology in the hippocampus, increased autophagosome numbers, and upregulated the expression of PINK1, Parkin, Beclin 1, and the LC3-Ⅱ/LC3-Ⅰ ratio, while reducing p62 expression. Additionally, the treatment with NMN or EBCQA both elevated ATP content, mitochondrial respiratory chain complex Ⅰ, Ⅲ, and Ⅳ activities, and mitochondrial membrane potential in the hippocampus. The above findings indicate that EBCQA improves cognitive impairment and mitochondrial dysfunction in AD, possibly through activation of PINK1/Parkin-mediated mitophagy.
    Keywords:  Alzheimer′s disease; PINK-1; Parkin; caffeoylquinic acids from Erigeron breviscapus; mitophagy
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250219.402
  31. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]
    MitoTraP: mitochondrial protection for cellular proteostasis.
    Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.
      Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.
    Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
  32. J Cell Sci. 2025 Sep 01. pii: jcs.264376. [Epub ahead of print]
    Histone deacetylase 7 mediates lipopolysaccharide-inducible mitochondrial fission in macrophages.
    Rishika Abrol, Syeda Farhana Afroz, James E B Curson, Karoline D Raven, Kaustav Das Gupta, Kimberley S Gunther, Alun Jones, Robert C Reid, Zherui Xiong, Jennifer H Gunter, Jessica A Engel, Christian R Engwerda, Antje Blumenthal, David P Fairlie, Robert G Parton, Steven Zuryn, Ronan Kapetanovic, Divya Ramnath, Matthew J Sweet.
      Histone deacetylase 7 (HDAC7) drives several immunometabolism-related processes in macrophages including lipopolysaccharide (LPS)-inducible glycolysis and inflammatory mediator production. Using an advanced biotin ligase TurboID system in human macrophages, we report 104 candidate HDAC7 interaction partners that may contribute to its immunometabolic functions. One such protein is the mitochondrial fission-promoting GTPase dynamin-related protein 1 (DRP1), which associates with HDAC7 in cells. Using gain- and loss-of-function genetic approaches, we show that HDAC7 promotes LPS-inducible mitochondrial fission in macrophages, as well as DRP1-dependent metabolic and inflammatory responses. HDAC7 enzymatic activity was dispensable for LPS-inducible fission, as previously reported for LPS-inducible glycolysis. However, a pharmacological inhibitor of HDAC7 attenuated fission in primary human and mouse macrophages, implicating its acetyl-lysine docking function in this response. HDAC7 thus drives inducible mitochondrial fission in macrophages. Small molecules targeting the acetyl-lysine docking function of HDAC7 may have applications in preventing pathological processes driven by dysregulated mitochondrial fission.
    Keywords:  Dynamin-related protein 1; Glycolysis; Histone deacetylase; Immunometabolism; Lysine deacetylase; Macrophages; Mitochondrial dynamics; Mitochondrial fission; Post-translational modification; Toll-like receptor
    DOI:  https://doi.org/10.1242/jcs.264376
  33. Bull Exp Biol Med. 2025 Aug 29.
    Methylene Blue Protects Spatial Working Memory after Traumatic Brain Injury in Mice by Affecting Mitochondrial Quality Control System.
    A P Gureev, P I Babenkova, V V Nesterova, D E Volodina, I S Sadovnikova, K A Starodubtsev, M E Ivanov, D N Silachev, E Yu Plotnikov.
      The levels of inflammatory markers increased in both mouse blood plasma and affected brain area 24 days after traumatic brain injury, which was accompanied by impairment of spatial working memory. Methylene blue administered during the first 3 days after injury reduced the levels of some inflammation markers and increased the expression of genes involved in the regulation of mitochondrial biogenesis and mitophagy, i.e. genes responsible for mitochondrial quality control. Additionally, methylene blue partially mitigated the cognitive deficits induced by the injury, suggesting it as a promising compound for maintaining brain function after traumas.
    Keywords:  inflammation; methylene blue; mitochondria; traumatic brain injury
    DOI:  https://doi.org/10.1007/s10517-025-06458-z
  34. Int Urol Nephrol. 2025 Sep 01.
    Mitophagy in kidney transplantation ischemia-reperfusion injury.
    Xingxia Wang, Rumeng Li, Bocheng Zhu, Xiaofeng Zhu, Baiyang Lou.
      Renal ischemia-reperfusion injury (IRI) remains a major challenge impacting graft survival following transplantation. During the ischemic phase, mitochondrial dysfunction leads to adenosine triphosphate (ATP) depletion and calcium overload. Upon reperfusion, reactive oxygen species (ROS) are generated, exacerbating mitochondrial damage and triggering inflammatory responses. This process is associated not only with delayed graft function (DGF) but also with allograft dysfunction. Mitochondria, serving as the high-energy-demand hub of the kidney, require precise regulation of their dynamic balance and mitophagy. Mitophagy selectively removes damaged mitochondria to maintain cellular homeostasis. In the context of IRI, mitophagy exhibits a bidirectional regulatory role: moderate activation can improve energy metabolism, whereas excessive or insufficient activation may exacerbate renal injury. To provide new insights for enhancing graft survival rates, this paper examines the molecular mechanisms, therapeutic targets, and dual regulatory roles involved.
    Keywords:  Kidney transplantation; Mitophagy; Renal ischemia–reperfusion; Therapeutic effect
    DOI:  https://doi.org/10.1007/s11255-025-04761-2
  35. Redox Biol. 2025 Aug 26. pii: S2213-2317(25)00358-1. [Epub ahead of print]86 103845
    Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity.
    Wen-Jing Hsu, Ming-Chien Hsu, Cheng-Ying Chu, Yu-Cheng Lee, Ching-Chieh Yang, Zei-Wei Liu, Chi-Ching Lee, Yang-Sen Lin, Cheng-Wei Lin.
      Metastatic tumor cells exhibit distinct metabolic flexibility in overcoming different microenvironmental obstacles and thriving in a secondary organ; thus, metabolic vulnerabilities can potentially be targeted. It was reported that mitochondrial biogenesis and dynamics play crucial roles in disseminated tumor cells satisfying their energy demands and metabolic plasticity. However, the detailed molecular mechanism by which mitochondrial dynamics promotes tumor metastasis is still unclear. Herein, we identified that metastatic breast cancer cells exhibited increased lipid contents in mitochondria and promoted a metabolic shift towards fatty acid oxidation (FAO). The increased FAO was accompanied by promotion of mitochondrial fission. Mechanistically, we found that upregulation of DEAD-box polypeptide 3, X-linked (DDX3) promoted mitochondrial fission and facilitated FAO. Suppression of DDX3 diminished FAO and elicited mitochondrial oxidative stress in metastatic tumor cells. Moreover, DDX3 mediated dynamin-related protein 1 (DRP1) phosphorylation at S616 through collaborating with cyclin-dependent kinase 1 (CDK1). Inhibition of the DDX3-DRP1-CDK1 axis reduced cancer stemness properties and tumor metastasis. Our findings indicate that DDX3 modulates mitochondrial plasticity to drive metabolic adaptation in breast tumor metastasis. DDX3 provides a potential diagnostic biomarker and therapeutic vulnerability through which cancer metabolism can be targeted.
    Keywords:  DDX3; DRP1; FAO; Mitochondrial fission; Tumor metastasis
    DOI:  https://doi.org/10.1016/j.redox.2025.103845
  36. Cancer Chemother Pharmacol. 2025 Aug 29. 95(1): 84
    A novel cardioprotective mechanism of rosuvastatin: restoring PINK1/parkin-mediated mitophagy via SIRT1/FOXO1 activation in doxorubicin-induced cardiotoxicity.
    Yomna S Momen, Mohamed A Kandeil, Mohamed O Mahmoud.
       BACKGROUND: Chemotherapy remains a key cancer treatment despite advancements in cancer therapy, with doxorubicin (DOX) widely used for solid and hematological tumors. However, its clinical use is limited by severe acute and chronic cardiotoxicity, primarily driven by oxidative stress and mitophagic dysregulation. Rosuvastatin (RSV), a lipid-lowering drug, has shown cardioprotective effects. This study aimed to investigate the molecular mechanism underlying RSV's protection against DOX-induced cardiotoxicity.
    METHODS: Adult male Wistar rats were assigned to eight groups: control, RSV-only (20 mg/kg, orally, for 3 weeks), DOX-only (18 mg/kg, intraperitoneally, over 2 weeks), RSV + DOX, CQ + RSV + DOX (chloroquine 25 mg/kg, intraperitoneally, for 2 weeks), CQ-only, RSV + CQ, and CQ + DOX. 48 h after the last DOX injection, serum myocardial injury markers, oxidative stress markers, and autophagic flux biomarkers (LC3II & P62) were assessed. RT-PCR evaluated lncRNA APF gene expression, while western blotting quantified p-SIRT1, FOXO1, p-PINK1, and p-Parkin protein levels.
    RESULTS: RSV mitigated DOX-induced myocardial injury and oxidative stress while restoring autophagic flux, as evidenced by P62 and LC3II reversal. RSV enhanced lncRNA APF gene expression, p-SIRT1, p-PINK1, and p-Parkin levels while downregulating FOXO1. The autophagy inhibitor CQ blunted RSV's cardioprotective effects.
    CONCLUSION: RSV protects against DOX-induced cardiotoxicity, at least in part, by restoring autophagic flux and rescuing PINK1/Parkin-mediated mitophagy via upregulation of the SIRT1/FOXO1 pathway. Thus, combining RSV with DOX may enable patients to complete chemotherapy with a reduced risk of cardiotoxicity. However, further studies are warranted to confirm its translational potential.
    Keywords:  Cardiotoxicity; Doxorubicin; Mitophagy; PINK1/Parkin; Rosuvastatin; SIRT1/FOXO1
    DOI:  https://doi.org/10.1007/s00280-025-04805-5
  37. Exp Cell Res. 2025 Sep 03. pii: S0014-4827(25)00331-3. [Epub ahead of print] 114731
    PRDX3 promotes nasopharyngeal carcinoma tumor growth by regulating PINK1/Parkin pathway-dependent lipid peroxidation and mitochondrial dysfunction.
    Hualong Qiang, Wei Wang, Xiaodong Zhan, Shiyin Ma.
       BACKGROUND: Nasopharyngeal carcinoma (NPC) is a challenging malignancy characterized by aggressive progression and limited therapeutic efficacy. Emerging evidence implicates peroxiredoxin 3 (PRDX3), a mitochondrial peroxidase, as a critical regulator of redox homeostasis and mitochondrial integrity. Given its role in modulating cell death through mitochondrial quality control, we investigated the therapeutic potential of targeting PRDX3 in NPC.
    METHODS: PRDX3 expression patterns were assessed in clinical NPC specimens using immunohistochemical and immunoblotting. Functional studies employed siRNA-mediated PRDX3 knockdown followed by cellular assays: CCK-8 proliferation, clonogenic survival, and mitochondrial parameter quantification (reactive oxygen species flux using DCFH-DA/C11-BODIPY, ATP biosynthesis, membrane polarization, and mtDNA integrity). Molecular interplay between PRDX3 and PTEN-induced kinase 1 (PINK1) was elucidated through co-immunoprecipitation and immunofluorescence analysis. In vivo therapeutic efficacy was validated using a xenograft model to evaluate tumor growth modulation.
    RESULTS: Clinical specimens revealed significant PRDX3 overexpression in NPC compared to non-malignant controls. PRDX3 knockdown substantially attenuated malignant behavior and induced mitochondrial dysfunction in NPC cells. Mechanistically, PRDX3 interacted with PINK1 to stabilize Parkin-mediated mitophagic flux. PRDX3 safeguarded against apoptosis by sustaining PINK1/Parkin-dependent mitophagy clearance of damaged mitochondria. In vivo validation confirmed that PRDX3 knockdown suppressed tumor growth.
    CONCLUSION: PRDX3 acts as an upstream activator of the PINK1/Parkin signaling cascade, regulating lipid peroxidation-mediated mitochondrial dysfunction, mitophagy, survival and apoptosis of NPC cell.
    Keywords:  PRDX3; mitochondrial dysfunction; mitophagy; nasopharyngeal carcinoma
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114731
  38. Mol Med Rep. 2025 Nov;pii: 299. [Epub ahead of print]32(5):
    Mitophagy as a pivotal axis in non‑alcoholic fatty liver disease: From pathogenic mechanisms to therapeutic strategies (Review).
    Yushu Huang, Xueqing Xia, Jingyang Xu, Zihan Wang, Yanting You, Qingfeng Du.
      Non‑alcoholic fatty liver disease (NAFLD), characterized by excessive lipid accumulation in hepatocytes, has emerged as the leading cause of chronic liver disorders globally. As the central metabolic organ, the liver critically depends on mitochondrial integrity. Mitophagy, a selective form of autophagy, plays a pivotal role in sustaining mitochondrial homeostasis by eliminating dysfunctional mitochondria. Dysregulated mitophagy contributes to the progression of NAFLD, while its restoration mitigates disease severity. The present review outlines the tripartite axis of mitophagy, namely, the PTEN‑induced putative kinase 1/Parkin, PI3K/AKT/mTOR and AMP‑activated protein kinase pathways, in NAFLD pathogenesis across the various stages of disease development, including steatosis, nonalcoholic steatohepatitis and fibrosis, and explores their therapeutic potential. Additionally, emerging regulators, including FUN14 domain‑containing protein 1, prohibitin 2, ceramide signaling and non‑coding RNAs, which fine‑tune mitophagy in NAFLD are highlighted. By integrating evidence from pharmacological and natural agents, including traditional Chinese medicines, mitophagy‑centric strategies to promote hepatic lipid metabolism, mitigate disease progression and inform novel NAFLD therapeutics are discussed. This exploration of the mechanisms that govern mitochondrial‑autophagic crosstalk not only advances mechanistic insights but also opens new avenues for precision medicine in the treatment of metabolic liver diseases.
    Keywords:  mechanisms; mitophagy; non‑alcoholic fatty liver disease; therapies
    DOI:  https://doi.org/10.3892/mmr.2025.13664
  39. Bioessays. 2025 Sep 01. e70062
    Conformational Rearrangement of Fission DSPs.
    Anelise N Hutson, Kristy Rochon, Jason A Mears.
      Dynamin superfamily proteins (DSPs) are large GTPases that play crucial roles in membrane remodeling processes, including vesicle uptake, mitochondrial fission, and opposing fusion events. Among them, dynamin and dynamin-related protein 1 (Drp1) share a conserved domain architecture, yet exhibit unique structural and regulatory features that tailor their functions. This review explores the conformational rearrangements of the mammalian fission DSPs, dynamin and Drp1, focusing on their dimeric and tetrameric structures, lipid-bound assemblies, and key regulatory elements that drive membrane constriction. Structural biology methods, including x-ray crystallography and cryo-electron microscopy, have provided insight into the mechanism of activation and constriction of these DSPs, revealing how domain interactions and intrinsically disordered regions regulate self-assembly and enzymatic activity. We briefly examine the role of sequence modifications and partner proteins in modulating DSP function, highlighting the impact of regulatory factors on their respective cellular functions. An ongoing goal is to better understand the molecular mechanisms governing the transitions from a pre-assembled cytosolic state to a self-assembled state for dynamin and Drp1 on membranes, which provides a foundation for studying subsequent helical constriction. This insight will enhance our knowledge of organelle dynamics and provide new avenues for therapeutic interventions targeting DSP-related pathologies.
    DOI:  https://doi.org/10.1002/bies.70062
  40. Hypertens Res. 2025 Sep 03.
    Prognostic impact of excessive mitochondrial fission in patients with heart failure and evaluation of mitochondrial dynamics-related miRNAs in heart failure.
    Akihiro Shirakabe, Yoshiyuki Ikeda, Yoshihiro Uchikado, Masato Matsushita, Tomofumi Sawatani, Shota Shigihara, Kenichi Tani, Masaki Morooka, Masahito Takahashi, Nobuaki Kobayashi, Mitsuru Ohishi, Junichi Sadoshima, Kuniya Asai.
      Mitochondria are dynamic organelles that can change their morphology. The role of these mitochondrial dynamics in cardiomyocytes remains obscure in patients with heart failure (HF). Endomyocardial biopsies were performed consecutively in 127 HF patients, and mitochondrial morphology data were obtained from 111 patients by electron microscopy. The patients were divided into three groups according to mitochondrial area quartiles (fission [Q1, area ≤ 0.119 μm2, n = 27], normal [Q2/Q3, 0.120 μm2 ≤ area ≤ 0.178 μm2, n = 55], and fusion [Q4, area ≥ 0.179 μm2, n = 28]). In the fission group, the serum N-terminal pro-brain natriuretic peptide and B-type natriuretic peptide (BNP) levels were significantly higher, and patients with HF and a reduced left ventricular ejection fraction were more common, than in the other groups. A multivariate logistic regression model showed that diabetes mellitus was independently associated with placement in the fission group (odds ratio: 2.835, 95%confidence interval [CI]: 1.037-7.752). A Kaplan-Meier curve analysis showed that the prognosis was significantly poorer in the fission group than in the other groups, and a multivariate Cox regression model revealed fission to be an independent predictor of 1500-day mortality (hazard ratio: 4.365, 95%CI: 1.198-15.909). The circulating levels of miR-140-5p (≥2500) were independently associated with the presence of mitochondrial fission (OR: 3.622, 95%CI: 1.260-10.413). Excessive mitochondrial fission was observed in patients with severe HF status, and was independently associated with adverse outcomes in HF patients. Circulating mitochondrial dynamics-related miRNA levels might be of use in detecting mitochondrial fission in the cardiomyocytes of HF patients.
    Keywords:  heart failure; implemental hypertension; miRNA; mitochondrial dynamics; mortality
    DOI:  https://doi.org/10.1038/s41440-025-02338-1
  41. FEBS Lett. 2025 Jul 22.
    Detyrosinated α-tubulin mediates mitochondrial dysfunction and diastolic impairment in heart failure with preserved ejection fraction.
    Shunsuke Miura, Tomofumi Misaka, Toranosuke Sekine, Ryo Ogawara, Shohei Ichimura, Yusuke Tomita, Tetsuro Yokokawa, Masayoshi Oikawa, Takafumi Ishida, Yasuchika Takeishi.
      Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, yet its molecular basis remains unclear. Here, we identified detyrosinated α-tubulin as a key cause of mitochondrial dysfunction and impaired mitophagy in HFpEF. In a SAUNA-induced HFpEF mouse model, elevated vasohibin-1 (VASH1) expression was associated with increased detyrosinated α-tubulin. In H9c2 cardiomyocytes, VASH1 overexpression or tubulin tyrosine ligase knockout raised detyrosinated α-tubulin levels, leading to reduced mitochondrial respiration. Detyrosinated α-tubulin on mitochondria impaired Parkin recruitment and polyubiquitination of voltage-dependent anion channel 1, suppressing mitophagy. Cardiac-specific VASH1 expression recapitulated HFpEF-like phenotypes, including diastolic dysfunction, reduced exercise capacity, and decreased mitochondrial complex activity. These findings suggest that α-tubulin detyrosination contributes to HFpEF pathogenesis and may serve as a therapeutic target. Impact statement This study reveals a novel cytoskeletal mechanism linking α-tubulin detyrosination to mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF). Our findings may advance understanding of the pathogenesis of HFpEF and provide new molecular targets for therapeutic strategies aimed at preserving mitochondrial quality control in heart failure.
    Keywords:  heart failure with preserved ejection fraction; mitochondria; mitophagy; vasohibin 1; α‐tubulin detyrosination
    DOI:  https://doi.org/10.1002/1873-3468.70119
  42. Chin Med J (Engl). 2025 Sep 01.
    CircRERE promotes myocardial ischemia/reperfusion injury by increasing UHRF1 mRNA decay through targeting PUM2 to reduce Drp1 promoter methylation.
    Shihui Fu, Yan Nie, Ping Ping, Zhitao Gao, Yali Zhao, Wang Wang, Zhirui Li, Qiong Liu.
       BACKGROUND: Myocardial ischemia/reperfusion (I/R) injury contributes significantly to cardiac dysfunction following myocardial infarction, mainly due to excessive oxidative stress and mitochondrial injury. Despite advances in reperfusion therapies, secondary injuries remain a challenge, necessitating deeper insight into the molecular mechanisms underlying I/R injury. In the present study, we aim to investigate the roles of circular ribonucleic acid (circRNA) RERE (circRERE) in myocardial I/R injury.
    METHODS: Hypoxia/reperfusion (H/R) cells and an I/R mouse model were used. Cell apoptosis was assessed using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. The cell reactive oxygen species (ROS) and secreted lactate dehydrogenase (LDH) levels were measured. Quantitative reverse transcription polymerase chain reaction, western blot, immunofluorescence staining, and immunohistochemistry were used to assess mRNA and protein expression. MitoTracker and electron microscopy were used to examine mitochondrial morphology. The interactions between circRERE, Pumilio 2 (PUM2), ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), and dynamin-related protein 1 (Drp1) were validated by RNA immunoprecipitation, RNA pull-down, and/or chromatin immunoprecipitation assays. I/R-induced pathological changes in cardiac tissues were evaluated by Hematoxylin and Eosin (H&E) and 2,3,5-triphenyltetrazolium chloride (TTC) staining. Statistical analyses were performed using one-way analysis of variance and Student's t-test, with P <0.05 considered statistically significant difference.
    RESULTS: CircRERE expression was significantly elevated during I/R injury (about a 3.1-fold increase, P <0.001). CircRERE knockdown reduced ROS levels by 39.5% (P <0.01), improved mitochondrial membrane potential (P <0.01), and decreased apoptotic rates (P <0.001). Mechanistically, circRERE promoted UHRF1 mRNA decay by interacting with PUM2, leading to reduced Drp1 promoter methylation, increased Drp1 expression, and subsequent mitochondrial fission and dysfunction. In vivo, circRERE knockdown significantly reduced infarct size by 24.27% (P <0.001), improved cardiac tissue morphology, and restored mitochondrial homeostasis.
    CONCLUSIONS: CircRERE exacerbated myocardial I/R injury by promoting UHRF1 mRNA degradation and mitochondrial dysfunction. Targeting the circRERE/UHRF1/Drp1 axis may represent a novel therapeutic strategy against myocardial I/R injury.
    Keywords:  Dynamin-related protein 1; Mitochondrial injury; Myocardial ischemia/reperfusion; Pumilio 2; Ubiquitin-like with plant homeodomain and ring finger domain 1; circRERE
    DOI:  https://doi.org/10.1097/CM9.0000000000003757
  43. Phytomedicine. 2025 Aug 22. pii: S0944-7113(25)00802-5. [Epub ahead of print]147 157163
    Traditional wisdom meets modern science: The protective role of sanhuang shu'ai decoction in ulcerative colitis models.
    Nianchao Zhang, Amei Liu, Mingyue Cao, Zhenglan Han, Dongmei Guo, Shumin Zhang, Jingping Zhang.
       OBJECTIVE: Despite extensive research on ulcerative colitis (UC), the mechanisms behind its pathogenesis remain incompletely elucidated. Sanhuang Shu'ai decoction (SSD) has granted attention for its potential therapeutic influences in inflammatory conditions, yet the protective mechanisms of SSD in UC models are lacking.
    METHODS: We investigated the protective effects of SSD extract utilizing two experimental models: lipopolysaccharide (LPS)-induced human colonic organoids and dextran sulfate sodium (DSS)-provoked murine models. In vitro and in vivo validations were conducted to ascertain the protective effects, epithelial barrier (EB) integrity, histological morphology, and inflammatory response following treatment with SSD. Moreover, mechanistic studies were applied to investigate the implication of autophagy modulation and mitophagy activation in the observed protective effects.
    RESULTS: Treatment with SSD significantly increased cell viability and EB integrity maintenance in organoids. In DSS-induced UC models, SSD treatment led to considerable improvements in tissue morphology, reduced inflammation, and restored the structural integrity of intestinal epithelial cells, thereby affirming its protective role against UC. Mechanistically, SSD was found to modulate autophagy via PIP4K2C and promote mitophagy through the wogonin-PIP4K2C-PINK1 signaling pathway.
    CONCLUSION: SSD effectively alleviates the symptoms of UC by promoting intestinal barrier functionality and decreasing inflammatory responses. The mechanism involves wogonin promoting the interaction between PIP4K2C and PINK1 to form a Wogonin-PIP4K2C-PINK1 trimer complex, start the PINK1/Parkin signaling axis, and then promote mitochondrial autophagy and repair the intestinal EB, thus exerting the effect of treating UC. It provides a new target for UC treatment and promotes the research of Chinese medicine compounds from empirical description to precise regulation.
    Keywords:  Mitophagy; PIP4K2C; Sanhuang Shu'ai decoction; Ulcerative colitis; autophagy; human colonic organoids
    DOI:  https://doi.org/10.1016/j.phymed.2025.157163
  44. Front Immunol. 2025 ;16 1580597
    Identification of the prognostic effect of mitophagy-related genes in acute myeloid leukemia.
    Fan Xuan, Wenyuan Zhu, Baoxi Zhang, Hui Zhao, Chaonan Li, Xiaoli Wu.
       Background: Mitophagy has been implicated in the pathogenesis of acute myeloid leukemia (AML), yet its precise molecular mechanisms remain poorly understood. Understanding the roles of mitophagy-related genes (MRGs) may provide new insights into AML classification, prognosis, and therapeutic response.
    Methods: We analyzed 72 MRGs using three independent AML datasets (TCGA-LAML, GSE24395, and GSE146173). Consensus clustering based on MRG expression was used to identify AML molecular subtypes. Differentially expressed genes (DEGs) common to AML subtypes and GSE24395 were identified. Prognostic genes were screened using univariate Cox regression and least absolute shrinkage and selection operator (Lasso) regression analyses. A prognostic risk model was constructed and validated. Functional enrichment, immune infiltration, and drug sensitivity analyses were conducted to explore the biological relevance of the model. In addition, regulatory elements including microRNAs, lncRNAs, and transcription factors targeting model genes were predicted.
    Results: Twenty-six overlapping DEGs were identified between AML subtypes and GSE24395. Five MRG-associated genes (ITGB2, VIP, PTK2, FHL2, BAG3) were selected to construct a prognostic model that stratified patients into high- and low-risk groups with significantly different overall survival. Multivariate Cox analysis confirmed that risk score, age, and treatment status were independent prognostic indicators. Gene set enrichment analysis (GSEA) revealed 731 significantly enriched pathways, including mononuclear cell migration. Immune cell infiltration analysis showed a positive correlation between risk score and monocytes, and negative correlations with plasma B cells and activated mast cells. Drug sensitivity prediction identified 84 compounds with differential responses between risk groups. Regulatory network prediction highlighted hsa-miR-135b-5p, FTX, and SOX11 as potential upstream regulators of the prognostic genes.
    Conclusion: This study identified five mitophagy-related genes as prognostic biomarkers in AML and developed a robust risk model that correlates with survival outcome, immune infiltration, and drug sensitivity. These findings offer new insights into mitophagy-related mechanisms in AML and may guide personalized therapeutic strategies.
    Keywords:  acute myeloid leukemia; biomarkers; immune infiltration; mitophagy-related genes; prognostic effect
    DOI:  https://doi.org/10.3389/fimmu.2025.1580597
  45. J Ethnopharmacol. 2025 Sep 02. pii: S0378-8741(25)01217-6. [Epub ahead of print] 120525
    Dingxin Recipe III Ameliorates Endothelial Cell Senescence in Atherosclerosis by Activating the FOXO3a/Pink1/Parkin Axis.
    Xiaoyu Liu, Yao Jin, Zhaoyong Li, Huashan Zhao, Xinghong Zhou, Yanxin Zhu, Yuyan Gu, Lifang Zhang, Yaxin Zhang, Peikun He, Saibo Cheng, Yuling Xu, Yuhua Jia.
       ETHNOPHARMACOLOGICAL RELEVANCE: Dingxin Recipe III (DXRIII) is a traditional Chinese medicinal formulation that has been employed in clinics for over two decades. It is utilized in the treatment of cardiovascular diseases associated with atherosclerosis (AS) through mechanisms purported to involve the clearing of heat and detoxification, as well as the promotion of blood circulation and the removal of blood stasis. Despite its widespread application and reported therapeutic benefits, its exact mechanisms remain incompletely elucidated.
    AIM OF THIS STUDY: This study aimed to confirm the anti-AS efficacy of DXRIII and elucidate its underlying mechanism, specifically focusing on the amelioration of endothelial senescence.
    METHODS: The mechanisms underlying the anti-AS effects of DXRIII were elucidated through network pharmacology analysis. In vivo and in vitro models were established using high-fat diet (HFD) induced ApoE-/- mice and H2O2-induced human umbilical vein endothelial cells (HUVECs), respectively. The histopathologic changes of aortic tissues, inflammatory response, oxidative stress, mitochondrial damage, mitophagy, senescence, and FOXO3a/PINK1/Parkin signaling pathway were evaluated through histological staining, transmission electron microscopy, fluorescent probe staining, RT-qPCR, and Western blot. The constituents of DXRIII were identified via liquid chromatography-mass spectrometry, and the binding affinity and stability of its active compounds with target proteins were investigated using molecular docking and cellular thermal shift assay. Foxo3a was silenced in vitro by lentiviral transfection to determine its involvement in DXRIII-induced mitophagy.
    RESULTS: DXRIII effectively ameliorated plaque pathology in AS mice and attenuated endothelial cell senescence. Meanwhile, DXRIII suppressed pro-inflammatory factors and adhesion molecules, mitigated oxidative stress and mitochondrial damage, while activating Pink1/Parkin-mediated mitophagy and upregulating FOXO3a expression. Notably, both mitophagy inhibition Mdivi-1 and silencing of FOXO3a in vitro blocked DXRIII's anti-senescence effects. Furthermore, the active ingredients of DXRIII, including berberine, kaempferol, quercetin and luteolin, showed strong binding affinity with FOXO3a and enhanced its protein stability.
    CONCLUSION: Our findings for the first time demonstrated that DXRIII effectively alleviates endothelial senescence and HFD-induced AS, possibly by activating FOXO3a and subsequently enhancing PINK1/Parkin-mediated mitophagy.
    Keywords:  Atherosclerosis; Dingxin Recipe Ⅲ; FOXO3a; Mitophagy; Senescence
    DOI:  https://doi.org/10.1016/j.jep.2025.120525
  46. Anal Chem. 2025 Sep 05.
    Super-Resolution Imaging Captures Mitophagy Dynamics: Tricolor Fluorescence Labels Mitochondria, Autophagosomes, and Lysosomes.
    Weikang Peng, Mei Li, Wenwen Li, Yuanjuan Wang, Cheng Tian, Zhilong Zhao, Min Gao, Lei Yang.
      Mitophagy is a vital lysosome-dependent process in which damaged mitochondria exhibiting elevated H2O2 production are selectively engulfed by autophagosomes and delivered to lysosomes for degradation, thereby maintaining intracellular homeostasis. Consequently, monitoring mitophagy holds significant potential for disease diagnosis and therapeutic development. In this study, H2O2-activated lysosome-targeted fluorescent probe, PLM, was developed for the super-resolution imaging of the mitophagic process. The initiation of mitophagy induces the significant production of autophagosomes. Red-stained mitochondria are engulfed by blue-stained autophagosomes and subsequently fuse with lysosomes, leading to an increase in the H2O2 concentration within the lysosomes. This activates the green fluorescence signal of PLM. The entire mitophagic process can be visualized and monitored by observing changes in the fluorescence intensity of the autophagosomes and lysosomes as well as the overlap of fluorescence signals. Super-resolution imaging enables the triple-signal nanoscale visualization of the dynamic processes in three organelles. This probe was successfully applied to monitor rapamycin- and starvation-induced mitophagy and was further utilized to assess the role of mitophagy inhibition in enhancing antitumor activity.
    DOI:  https://doi.org/10.1021/acs.analchem.5c03247
  47. Inflammopharmacology. 2025 Sep 01.
    Therapeutic potential of alpha-lipoic acid on mitochondrial dynamics, oxidative/nitrosative stress, and histopathological changes in rat ulcerative colitis model.
    İrem Taner, Nur Banu Bal, Saadet Özen Akarca Dizakar, Veysel Bay, Mürşide Ayşe Demirel.
      Ulcerative colitis is a chronic inflammatory disease affecting the gastrointestinal tract. In addition to treatments aimed at healing inflammation and tissue damage, addressing redox imbalance and mitochondrial dysfunction is crucial. The aim of the present study is to investigate the effects of Alpha-Lipoic Acid (ALA), either alone or in combination with mesalamine, on oxidative/nitrosative stress, mitochondrial dynamics, and histopathological changes in a rat model of ulcerative colitis. Rats were divided into Control (C), Ulcerative Colitis (UC), Mesalamine (M), ALA, and Mesalamine + Alpha-lipoic acid (M + ALA) groups. Colitis was induced by intrarectal administration of 4% acetic acid. The disease activity index was the highest in the UC group and the lowest in the M + ALA group among the treatment groups. Macroscopic scores in the UC, M, and ALA groups were significantly higher compared to the C group. The oxidative stress index was the highest in the UC group, with significantly elevated levels compared to the C, ALA, and M + ALA groups. The nitrotyrosine level was also highest in the UC group and significantly elevated compared to the C, M, ALA, and M + ALA groups. Dynamin-related protein 1, Mitofusin-2, and PTEN-induced putative kinase 1 proteins showed significant increases in the UC group compared to the C group. In contrast, these protein levels were significantly reduced in the M + ALA group compared to the UC group. Histopathological scoring in the UC group increased, and ALA administration significantly ameliorated these parameters. Our results indicate that ALA has beneficial effects on increased oxidative stress, impaired mitochondrial dynamics, and altered histopathological scores in the rat colitis model.
    Keywords:  Alpha lipoic acid; Mitochondrial dynamics; Oxidative/nitrosative stress; Rat; Ulcerative colitis
    DOI:  https://doi.org/10.1007/s10787-025-01918-4
  48. Mol Cell Biochem. 2025 Aug 30.
    Mitochondrial dysfunction in hepatocellular carcinoma: from metabolism to targeted therapies.
    Faezeh Sharafi, Elham Rismani, Mohamad Rhmanian, Arezoo Khosravi, Ali Zarrabi, Massoud Vosough.
      Globally, liver cancer is reported to be the third leading cause of cancer-related mortality. The most common type of these cancers is hepatocellular carcinoma (HCC). Current preventive strategies, including lifestyle modifications, antiviral therapies, and surveillance, are limited in their effectiveness. Mitochondria play critical roles in regulating cellular metabolism, oxidative stress, and apoptosis. Mitochondrial dysfunction can accelerate HCC progression, particularly in patients with liver diseases such as metabolic-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this review, we discuss the mechanisms of mitochondrial dysfunction in HCC from a molecular point of view, including oxidative stress, mitophagy dysregulation, mitochondrial dynamics dysregulation, and mitochondrial DNA (mtDNA)-mediated dysregulation of innate immune responses. Additionally, we explore molecular-targeted therapies aimed at restoring mitochondrial function. Critical approaches include targeting reactive oxygen species pathways through agents such as iridium (III) complexes and Mito Rh S, which induce cancer cell death through apoptosis and ferroptosis. Other compounds, including dehydrocrenatidine, enhance oxidative phosphorylation and promote apoptosis. Inhibitors of dynamin-related protein 1 (Drp1) target mitochondrial fission to reduce tumor growth. Furthermore, mitophagy modulators, such as SIRT1 activators, improve mitochondrial quality control, minimize the negative effects of oxidative stress, and reduce cancer development. Clinical trials are ongoing for the mitochondrial enzyme-targeting agents CPI-613 and Gamitrinib, a heat shock protein-targeting agent, which have hence shown great promise for these therapies. With further investigation, mitochondrial-targeted interventions could be promising for preventing or reducing HCC incidence and recurrence, increasing long-term survival, and improving the quality of life of patients with advanced-stage disease.
    Keywords:  Hepatocellular carcinoma; Mitochondrial dysfunction; Molecular targeted therapy; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s11010-025-05377-x
  49. Toxicon. 2025 Aug 27. pii: S0041-0101(25)00330-7. [Epub ahead of print]266 108555
    Melittin-induced modulation of mitochondrial physiology: Beyond the antitumoral actions.
    Marcos Roberto de Oliveira.
      Melittin (MEL), a cationic amphipathic peptide derived from bee venom, exhibits dual roles in mitochondrial physiology, with both cytoprotective and cytotoxic outcomes. This review synthesizes current findings on MEL-induced modulation of mitochondrial pathways in normal and cancer cells. Beyond its well-documented roles in apoptosis regulation, MEL influences mitochondrial function by altering membrane potential, regulating respiratory chain activity, and impacting ATP production. These effects are context-dependent and vary across normal and tumor cell models. MEL can attenuate mitochondrial dysfunction by preserving mitochondrial membrane integrity and reducing reactive oxygen species, while in cancer cells, it often promotes mitochondrial depolarization, cytochrome c release, and caspase activation, culminating in intrinsic apoptotic signaling. Importantly, MEL modulates the expression of key proteins such as BAX, BCL-2, and APAF-1, and interacts with signaling cascades including PI3K/Akt, NF-κB, MAPKs, and Nrf2/HO-1. Recent studies have demonstrated that MEL also regulates mitochondrial quality control mechanisms, including the stimulation of mitophagy through PINK1/Parkin and AMPK-related pathways. Moreover, MEL interacts directly with mitochondrial membranes and affects enzymes critical for energy metabolism, such as F1-ATPase, contributing to altered bioenergetic output. These actions suggest that MEL's mitochondrial effects extend beyond cell death regulation, encompassing broader control over metabolic activity, oxidative stress, and organelle maintenance. Future investigations should integrate redox biology, bioenergetics, and mitochondrial signaling to optimize MEL's therapeutic applications. Altogether, MEL represents a unique modulator of mitochondrial health, whose dual actions necessitate rigorous contextual evaluation for clinical translation.
    Keywords:  Anti-apoptosis; Antioxidant; Melittin; Mitochondria; Mitophagy; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.toxicon.2025.108555
  50. Neurosci Bull. 2025 Aug 30.
    Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
    Yilin Sun, Chunying Liu, Yakun Liang, An Lv, Wang Nie, Shuyue Bao, Xiaoyi Li, Jing Zhou, Weimin Tong, Yong Tao, Xueling Wang, Tingting Dong.
      Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.
    Keywords:  Antioxidant; Auditory neuropathy; Mic60; Mitochondria; Mitophagy; N-acetylcysteine
    DOI:  https://doi.org/10.1007/s12264-025-01485-2
  51. J Physiol Investig. 2025 Sep 04.
    Niujiaodihuang Detoxify Decoction Inhibits D-GalN/LPS-induced Hepatocyte Ferroptosis by Maintaining Mitochondrial Homeostasis Via OMA1-OPA1 Pathway.
    Yanping Lu, Henghui Sun, Qinyan Zhu, Sichen Liu, Junjie Chai, Zichen Ouyang, Lu Wang, Qianqian Liu, Hongxuan Chen, Huiji Chen, Hualong Liu, Shu Li, Jingbao Hu.
       ABSTRACT: Niujiaodihuang Detoxify Decoction (NDD) has been shown to attenuate liver injury during acute liver failure by inhibiting ferroptosis, whereas the specific mechanism regulating ferroptosis remains to be elucidated. The LO2 liver cell injury model was induced with a combination of D-Galactosamine hydrochloride (D-GaIN) and lipopolysaccharide (LPS), followed by treatment with NDD-medicated serum. Hepatocyte injury, ferroptosis, and mitochondrial function homeostasis were assessed by measuring cell viability, inflammatory factors levels, lipid peroxidation, oxidative stress, expression of ferroptosis-related proteins, mitochondrial membrane potential, and expression of mitochondrial injury-related proteins. Ferroptosis inhibitors were used to determine the relationship between ferroptosis and D-GaIN/LPS-induced hepatocellular injury. Ferroptosis inducers and SiRNA-OPA1 were utilized to validate the mechanism of action of NDD. D-GalN/LPS treatment reduced cell viability, increased the release of inflammatory cytokines, and induced ferroptosis. The use of ferroptosis inhibitors attenuated D-GaIN/LPS-induced hepatocyte injury. 10% NDD-medicated serum effectively restored hepatocyte viability and reduced inflammatory cytokine levels. Furthermore, NDD decreased lipid peroxidation and oxidative stress levels in LO2 cells, restored mitochondrial membrane potential, upregulated the expression of SLC7A11, SLC3A2, GPX4, MFN1, MFN2, and L-OPA1, and downregulated the protein expression of ACSL4, DRP1, and OMA1. Ferroptosis inducers weakened the protective effect of NDD on LO2 cells, and interfering with OPA1 inhibited the regulation of mitochondrial function and ferroptosis in LO2 cells by NDD. NDD inhibits ferroptosis in LO2 cells by maintaining mitochondrial functional homeostasis through OMA1-OPA1 pathway, thereby attenuating D-GaIN/LPS-induced LO2 cell injury.
    Keywords:  Acute liver failure; Niujiaodihuang detoxify decoction; OMA1–OPA1 pathway; ferroptosis; mitochondria
    DOI:  https://doi.org/10.4103/ejpi.EJPI-D-24-00104
  52. Autophagy. 2025 Sep 03. 1-20
    Reconstitution of autophagic-like membrane tethering reveals that Atg11 can bind and cluster vesicles on cargo mimetics.
    Devika Andhare, Sarah Katzenell, Sarah I Najera, Sylvie C Mauras, Katherine M Bauer, Michael J Ragusa.
      Macroautophagy (hereafter, autophagy) is essential for the degradation of mitochondria from yeast to humans. Mitochondrial autophagy in yeast is initiated when the selective autophagy scaffolding protein Atg11 is recruited to mitochondria through its interaction with the selective autophagy receptor Atg32. This also results in the recruitment of small 30-nm vesicles that fuse to generate the initial phagophore membrane. We demonstrate that Atg11 can bind to autophagic-like membranes in vitro in a curvature-dependent manner in part via a predicted amphipathic helix. Deletion of the amphipathic helix from Atg11 results in a delay in the formation of mitophagy initiation sites in yeast. Furthermore, using a novel biochemical approach, we demonstrate that the interaction between Atg11 and Atg32 results in the tethering of autophagic-like vesicles in clusters to giant unilamellar vesicles containing a lipid composition designed to mimic the outer mitochondrial membrane. We also demonstrate that the N-terminal region of Atg11 is an important mediator of vesicle tethering to cargo mimetics and that clustering of autophagic-like vesicles requires the C-terminal region of Atg11. Taken together, our results reveal that Atg11 clusters into high-order oligomers, can tether autophagic-like membranes and due to its ability to oligomerize can cluster vesicles on the surface of cargo mimetics. This work provides new insight into the mechanisms of protein and membrane clustering by Atg11. Given the increasing importance of protein oligomerization and clustering in autophagy, these results have important implications in the initiation of mitochondrial autophagy.Abbreviations Atg11: autophagy related 11; Atg11-Cterm: C-terminal region of Atg11; Atg11-Nterm: N-terminal region of Atg11; Atg32: autophagy related 32; COV: coefficient of variance; DOPC: 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOPS: 1,2-dioleoyl-sn-glycero-3-phospho-L-serine; FRAP: fluorescence recovery after photobleaching; GLT: GUV and liposome tethering; GUV: giant unilamellar vesicle; MKO: multiple knockout; OMM: outer mitochondrial membrane; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; RhPE: rhodamine phosphatidylethanolamine; SAR: selective autophagy receptor; SEC: size-exclusion chromatography; SLB: supported lipid bilayers; SMrT: supported membrane templates; YPL: yeast polar lipids.
    Keywords:  Biochemistry; membrane tethering; mitophagy; reconstitution; selective autophagy; yeast
    DOI:  https://doi.org/10.1080/15548627.2025.2551678
  53. J Ethnopharmacol. 2025 Aug 27. pii: S0378-8741(25)01162-6. [Epub ahead of print]354 120470
    Maidong Dishao Decoction can inhibit the activation of the cGAS-STING signaling pathway of Sjögren's syndrome by reducing oxidative stress in salivary gland epithelial cells.
    Wen Zhu, Li Chen, Yu Li, Rong Gu, Yue Zhang, Yan Lu, Yue Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Sjögren's syndrome (SS) is an autoimmune disorder primarily characterized by the involvement of exocrine glands. Currently, effective interventions need to be explored to preserve glandular function. Maidong Dishao Decoction (MDDST), which has been widely used in the treatment of Sjögren's syndrome for over 20 years, functions to nourish yin and promote fluid production, as well as to regulate lung qi to distribute body fluids-particularly benefiting patients with yin and fluid deficiency. However, its exact pharmacological mechanism remains unclear.
    AIM OF THE STUDY: This study aimed to investigate the underlying mechanism of MDDST in the treatment of Sjögren's syndrome.
    MATERIALS AND METHODS: First, the UHPLC-QE-MS analysis was used to identify the key components of MDDST drug-containing serum. The study selected female non-obese diabetic (NOD) mice and ICR mice, which were intragastrically administered with varying doses of MDDST or normal saline daily for 8 weeks. The effect of MDDST on NOD mice was assessed by water intake volume, histopathological analysis, and serum level of IgG and SSA. Transcriptome sequencing was performed to investigate the molecular mechanisms and potential targets of MDDST in the SS. The protein expression levels of the relevant pathways were assessed using Western blot, immunohistochemistry, and immunofluorescence techniques. Finally, in vitro experiments were performed to investigate the specific action mechanism of MDDST.
    RESULTS: MDDST treatment for 8 weeks significantly improved the disease state of NOD mice. Transcriptome sequencing results suggested that the oxidative phosphorylation signaling pathway was significantly changed after the intervention of MDDST. Furthermore, MDDST can inhibit excess ROS accumulation and maintain mitochondrial membrane potential in the submandibular gland epithelial cells of NOD mice. Moreover, it can also suppress the key protein expression of the cGAS-STING signaling pathway and mitophagy signaling pathway. However, the autophagy inhibitor 3 MA can partially reverse the therapeutic effect of MDDST in NOD mice. Through in vitro experiments, we further discovered that the application of the 3 MA could reverse the therapeutic effect of MDDST-containing serum, thereby enhancing the activation of ROS and the cGAS-STING signaling pathway in A253 cells. Conversely, the use of NAC to inhibit ROS production not only suppressed the cGAS-STING signaling pathway but also attenuated maladaptive autophagy induced by H2O2, thus mimicking the therapeutic effects of MDDST-containing serum.
    CONCLUSIONS: Maidong Dishao Decoction alleviates the activation of the cGAS-STING signaling pathway and maladaptive mitophagy in Sjögren's syndrome by suppressing ROS production and preserving mitochondrial homeostasis in Salivary gland epithelial cells (SGECs).
    Keywords:  Maidong Dishao Decoction; Oxidative stress; Salivary gland epithelial cell; Sjögren's syndrome; cGAS-STING
    DOI:  https://doi.org/10.1016/j.jep.2025.120470
  54. Cancer Res. 2025 Aug 29.
    Loss of SETD8 Impairs Mitochondrial Homeostasis to Suppress Leukemia Stem Cell Function in t(8;21) Acute Myeloid Leukemia.
    Yongwei Su, Shuyi Li, Lei Wang, Yiran Wang, Shujiao He, Xiaotong Li, Jingqiao Qiao, Jingfeng Zhou, Li Yu.
      Leukemic stem cells (LSCs) contribute to relapse and resistance in patients with t(8;21) acute myeloid leukemia (AML). Chromatin accessibility remodeled by epigenetic alterations represents a defining hallmark of LSCs that endows them with enhanced survival and self-renewal capacities, which may offer potential therapeutic opportunities for intervention. Here, we showed that SETD8, a lysine methyltransferase that monomethylates lysine 20 of histone H4 (H4K20me1), is essential for the maintenance of stemness in t(8;21) AML LSCs. Genetic deletion or pharmacological inhibition of SETD8 impaired the survival and self-renewal of LSCs in retroviral AML1-ETO9a-driven t(8;21) AML mice and primary t(8;21) AML CD34+ cells. Mechanistically, SETD8 promoted the expression of the mitochondrial outer membrane protein RHOT1 by increasing chromatin accessibility at the enhancer region, thereby reprogramming mitochondrial homeostasis. These findings improve our understanding of gene regulation through chromatin accessibility remodeling and establish a link between histone lysine methylation and mitochondrial homeostasis, suggesting a potential strategy for eliminating LSCs in t(8;21) AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3659
  55. Obesity (Silver Spring). 2025 Sep 02.
    FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
    Joshua Peterson, Jayashree Jena, Ayushi Sood, Shelly Roitershtein, David Smith, Renata O Pereira.
       OBJECTIVE: Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet-induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice.
    METHODS: We generated mice simultaneously lacking the Opa1, Fgf21, and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high-fat diet feeding.
    RESULTS: Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice.
    CONCLUSIONS: FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.
    Keywords:  Brown Adipose Tissue; FGF21; GDF15; Mitochondrial Stress; Obesity
    DOI:  https://doi.org/10.1002/oby.70004
  56. Cell Signal. 2025 Aug 28. pii: S0898-6568(25)00502-9. [Epub ahead of print] 112087
    Corrigendum to "High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway" [Cell Signal, 135 (2025), 112027].
    Fadian Ding, Yikun Guo, Han Zhang, Yun Zhong, Denghan Zhang, Qiang Huang, Zhou Zheng, Guozhong Liu, Xiang Zhang, Shangeng Weng.
      
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112087
  57. J Vis Exp. 2025 Aug 15.
    Understanding the Changes in Mitochondrial Morphology through Dynamic and Three-dimensional Fluorescence Micrographs.
    Sholto de Wet, Rensu Theart, Ben Loos, G Angus McQuibban.
      Mitochondria are highly dynamic organelles that are vital to the survival of any animal, undergoing regular fission and fusion events in response to the needs or stresses of the host, leading to the constant remodeling of the mitochondrial network. Because of this, being able to evaluate the mitochondrial network in three dimensions, as well as over time, offers a benefit in understanding how the system responds to factors such as stress or pharmaceutical intervention. Fluorescence imaging of the mitochondrial networks of cells enables the ability to visualize and monitor these changes. However, the mitochondrial network is often described as a two-dimensional and static structure that is defined by unstandardized metrics. Therefore, we set out to describe a pipeline that enables the user to prepare their images for the mitochondrial event localizer (MEL), an ImageJ plugin tool that detects fission and fusion events in the mitochondrial network over time and in a 3-dimensional manner, thus, offering insight into the dynamic changes that this network undergoes. Additionally, we describe the benefits of understanding fission and fusion in light of the changes in the mitochondrial count and morphological changes.
    DOI:  https://doi.org/10.3791/68478
  58. Genes Genomics. 2025 Aug 31.
    Sex-specific programming of the gastric and duodenal mitochondrial biogenesis by early-life stress.
    Keziban Korkmaz Bayram, Merve Hilal Donmez, Aida Nurul Barokah, Arslan Bayram.
       BACKGROUND: Early-life stress (ELS) is a significant risk factor for the development of numerous metabolic and physiological disorders later in life.
    OBJECTIVE: This study aims to investigate the effects of early-life stress on mitochondrial biogenesis, thermogenesis-related genes, and developmental signalling pathways in the stomach and duodenum of offspring.
    METHODS: This study consists of three groups: the first is the control group, and the second and third groups were randomly exposed to unpredictable maternal separation (MS) for three hours a day on postnatal days (PND) 1-14. The third group was exposed to unpredictable maternal stress (MSUS) in addition to MS. Mice were sacrificed at PND35. Total RNA was extracted from the tissues (corpus region of the stomach and the start zone of the duodenum) via the phenol‒chloroform technique. The expression levels of miR-34c-5p, Notch1, Prdm16, Ppargc1a, and Ucp1 were measured via Rotor-Gene Q.
    RESULTS: Although the expression of miR-34c-5p remained unchanged between the groups, the mRNA expression of genes associated with mitochondrial biogenesis and thermogenesis increased significantly with increasing stress in females. In males, the expression also increased significantly in the MS but returned to control levels in the MSUS.
    CONCLUSIONS: ELS can stimulate Ucp1-mediated thermogenesis in gastrointestinal tissues by promoting mitochondrial biogenesis, which is driven by Prdm16 and mediated by Ppargc1a. ELS might initiate mitochondrial biogenesis to accommodate the growing energy demands of the digestive system. However, increased stress alters mitochondrial biogenesis and thermogenesis-related gene expression in a sex-specific manner.
    Keywords:  Chronic stress; Intestine; MSU; MitBio; miR-34c
    DOI:  https://doi.org/10.1007/s13258-025-01672-5
  59. MicroPubl Biol. 2025 ;2025
    Dnm1 Is Required for the Focal Clustering of Fis1 on the Mitochondrial Outer Membrane.
    Miyu Sasahara, Shunsuke Matsumoto, Yasushi Tamura.
      In yeast, mitochondrial fission is mediated by the dynamin-like GTPase Dnm1, which is recruited to the mitochondrial outer membrane by its receptor, Fis1. To investigate the spatial distribution of Fis1, we used the CRISPR-Cas9 system to insert the gene fragment encoding mNeonGreen into the FIS1 gene for its N-terminal tagging. Fluorescence microscopy revealed that mNeonGreen-Fis1 appeared as discrete puncta on mitochondria, in addition to a diffuse signal. Here, we show that the focal clustering of Fis1 is dependent on Dnm1. Our findings provide insight into the spatial organization of membrane proteins, highlighting a mechanism by which a downstream effector can influence the distribution of its upstream receptor.
    DOI:  https://doi.org/10.17912/micropub.biology.001780
  60. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2426992122
    Therapeutic restoration of mitochondria-endoplasmic reticulum cross talk for osteoarthritis.
    Mingzhuang Hou, Yifan Ma, Yaoge Deng, Yubin Wu, Yanrun Zhu, Yang Liu, Xiaoping Li, Lili Yu, Zirui He, Yifan Wang, Shiyan Dong, Xiaowei Xia, Jianfeng Yu, Chenqi Yu, Kang Kang, Yingjie Lu, Lili Sun, Betty Y S Kim, Yuan Yuan, Yijian Zhang, Wen Jiang, Xuesong Zhu.
      Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial-endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.
    Keywords:  endoplasmic reticulum; extracellular vesicles; mitochondrial dynamics; osteoarthritis; posttranslational modifications
    DOI:  https://doi.org/10.1073/pnas.2426992122
  61. Cell Death Differ. 2025 Sep 01.
    Correction: TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancer.
    Kang Chen, Jinyu Chen, Yukun Cong, Qingliu He, Chunyu Liu, Jiawei Chen, Haoran Li, Yunjie Ju, Liang Chen, Yarong Song, Yifei Xing.
      
    DOI:  https://doi.org/10.1038/s41418-025-01571-y
  62. FEBS J. 2025 Sep 02.
    Propionibacterium acnes evades microbicidal phagocytosis by inhibiting the mitochondrial biogenesis of nucleus pulposus cells.
    Lemeng Ren, Changwei Li, Juntao Sun, Yuehuan Zheng, Yucheng Jiao, Jiancheng Zheng, Fangke Zhang, Yazhou Lin, Wenjian Wu, Peng Cao.
      Although an increasing number of investigators confirm the latent infection of Propionibacterium acnes in degenerated nucleus pulposus tissue, the molecular mechanism by which P. acnes evades being eliminated and establishes persistent colonization in the nucleus pulposus (NP) tissue remains unknown. In this study, we ascertained that despite the resistance by nucleus pulposus cells (NPCs) to the invasion of P. acnes through microbicidal phagocytosis, P. acnes is able to nevertheless promote its long-term colonization by inhibiting the sustained bactericidal capability of NPCs. This allows P. acnes to reside in intervertebral discs for an extended period, ultimately inducing chronic infectious intervertebral disc degeneration (IVDD). Mechanistically, P. acnes impairs the mitochondrial biogenesis of NPCs through the AMPK/SIRT-1/PGC-1α signaling pathway. This results in impaired mitochondria that are unable to generate sufficient ATP and deliver mitochondrial reactive oxygen species (mROS) to carry out the bactericidal process effectively, thus hampering the sustained microbicidal function. These findings provide novel insights into how P. acnes evades being phagocytosed and killed by NPCs and may offer potential therapeutic targets for the treatment of infectious IVDD.
    Keywords:  Propionibacterium acnes; bactericidal; intervertebral disc degeneration; mitochondrial biogenesis; mitochondrial reactive oxygen species
    DOI:  https://doi.org/10.1111/febs.70247
  63. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2025 Aug 25. 42(4): 707-715
    [Effect of 40 Hz pulsed magnetic field on mitochondrial dynamics and heart rate variability in dementia mice].
    Lifan Zhang, Duyan Geng, Guizhi Xu, Hongxia An.
      Alzheimer's disease (AD) is the most common degenerative disease of the nervous system. Studies have found that the 40 Hz pulsed magnetic field has the effect of improving cognitive ability in AD, but the mechanism of action is not clear. In this study, APP/PS1 double transgenic AD model mice were used as the research object, the water maze was used to group dementia, and 40 Hz/10 mT pulsed magnetic field stimulation was applied to AD model mice with different degrees of dementia. The behavioral indicators, mitochondrial samples of hippocampal CA1 region and electrocardiogram signals were collected from each group, and the effects of 40 Hz pulsed magnetic field on mouse behavior, mitochondrial kinetic indexes and heart rate variability (HRV) parameters were analyzed. The results showed that compared with the AD group, the loss of mitochondrial crest structure was alleviated and the mitochondrial dynamics related indexes were significantly improved in the AD + stimulated group ( P < 0.001), sympathetic nerve excitation and parasympathetic nerve inhibition were improved, and the spatial cognitive memory ability of mice was significantly improved ( P < 0.05). The preliminary results of this study show that 40 Hz pulsed magnetic field stimulation can improve the mitochondrial structure and mitochondrial kinetic homeostasis imbalance of AD mice, and significantly improve the autonomic neuromodulation ability and spatial cognition ability of AD mice, which lays a foundation for further exploring the mechanism of ultra-low frequency magnetic field in delaying the course of AD disease and realizing personalized neurofeedback therapy for AD.
    Keywords:  Alzheimer’s disease; Extremely low frequency magnetic field; Heart rate variability; Mitochondrial dynamics
    DOI:  https://doi.org/10.7507/1001-5515.202501061
  64. Mater Today Bio. 2025 Oct;34 102215
    Genetically engineered MSC-derived hybrid cellular vesicles for ROS-scavenging and mitochondrial homeostasis in hepatic ischemia-reperfusion injury.
    Pu Shen, Kaijun Huang, Xuanlin Zhang, Guiyuan Yin, Meiting Qin, Hua Ma, Zhijin Fan, Yuhui Liao.
      Hepatic ischemia-reperfusion injury (IRI) poses a significant clinical challenge in liver surgery and transplantation, primarily mediated through oxidative stress, mitochondrial dysfunction, and inflammatory activation. Herein, we developed SOD2-Res@CVs, an engineered vesicular platform combining SOD2-overexpressing mesenchymal stem cell-derived vesicles with liver-targeted and ROS-responsive resveratrol (Res)-loaded liposomes for multi-mechanistic intervention. In vivo imaging demonstrated that SOD2-Res@CVs selectively accumulated in IRI-damaged hepatic tissues. Within oxidative stress microenvironments, the system exhibited responsive liberation of SOD2 and resveratrol, which cooperatively mitigated oxidative damage through redox homeostasis modulation - evidenced by reduced lipid peroxidation (MDA suppression) and enhanced antioxidant defense (GSH/SOD2 upregulation). This therapeutic cascade facilitated mitochondrial structural and functional restoration via multiple pathways: Resveratrol specifically activated PINK1-mediated mitophagy, as confirmed by increased LC3 and beclin-1 expression, thereby promoting selective clearance of depolarized mitochondria. Comparative analyses revealed SOD2-Res@CVs' superior therapeutic efficacy over individual components in histological recovery and organ function preservation. Transcriptomic profiling further validated the system's multi-target regulatory capacity, highlighting its concurrent suppression of oxidative stress pathways, mitigation of inflammatory signaling, and improvement of mitochondrial bioenergetics during IRI progression. This study establishes SOD2-Res@CVs as a multifunctional nanotherapeutic strategy that harmonizes spatial targeting with pathological microenvironment responsiveness and a promising approach for liver protection in transplantation.
    Keywords:  Cellular vesicles; Hepatic ischemia-reperfusion injury; Mesenchymal stem cell; Mitochondrial homeostasis; Resveratrol
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102215
  65. IUBMB Life. 2025 Sep;77(9): e70048
    PLEKHF1 Induces Mitochondrial Dysfunction to Inhibit Osteosarcoma Growth and Metastasis.
    Jun Wan, Xinyan Cai, Zhan Liao, Yupeng Liu, Qing Liu, Can Zhang, Feng Long.
      Osteosarcoma (OS) is an uncommon malignancy with stagnant survival rates over the past four decades and early-stage metastasis, predominantly affecting children and adolescents. This study identified significant metabolic differences between metastatic and non-metastatic OS samples through bioinformatics analysis, highlighting key processes such as cell proliferation, mitochondrial assembly, and changes in mitochondrial membrane permeability. Among differentially expressed genes, Pleckstrin Homology And FYVE Domain Containing 1 (PLEKHF1) was the most significantly downregulated in metastatic OS samples. Functional experiments demonstrated that PLEKHF1 overexpression in Saos-2 and U2OS cells induced mitochondrial dysfunction, evidenced by increased mtROS levels, decreased mitochondrial membrane potential, and altered cytochrome C distribution. Additionally, PLEKHF1 overexpression inhibited OS cell viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT), while promoting apoptosis. Conversely, knockdown of PLEKHF1 had the opposite effects on Saos-2 and U2OS cells. In vivo, PLEKHF1 overexpression reduced tumor growth and lung metastasis in a mouse model. Conversely, PLEKHF1 knockdown ameliorated Rotenone-induced mitochondrial dysfunction and mitophagy, partially reversing the suppressive effects of Rotenone on OS cell aggressiveness. These findings suggest that PLEKHF1 could serve as an anti-tumor factor by inducing mitochondrial dysfunction, thereby inhibiting OS growth and metastasis. The study highlights the potential of PLEKHF1 as a therapeutic target for managing osteosarcoma, providing valuable insights into the role of mitochondrial dysfunction in OS pathogenesis.
    Keywords:  PLEKHF1; mitochondrial dysfunction; mitophagy; osteosarcoma
    DOI:  https://doi.org/10.1002/iub.70048
  66. Nat Commun. 2025 Sep 01. 16(1): 8173
    Temporal transcriptional regulation of mitochondrial morphology primes activity-dependent circuit connectivity.
    Iryna Mohylyak, Maheva Andriatsilavo, Mercedes Bengochea, Carlos Pascual-Caro, Noemi Asfogo, Sara Fonseca-Topp, Natasha Danda, Marlene Cassar, Corentine Marie, Zeynep Kalender Atak, Maxime De Waegeneer, Stein Aerts, Olga Corti, Jaime de Juan-Sanz, Bassem A Hassan.
      Synaptic connectivity during development is known to require rapid local regulation of axonal organelles. Whether this fundamental and conserved aspect of neuronal cell biology is orchestrated by a dedicated developmental program is unknown. We hypothesized that developmental transcription factors regulate critical parameters of organelle structure and function which contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Drosophila CG7101, which we rename mitochondrial integrity regulator of neuronal architecture (Mirana), as a temporal developmental regulator of neuronal mitochondrial quality control genes, including Pink1. Remarkably, a brief developmental downregulation of either Mirana or Pink1 suffices to cause long-lasting changes in mitochondrial morphology and abrogates neuronal connectivity which can be rescued by Pink1 expression. We show that Mirana has functional homology to the mammalian transcription factor TZAP whose loss leads to changes in mitochondrial function and reduced neurotransmitter release in hippocampal neurons. Our findings establish temporal developmental transcriptional regulation of mitochondrial morphology as a prerequisite for the priming and maintenance of activity-dependent synaptic connectivity.
    DOI:  https://doi.org/10.1038/s41467-025-62908-2
  67. Chem Biol Interact. 2025 Sep 03. pii: S0009-2797(25)00351-5. [Epub ahead of print] 111721
    Paraquat Induced Neuro-immunotoxicity: Dysregulated Microglial Antigen Processing and Mitochondrial Activated Mechanisms.
    Ge Shi, Kaidong Wang, Qi Liu, Chenyang Wu, Qianrong Zhang, Yuan Ma, Ai Qi, Min Huang.
      Paraquat (PQ) is characterized by neurotoxicity. In daily life, PQ exposure mainly occurs through chronic and trace pathways, which induce progressive neuronal damage or neuronal synaptic loss. Previously, mitochondrial dysfunction was a critical underlying mechanism. Emerging evidence suggests that neuroinflammation mediated by microglial activation and T-cell infiltration may trigger accelerated neuronal degeneration. While antigen presentation constitutes an essential prerequisite for T-cell infiltration and functional activation, the potential association between mitochondrial impairment and microglial antigen presentation dysregulation remains unexplored. In this study, we initially identified paraquat-associated target gene clusters from the CTD database. Following the enrichment analyses of GO and KEGG revealed Parkinson's disease pathways and mitochondrial processes. Further, we constructed a time-dependent model for C57BL/6J (♂) mice continuously treated with PQ (1.25 mg/kg) once/day to imitate early-stage neurotoxicity. For mice, neurobehavioral symptoms showed a decrease in learning and memory abilities. Pathologically, the neuroinflammatory response dominated by microglial activation and T-cell infiltration preceded observable synaptic loss. This correlated with microglial two distinct processes: 1) upregulated surface chemokine expression (CCL2, CCL3, CCL4, CCL5), and 2) enhanced antigen recognition, phagocytosis, and presentation machinery (TLR4, LAMP2, MHC II), facilitating CD4+/CD8+ T-cell recruitment. Notably, α-synuclein aggregates may act as antigens triggering microglial mitochondrial stress responses, as evidenced by altered expression of mitochondrial proteases (LONP1, CLPP, HTRA2). Remarkably, resveratrol effectively restored BV-2 microglial mitochondrial homeostasis and normalized antigen presentation. This study demonstrated that microglial mitochondrial dysregulation mediates aberrant antigen presentation, thereby driving neuroinflammatory cascades. And provides novel and potential mechanistic insights into chemical neurotoxicity.
    Keywords:  Antigen presentation; Microglia; Mitochondrion; Paraquat; T-cell infiltration
    DOI:  https://doi.org/10.1016/j.cbi.2025.111721
  68. Cytoskeleton (Hoboken). 2025 Jul 30.
    Comparative Analysis of Septin Modifiers, Forchlorfenuron and UR214-9, on Mitochondrial Fragmentation and Lytic Cell Death.
    Dominik Brokatzky, Rajdeep Das, Hannah Painter, Rakesh K Singh, Serge Mostowy.
      Septins are conserved GTP-binding proteins that play key roles in cell division, mitochondrial dynamics and immune responses. Despite their importance to human health, pharmacological compounds to modify septins remain limited. Forchlorfenuron (FCF) was the first small molecule identified to modify septins, disrupting their organisation and promoting mitochondrial fragmentation. A more potent FCF analog (UR214-9) has recently been developed, but its effects on mitochondria were unknown. Here, we compare FCF and UR214-9 in vitro using macrophages and in vivo using zebrafish larvae. We demonstrate that both modifiers induce mitochondrial fragmentation in macrophages without altering mitochondrial mass or SEPT7 expression. Consistent with mitochondrial fragmentation, both modifiers trigger lytic cell death in a dose-dependent manner following lipopolysaccharide (LPS) priming. In vivo, both modifiers exhibit dose-dependent effects on the survival of zebrafish larvae, although UR214-9 was significantly more toxic. In agreement with in vitro results, we observed that FCF induces macrophage cell death and caspase-1 activity in zebrafish larvae. Together, our findings show that both septin modifiers impact mitochondrial integrity and macrophage survival. Understanding how septin modifiers regulate immune responses may have important implications for inflammatory disease research and could lead to the development of septin-based medicines for conditions characterised by dysregulated inflammation.
    Keywords:  cell death; macrophages; septin modifiers; septins; zebrafish
    DOI:  https://doi.org/10.1002/cm.70013
  69. J Mol Histol. 2025 Sep 06. 56(5): 299
    FGF5 alleviates ferroptosis in renal tubular epithelial cells by inducing mitophagy under in vitro ischemia-reperfusion-like injury.
    Dongxu Lin, Tianen Wu, Hongyuan Huang, Xiaoyu Hong.
      Renal ischemic disease represents a severe clinical pathological condition commonly observed in acute kidney injury (AKI), renal transplantation, and kidney surgery. It leads to renal tubular epithelial cell damage, inflammatory responses, and cell death, potentially progressing to chronic kidney disease (CKD) or even renal failure, significantly impairing patients' quality of life and survival rates. Current therapeutic strategies for renal ischemia-reperfusion injury (IRI) include pharmacological interventions, cell therapy, and gene therapy, yet their efficacy remains limited and may be accompanied by adverse effects. Thus, there is an urgent need to explore novel therapeutic targets and strategies. Fibroblast growth factor 5 (FGF5), a key member of the FGF family, plays crucial roles in cell proliferation, differentiation, and tissue repair. However, its specific mechanism in renal IRI remains unclear. This study aimed to investigate the therapeutic effects of FGF5 on renal IRI and its underlying molecular mechanisms in vitro. Using normal rat kidney-52E (NRK-52E) and human kidney-2 (HK-2 cell) models, we evaluated the impact of FGF5 on cell viability, oxidative stress, inflammatory responses, and renal cell death. Our findings demonstrate that FGF5 exhibits significant biological activity and further reveal its regulatory role in suppressing ferroptosis through activation of the Mitophagy. In conclusion, this study identifies FGF5 as a potential therapeutic agent for renal IRI and provides a theoretical foundation for developing FGF5-based treatment strategies. These findings hold substantial scientific and clinical value, potentially opening new avenues for treating renal ischemic diseases.
    Keywords:  FGF5; Inflammation; Ischemia–reperfusion; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s10735-025-10594-1
  70. Geroscience. 2025 Sep 01.
    Failure of efficient cardiac proteostatic adaptations to chronic cAMP-stress is associated with accelerated heart aging.
    Maria Grazia Perino, Miguel Calvo-Rubio Barrera, Daniel R Riordon, Giulio Agnetti, Alexander Maltsev, Admira Parveen, Christopher H Morrell, Ismayil Ahmet, Khalid Chakir, Yelena S Tarasova, Jia-Hua Qu, Kirill V Tarasov, Alexey E Lyashkov, Yevgeniya O Lukyanenko, Hikmet Kadioglu, Mark Ranek, Rafael De Cabo, Edward G Lakatta.
      Dysregulated proteostasis is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic-adenosine-monophosphate (cAMP)-dependent stress change with aging in mice harboring marked cardiac-specific over-expression of adenylyl cyclase VIII (TGAC8). We assessed protein quality control mechanisms (PQC) (ubiquitin proteasome system, autophagic flux via macroautophagy, and mitophagy) in left ventricles of TGAC8 and wild-type littermates (WT) at 3-4 and 17-21 months of age. At 3-4 months, TGAC8 exhibited markers of increased autophagic flux (microtubule-associated protein 1A/1B light chain 3B (LC3), p62, and their phospho-forms) and enhanced canonical mitophagy signaling (PARKIN, p62S405 and p62S349 receptors), confirming a more efficient proteostasis, vs WT. In aged TGAC8, however, the PQC mechanisms were overwhelmed by proteotoxic stress, manifested in insufficient proteasome activity, slower autophagic flux, and increased mitochondrial dysfunction (network fragmentation). The accumulation of protein aggregates (increased ratio of insoluble/soluble protein fractions), of lipofuscin bodies and of desmin cardiac preamyloid oligomers, and of LC3+- and p62+-inclusions of aberrant sizes was increased in aged TGAC8 compared to young TGAC8. Thus, while increased proteostatic mechanisms maintain cardiac health in TGAC8 in youth (3-4 months), long-term exposure to sustained activation of the AC/cAMP/PKA/Ca2+ signaling axis results in severe proteostasis insufficiency in aged TGAC8, leading to cardiomyopathy and accelerated cardiac aging.
    Keywords:  Aging; Dysregulated proteostasis; Protein quality control
    DOI:  https://doi.org/10.1007/s11357-025-01851-y
  71. Cell Commun Signal. 2025 Sep 03. 23(1): 393
    Targeting mitochondrial proteases CLPP and LONP1 via disruption of mitochondrial redox homeostasis induces proteotoxic stress and suppresses tumor progression.
    Shivani R Nandha, R S Patwardhan, Deepak Sharma, Santosh K Sandur, Rahul Checker.
       BACKGROUND: Cancer cells, which rely heavily on mitochondria for their energy demands and oncometabolites, have a high mitochondrial load, often associated with an aggressive, invasive, and metastatic phenotype. Mitochondrial ROS (mtROS), which play a causal role in cancer, represent the Achilles' heel of cancer since excessive mtROS causes protein misfolding/aggregation, resulting in cell death via proteotoxic stress. Furthermore, the detailed underlying mechanism(s) of mitochondrial oxidative stress-induced cell death remain obscure.
    METHODS: Cell growth was estimated by MTT assay, clonogenic assay, live-cell imaging and flow cytometry. Intracellular ROS, mtROS, glutathione and antioxidant levels were studied by spectrophotometry. RNAseq and Western blotting were performed to elucidate the underlying mechanism(s). In vivo efficacy was evaluated using a syngeneic mouse model.
    RESULTS: We employed a mitochondria-targeted agent to disrupt the mitochondrial redox balance. Among tumors of different origins, such as lung, breast, prostate, bone, skin, cervical and liver, triple-negative breast cancer (TNBC) exhibited the highest sensitivity to mitochondrial oxidative stress. Compared with the parent compound, mitochondria-targeted agent showed 39-fold more effectiveness in killing TNBCs. We observed a possible correlation between the mitochondrial load in different cancer cell lines and their sensitivity to mitochondrial oxidative stress. Transcriptomic analysis revealed an enrichment of biological response to unfolded and/or misfolded proteins, which are regulated by two key proteases, Lon peptidase 1 (LONP1) and Caseinolytic protease P (CLPP), that control mitochondrial proteostasis. Bioinformatics analyses revealed enhanced expression and a strong positive correlation between these proteases in breast cancer patients, with highest expression observed in TNBC. Additionally, an early relapse was observed in breast cancer patients over-expressing both LONP1 and CLPP. Mitochondrial oxidative stress triggered a decrease in the native functional forms and an increase in the aggregated forms of LONP1 and CLPP, thereby disrupting mitochondrial proteostasis. Interestingly, no such changes were observed in normal cells. Mechanistically, excess mtROS induced proteotoxic stress and mitochondrial dysfunction, culminating in growth inhibition both in vitro and in vivo.
    CONCLUSION: Our studies, for the first time, show that the mitochondrial load and induction of mtROS for concomitant inhibition of LONP1 and CLPP to induce proteotoxic stress, could be novel therapeutic targets for cancer.
    Keywords:  Mitochondria; Mitochondrial proteases; Oxidative stress; Proteotoxic stress; Unfolded protein response
    DOI:  https://doi.org/10.1186/s12964-025-02127-w
  72. Nat Struct Mol Biol. 2025 Aug 28.
    Dynamic TOM-TIM23 supercomplex directs mitochondrial protein translocation and sorting.
    Yuqi Yang, Shanshan Wang, Guopeng Wang, Yuke Lian, Lingfeng Xue, Wenhong Jiang, Qiang Guo, Chen Song, Long Li.
      The mitochondrial translocase of the outer membrane (TOM) and translocase of the inner membrane 23 (TIM23) complexes are coupled to control protein import across the outer and inner membranes, respectively. However, the mechanisms of protein recognition and sorting in the TOM-TIM23 pathway remain unclear. Here we report cryo-electron microscopy structures of a translocating polypeptide substrate captured in the active TOM-TIM23 supercomplex from Saccharomyces cerevisiae. In the TOM complex, the polypeptide substrate adopts multiple conformations stabilized by hydrophilic residues from distinct regions of the Tom40 channel. In the TIM23 complex, the Tim17 and Mgr2 subunits create the translocation pathway, with a central restriction formed by four highly conserved hydrophobic residues. The substrate primarily interacts with hydrophobic residues along the Tim17-Mgr2 pathway. Substrate hydrophobicity modulates the association of Mgr2 with Tim17, enabling dynamic regulation of protein sorting toward either the matrix or membrane. These findings reveal a sophisticated translocation mechanism of the TOM-TIM23 supercomplex that ensures the efficient import of diverse mitochondrial proteins.
    DOI:  https://doi.org/10.1038/s41594-025-01662-x
  73. Zhongguo Zhong Yao Za Zhi. 2025 Jul;50(13): 3738-3753
    [Effects and mechanisms of total flavones of Abelmoschus manihot combined with empagliflozin in attenuating diabetic tubulopathy through multiple targets based on mitochondrial homeostasis and ZBP1-mediated PANoptosis].
    Si-Yu Cha, Meng Wang, Yi-Gang Wan, Si-Ping Ding, Yu Wang, Shi-Yu Shen, Wei Wu, Ying-Lu Liu, Qi-Jun Fang, Yue Tu, Hai-Tao Tang.
      This study aimed to explore the mechanisms and molecular targets of total flavones of Abelmoschus manihot(TFA) plus empagliflozin(EM) in attenuating diabetic tubulopathy(DT) by targeting mitochondrial homeostasis and pyroptosis-apoptosis-necroptosis(PANoptosis). In the in vivo study, the authors established the DT rat models through a combination of uninephrectomy, administration of streptozotocin via intraperitoneal injections, and exposure to a high-fat diet. Following modeling successfully, the DT rat models received either TFA, EM, TFA+EM, or saline(as a vehicle) by gavage for eight weeks, respectively. In the in vitro study, the authors subjected the NRK52E cells with or without knock-down Z-DNA binding protein 1(ZBP1) to a high-glucose(HG) environment and various treatments including TFA, EM, and TFA+EM. In the in vivo and in vitro studies, The authors investigated the relative characteristics of renal tubular injury and renal tubular epithelial cells damage induced by reactive oxygen species(ROS), analyzed the relative characteristics of renal tubular PANoptosis and ZBP1-mediatted PANoptosis in renal tubular epithelial cells, and compared the relative characteristics of the protein expression levels of marked molecules of mitochondrial fission in the kidneys and mitochondrial homeostasis in renal tubular epithelial cells, respectively. Furthermore, in the network pharmacology study, the authors predicted and screened targets of TFA and EM using HERB and SwissTargetPrediction databases; The screened chemical constituents and targets of TFA and EM were constructed the relative network using Cytoscape 3.7.2 network graphics software; The relative targets of DT were integrated using OMIM and GeneCards databases; The intersecting targets of TFA, EM, and DT were enriched and analyzed signaling pathways by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG) software using DAVID database. In vivo study results showed that TFA+EM could improve renal tubular injury, the protein expression levels and characteristics of key signaling molecules in PANoptosis pathway in the kidneys, and the protein expression levels of marked molecules of mitochondrial fission in the kidneys. And that, the ameliorative effects in vivo of TFA+EM were both superior to TFA or EM. Network pharmacology study results showed that TFA+EM treated DT by regulating the PANoptosis signaling pathway. In vitro study results showed that TFA+EM could improve ROS-induced cell injury, ZBP1-mediatted PANoptosis, and mitochondrial homeostasis in renal tubular epithelial cells under a state of HG, including the protein expression levels of marked molecules of mitochondrial fission, mitochondrial ultrastructure, and membrane potential level. And that, the ameliorative effects in vitro of TFA+EM were both superior to TFA or EM. More importantly, using the NRK52E cells with knock-down ZBP1, the authors found that, indeed, ZBP1 was mediated PANoptosis in renal tubular epithelial cells as an upstream factor. In addition, TFA+EM could regulate the protein expression levels of marked signaling molecules of PANoptosis by targeting ZBP1. In summary, this study clarified that TFA+EM, different from TFA or EM, could attenuate DT with multiple targets by ameliorating mitochondrial homeostasis and inhibiting ZBP1-mediated PANoptosis. These findings provide the clear pharmacological evidence for the clinical treatment of DT with a novel strategy of TFA+EM, which is named &quot;coordinated traditional Chinese and western medicine&quot;.
    Keywords:  PANoptosis; diabetic tubulopathy; empagliflozin; mitochondrial homeostasis; total flavones of Abelmoschus manihot
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250311.706
  74. Nat Commun. 2025 Aug 30. 16(1): 8134
    Silicon-rhodamine-enabled identification for near-infrared light controlled proximity labeling in vitro and in vivo.
    Wenjing Wang, Hongyang Guo, Xiaosa Yan, Xuanzhen Pan, Xiaofei Wang, Yiming Rong, Zexiao Bai, Liwan Zhang, Zhaofa Wu, Xinyu Zhao, Weiren Huang, Wei Qin, Ling Chu.
      Advancement in fluorescence imaging techniques enables the study of protein dynamics and localization with unprecedented spatiotemporal resolution. However, current imaging tools are unable to elucidate dynamic protein interactomes underlying imaging observations. Conversely, proteomics tools such as proximity labeling enable the analysis of protein interactomes at a single time point but lack information about protein dynamics. We herein develop Silicon-rhodamine-enabled Identification (SeeID) for near-infrared light controlled proximity labeling that could bridge the gap between imaging and proximity labeling. SeeID is benchmarked through characterization of various organelle-specific proteomes and the KRAS protein interactome. The fluorogenic nature of SiR allows for intracellular proximity labeling with high subcellular specificity. Leveraging SiR as both a fluorophore and a photocatalyst, we develop a protocol that allows the study of dynamic protein interactomes of Parkin during mitophagy. We discover the association of the proteasome complex with Parkin at early time points, indicating the involvement of the ubiquitin-proteasome system for protein degradation in the early phase of mitophagy. Additionally, by virtue of the deep tissue penetration of near-infrared light, we achieve spatiotemporally controlled proximity labeling in vivo across the mouse brain cortex with a labeling depth of ~2 mm using an off-the-shelf 660 nm LED light set-up.
    DOI:  https://doi.org/10.1038/s41467-025-63496-x
  75. Biochem Pharmacol. 2025 Aug 28. pii: S0006-2952(25)00552-0. [Epub ahead of print]242(Pt 1): 117287
    Flubendazole inhibits cervical carcinoma by targeting DHODH to induce ferroptosis and mitophagy.
    Xiaokun Liu, Yuxuan Yang, Bingqiang Zhang, Xiao Gao, Di Yang, Yani Sun, Lianhui Li, Mingkang Yu, Lin Hou, Ning Li, Yuling Yang.
      Cervical carcinoma remains a major public health challenge due to its elevated incidence and mortality rates. Dihydroorotate dehydrogenase (DHODH) is a crucial enzyme in de novo pyrimidine biosynthesis and ferroptosis defense with a targetable susceptibility in cancer. However, effective inhibitors of DHODH and their potential application in cervical cancer therapy have not yet been explored. This study aims to evaluate the inhibitory effects of flubendazole, a benzimidazole anthelmintic, on cervical carcinoma and the mechanisms involved. This study demonstrated that flubendazole effectively inhibited cervical cancer cell proliferation and tumor growth by inducing ferroptosis and PINK1/Parkin-mediated mitophagy. Mechanistically, flubendazole targeted DHODH and promoted its degradation via direct binding. Overexpression of DHODH prevented flubendazole-induced ferroptosis and mitophagy and markedly attenuated its anti-cancer effects in cervical cancer cells. Additionally, flubendazole enhanced the sensitivity of cervical cancer cells to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition and showed a potent synergistic anti-tumor effect in combination with GPX4 inhibitor in xenograft mouse models. These findings highlight the promising potential of flubendazole as a repurposed drug for cervical cancer therapy by inducing ferroptosis through inhibition of DHODH.
    Keywords:  Cervical carcinoma; DHODH; Ferroptosis; Flubendazole; Mitophagy
    DOI:  https://doi.org/10.1016/j.bcp.2025.117287
  76. Ecotoxicol Environ Saf. 2025 Aug 30. pii: S0147-6513(25)01265-5. [Epub ahead of print]303 118920
    Tetrabromophthalate bis(2-ethylhexyl) ester (TBPH) exposure induces renal inflammation injury by activating MAVS-IRF3 signaling pathway in vitro and in vivo models.
    Baopeng Xing, Hainan Lan, Haifeng Li.
      Tetrabromophthalate bis(2-ethylhexyl) ester (TBPH) is a common brominated flame retardant, which exhibits environmental persistence, the potential for bioaccumulation, and concerning toxicological effects. But until now, there is limited data on TBPH-induced nephrotoxicity. Therefore, this study assessed the impact of TBPH exposure on renal cells and tissues through in vitro and in vivo models. A series of biochemical experiments, including Western-blot, indirect immunofluorescence, ELISA, SiRNA, H&E and immunohistochemistry were carried out. In in vitro models, TBPH exposure dose-dependently inhibited renal cell proliferation. In addition, TBPH exposure induces significant inflammation through the mitochondrial retinoic acid-inducible gene I-mitochondrial antiviral-signaling protein (RIG-I-MAVS) signaling pathway, and TBPH treatment also results in oxidative stress responses across two distinct renal cell models. In vivo, TBPH exposure induces renal tissue damage and abnormal renal function. Additionally, TBPH treatment induces renal inflammation and fibrosis, demonstrated by up-regulation of characteristic markers (such as TNF-α/IL-6 for inflammation; α-SMA/fibronectin for fibrosis). Mechanistic investigations revealed that TBPH exposure causes kidney damage through impaired mitochondrial autophagy and excessive mitochondrial fission. These findings underscore TBPH's nephrotoxic potential and the necessity for further investigation into the risks associated with prolonged, low-dose exposure. Additionally, appropriate regulatory measures should be developed to mitigate its environmental and health impacts.
    Keywords:  Inflammation; Kidney; MAVS; Oxidative stress; TBPH
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118920
  77. Cell Rep. 2025 Sep 04. pii: S2211-1247(25)00992-1. [Epub ahead of print]44(9): 116221
    Replication competition drives the selective mtDNA inheritance in Drosophila ovary.
    Cheng Zhang, Zhe Chen, Hansong Ma, Hong Xu.
      Purifying selection that limits the transmission of harmful mitochondrial DNA (mtDNA) mutations has been observed in both human and animal models. Yet, the precise mechanism underlying this process remains undefined. Here, we present a highly specific and efficient in situ imaging method capable of visualizing mtDNA variants that differ by only a few nucleotides at single-molecule resolution in Drosophila ovaries. Using this method, we revealed that selection primarily occurs within a narrow developmental window during germline cyst differentiation. At this stage, the proportion of the deleterious mtDNA variant decreases without a reduction in its absolute copy number. Instead, the healthier mtDNA variant replicates more frequently, thereby outcompeting the co-existing deleterious variant. These findings provide direct evidence that mtDNA selection is driven by replication competition rather than by active elimination processes, shedding light on a fundamental yet previously unresolved mechanism governing mitochondrial genome transmission.
    Keywords:  CP: Molecular biology; germline; mitochondria; mitophagy; mtDNA inheritance; mtDNA mutation; mtDNA replication; oogenesis; purifying selection; rolling circle amplification; single-molecule imaging
    DOI:  https://doi.org/10.1016/j.celrep.2025.116221
  78. Can J Urol. 2025 Aug 29. 32(4): 255-269
    Crosstalk between mitochondrial dysfunction and benign prostatic hyperplasia: unraveling the intrinsic mechanisms.
    Huan Liu, Yan Li, Jizhang Qiu, Junchao Zhang, Huan Lai, Xinhua Zhang.
      Benign prostatic hyperplasia (BPH) represents a prevalent etiology of lower urinary tract symptoms (LUTS) in the male population, clinically defined by a non-malignant proliferation of prostatic tissue. While BPH exhibits a high prevalence among older male populations globally, the precise underlying mechanisms contributing to its development remain incompletely elucidated. Mitochondria, essential organelles within eukaryotic cells, are critical for cellular bioenergetics, the regulation of reactive oxygen species (ROS) generation, and the modulation of cell death pathways. The maintenance of mitochondrial homeostasis involves a complex interplay of processes. By synthesizing previous literature, this review discusses mitochondrial homeostasis in prostate glands and the role of mitochondrial dysfunction in the context of BPH. Furthermore, the review delved into each dimension of mitochondrial dysfunction in the specific etiology of BPH, highlighting its impact on cell survival, apoptosis, ferroptosis, oxidative stress and androgen receptor (AR). Overall, this review aims to unveil the crosstalk between mitochondrial dysfunction and BPH and identify intrinsic mechanisms.
    Keywords:  benign prostatic hyperplasia; intrinsic mechanism; lower urinary tract symptoms; mitochondrial dysfunction
    DOI:  https://doi.org/10.32604/cju.2025.066523
  79. Vet Microbiol. 2025 Sep 01. pii: S0378-1135(25)00338-4. [Epub ahead of print]310 110703
    TRPM2 knockdown alleviated H9N2 influenza virus infected ferroptosis in mouse pulmonary microvascular endothelial cells.
    Yu Xia, Jiaxin Yuan, Tianci Liu, Ruihua Zhang, Caixia Wu, Nana Sui, Longfei Li, Tong Xu.
      H9N2 influenza virus, a prevalent influenza A virus, causes acute lung injury through mitochondrial damage associated with oxidative stress. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+ permeable non-selective cation channel that can trigger oxidative stress via Ca2+ overload. Excessive ROS generation leads to mitochondrial dysfunction and lipid peroxides accumulation, contributing to ferroptosis. However, it remains unclear whether H9N2 virus infection can trigger ferroptosis in mouse lungs and its relationship with TRPM2. Therefore, this study investigates the protective effect of TRPM2 knockdown against lung injury infected by H9N2 virus and explores its potential molecular mechanisms, with a particular focus on its association with ferroptosis. In vitro, we infected mouse pulmonary microvascular endothelial cells (PMVECs) with H9N2 virus, or/and transfected them with siTRPM2 at 80 nM. Our findings revealed that TRPM2 knockdown significantly reduced Ca2+ overload and ROS generation, and upregulated the mRNA and protein expression levels of catalase (CAT), superoxide dismutase 1 (SOD1), and heme oxygenase-1 (HO-1). This intervention also alleviated mitochondrial damage and maintained mitochondrial dynamics balance. H9N2 virus infection disrupted the Glutathione/Glutathione oxidized (GSH/GSSG) system and increased lipid peroxidation-related factors (Lysophosphatidylcholine acyltransferase 3 [LPCAT3] and Acyl-CoA synthetase long chain family member 4 [ACSL4]), which were mitigated by TRPM2 knockdown. Additionally, TRPM2 ablation reduced Fe2+ intensity and the expression levels of iron metabolism-related factors (Transferrin [TF] and Transferrin receptor [TFR]). In conclusion, TRPM2 knockdown inhibited H9N2 virus-induced ferroptosis by mitigating Ca2+ overload, oxidative stress, mitochondrial dysfunction, GSH/GSSG system imbalance, lipid peroxidation, and iron metabolism imbalance.
    Keywords:  Ferroptosis; H9N2 virus; Mitochondria dynamics; Mouse pulmonary microvascular endothelial cells; TRPM2
    DOI:  https://doi.org/10.1016/j.vetmic.2025.110703
  80. J Mol Histol. 2025 Sep 05. 56(5): 295
    TRIB1 silencing attenuates epilepsy by restoring mitochondrial homeostasis and suppressing microglia-driven neuroinflammation via MAPK pathway inhibition.
    Chunying Liao, Jie Cao, Hanyi Zeng, Cuiyin Chen, Jianqing Yuan.
      
    Keywords:  Epilepsy; Hub genes; Mitogen-activated protein kinase (MAPK) signaling pathway; Tribbles homolog 1 (TRIB1)
    DOI:  https://doi.org/10.1007/s10735-025-10580-7
  81. Cell Death Discov. 2025 Aug 28. 11(1): 414
    Iron-responsive ZNF185 overexpression drives mitochondrial fission and endoplasmic reticulum stress via cytoskeletal remodeling in granulosa cells.
    Zhaoyue Huang, Yang You, Qi Qiu, Nan Dong, Xinye Hu, Meihong Cai, Yaoqiu Wu, Chunwei Cao, Qingxue Zhang.
      Ovarian endometrioma (OMA), an estrogen-dependent gynecological disorder, is characterized by the presence of abundant free iron resulting from recurrent hemorrhage of endometrial cells within the cyst, which adversely affects ovarian function. However, the underlying mechanisms through which iron overload impairs ovarian function remain unclear. In this study, we stimulated KGN cells with ferric ammonium citrate (FAC) in vitro and observed dose-dependent significant alterations, including decreased mitochondrial membrane potential, increased reactive oxygen species (ROS), decreased cell viability, and elevated apoptosis rates. RNA sequencing analysis of iron-overloaded KGN cells demonstrated significant upregulation of ZNF185 expression across multiple concentration gradients and treatment durations. ZNF185 overexpression was found to disrupt F-actin dynamics, triggering a cascade of cellular events including Drp1-mediated mitochondrial hyperfission, endoplasmic reticulum stress, and cytochrome C release, ultimately leading to granulosa cell apoptosis. Importantly, knockdown of ZNF185 was shown to preserve cytoskeletal integrity and attenuate apoptotic responses under conditions of iron overload. Our findings demonstrated that ZNF185 served as a novel iron-responsive regulator involved in iron overload-induced granulosa cell apoptosis. These results might provide potential therapeutic strategies for ovarian fertility preservation in OMA patients.
    DOI:  https://doi.org/10.1038/s41420-025-02719-y
  82. Redox Biol. 2025 Aug 21. pii: S2213-2317(25)00352-0. [Epub ahead of print]86 103839
    Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
    Michel N Kanaan, Charbel Y Karam, Luke S Kennedy, Chantal A Pileggi, Lauren Hamilton, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.
      Muscle satellite cell (MuSC) proliferation is tightly regulated by redox homeostasis and nutrient availability, which are often disrupted in muscular pathologies. Beyond its role in maintaining cellular redox homeostasis, this study identified a key metabolic role for cystine/glutamate antiporter xCT in proliferating MuSCs. We investigated the impact of impaired xCT-mediated cystine import in Slc7a11sut/sut MuSCs isolated from mice that harbor a mutation in the SLC7A11 gene, which encodes xCT. We used complementary approaches to study how disrupted cystine import affects glutathione (GSH) redox, cellular bioenergetics, mitochondrial dynamics, and metabolism. Oxygen consumption rates of Slc7a11sut/sut MuSCs were lower, indicative of compromised mitochondrial oxidative capacity. This was accompanied by a fragmented mitochondrial network associated with OPA1 cleavage and redox-sensitive DRP1 oligomerization. Metabolomic profiling revealed a distinct metabolic signature in Slc7a11sut/sut MuSCs, manifested by major differences in BCAAs, pyrimidines, cysteine, methionine, and GSH. Despite lower overall bioenergetic flux, stable-isotope tracing analyses (SITA) showed that xCT deficiency increased glucose uptake, channeling glucose-derived carbons into de novo serine biosynthesis to fuel cysteine production via the transsulfuration pathway, partially compensating for disrupted GSH redox. Furthermore, xCT deficiency triggered upregulated pyrroline-5-carboxylate synthase (P5CS)-mediated proline reductive biosynthesis. By directing glutamate into proline synthesis, MuSCs apparently downregulate oxidative phosphorylation (OXPHOS) and regulate intracellular glutamate levels in response to impaired cystine/glutamate antiporter function. Our findings highlight the roles of xCT in regulating redox balance and metabolic reprogramming in proliferating MuSCs, providing insights that may inform therapeutic strategies for muscular and redox-related pathologies.
    Keywords:  Cysteine; Cystine/glutamate antiporter; Glycolysis; Metabolic reprogramming; Mitochondria; Myopathy; Oxidative phosphorylation; Proline; Skeletal muscle; Slc7a11; System Xc−; Transsulfuration pathway
    DOI:  https://doi.org/10.1016/j.redox.2025.103839
  83. CNS Neurosci Ther. 2025 Sep;31(9): e70571
    Reorganization of Mitochondrial Function and Architecture in Response to Plant-Derived Alkaloids: Anatabine, Anabasine, and Nicotine, Investigated in SH-SY5Y Cells and in a Cellular Model of Parkinson's Disease.
    Dominika Malińska, Karolina Drabik, Bernadeta Michalska, Jarosław Walczak, Małgorzata Partyka, Monika Prill, Jędrzej Szymański, Paulina Patalas-Krawczyk, Karolina Piecyk, Jerzy Duszyński, Mariusz R Więckowski, Joanna Szczepanowska.
       AIMS: Nicotine, anatabine, and anabasine are the most prevalent alkaloids in Nicotiana species. While nicotine is the main addictive ingredient in tobacco products, it was also shown to have neuroprotective properties. Mitochondria appear to be one of the targets of nicotine in the cell. These multifunctional organelles are also the first responders to various cellular stresses. Thus, we characterized the impact of tobacco alkaloids on these organelles.
    METHODS: We investigated the effects of structurally similar alkaloids, anatabine, anabasine, and nicotine, on mitochondrial function in SH-SY5Y neuroblastoma cells under basal conditions and in the presence of rotenone, a mitochondrial stressor commonly used to model the cellular pathology underlying Parkinson's disease.
    RESULTS: We observed changes in mitochondrial behavior, including hyperpolarization, alterations in mitochondrial network morphology, increased mitochondrial turnover rates, and upregulation of mitochondrial biogenesis regulators. The profiles of changes induced by particular alkaloids slightly differed; however, they shared many features with the stress response observed upon treatment with rotenone. Interestingly, the effects of the alkaloids and rotenone were not additive. Moreover, some parameters altered by rotenone were normalized upon cotreatment with the alkaloids.
    CONCLUSIONS: The results indicate that the investigated alkaloids stimulate mitochondrial stress adaptation. Despite structural similarity, they act through slightly different mechanisms.
    Keywords:  anabasine; anatabine; mitochondria; mitochondrial remodeling; nicotine
    DOI:  https://doi.org/10.1111/cns.70571
  84. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2502483122
    Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
    Haowen Jiang, Sarah Jane Tiche, Clifford Jiajun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert M Li, Anh T Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J Svensson, Daniel J Cuthbertson, Florette K Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.
      Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
    Keywords:  differentiation; mitochondria; neuroblastoma; retinoic acid; uncoupler
    DOI:  https://doi.org/10.1073/pnas.2502483122
  85. Front Cell Neurosci. 2025 ;19 1623747
    SFXN2 contributes mitochondrial dysfunction-induced apoptosis as a substrate of Parkin.
    Shishi Luo, Yechuan He, Yaohui He, Danling Wang.
       Introduction: Mitochondria, situated at the center of intricate signaling networks, play crucial roles in maintaining health and driving disease progression. SFXN2, a recently identified member of the mitochondrial transporter family, is localized to the outer mitochondrial membrane and regulates several critical mitochondrial functions, including iron metabolism, heme biosynthesis, bioenergetics, and redox homeostasis. New evidence also suggests a connection between SFXN2 and mitochondrial dysfunction related human diseases such as Parkinson's disease (PD). Despite growing insights into SFXN2's roles across various mitochondrial functions, its regulation under mitochondrial dysfunction and the resulting biological consequences remains unclear.
    Methods: The expression levels of SFXN2 protein were analyzed by Western blotting WB. The interaction between SFXN2 and Parkin was examined using co-immunoprecipitation and immunofluorescence assays. Furthermore, the effect of Parkin on SFXN2 ubiquitination was assessed via ubiquitination assay. Finally, RNA sequencing and flow cytometry were employed to investigate that SFXN2 regulates the apoptotic pathway.
    Results: In this study, we identify SFXN2 as a key regulator of mitochondrial homeostasis, demonstrating that its level is tightly regulated via Parkin-mediated ubiquitination and proteasomal degradation. Under conditions of mitochondrial damage, Parkin enhances the degradation of SFXN2, and the reduction of SFXN2 contributes to apoptotic cell death. Functional studies across multiple cell lines, including HEK293, SH-SY5Y, and N2a cells, reveal that the reduction of SFXN2 exacerbates mitochondrial damage-induced apoptosis, whereas overexpression of SFXN2 exhibits an anti apoptotic effect.
    Discussion: Our findings offer new insights into the regulation of SFXN2 in mitochondrial dysfunction through Parkin mediated ubiquitin proteasome system activity, underscoring SFXN2's potential implications in nerodegenerative diseases, particularly PD.
    Keywords:  Parkin; SFXN2; apoptosis; mitochondrial dysfunction; ubiquitination
    DOI:  https://doi.org/10.3389/fncel.2025.1623747
  86. Adv Sci (Weinh). 2025 Aug 29. e08161
    Targeting ROCK2 to Restore Epileptic Synaptic Networks via Mitophagy Activation: Insights from Translational Imaging of SV2A In Vivo.
    Ling Xiao, Jing Wang, Bei Chen, Jinhui Yang, Fangyu Wu, Chunyao Zhou, Yifei Zhang, Zhiquan Yang, Dingyang Liu, Lei Tian, Jianhua Yu, Fei Han, Yongxiang Tang, Li Feng, Shuo Hu.
      Temporal lobe epilepsy (TLE) is increasingly recognized as a network-level disorder, with contemporary strategies shifting focus from localized epileptic lesions to targeting dysfunctional epileptogenic networks. Leveraging recent advancements in neuroimaging genetics and the growing understanding of brain network remodeling in epilepsy, partial least squares regression is employed to integrate the altered synaptic connectome in TLE patients with a human transcriptomics dataset. The findings reveal a strong association between disruptions in synaptic density similarity networks and the spatial transcriptional profiles of TLE risk genes, identifying Rho-associated protein kinase 2 (ROCK2) as a pivotal gene. In TLE mouse models, treatment with a ROCK2-specific inhibitor mitigates synaptic and neuronal loss, enhances network efficiency within the synaptic density connectome, and significantly reduces seizure frequency. Additionally, transcriptome profiling identifies multiple autophagy-related pathways, and electron microscopy verifies that the administration of the ROCK2 inhibitor restores mitochondrial autophagy and reduces the accumulation of damaged mitochondria. These findings suggest that ROCK2 inhibitors may modulate synaptic networks and mitochondrial dysfunction, offering promising therapeutic potential for the treatment of TLE. This study provides novel insights into the genetic and molecular mechanisms driving epileptic network dysfunction and highlights ROCK2 as a compelling target for translational epilepsy research.
    Keywords:  PET; ROCK2; SV2A; [18F]SynVesT‐1; epilepsy; imaging transcriptomics
    DOI:  https://doi.org/10.1002/advs.202508161
  87. Commun Biol. 2025 Aug 29. 8(1): 1308
    TRIM2 inhibits apoptosis by ubiquitinating BNIP3 to protect the intestine against ischemia-reperfusion injury in mice.
    Jinping Nie, Chao Mei, Aiping Wei, Yingjie Wang, Chenlu Fan, Yingjie Huang, Ming Jiang, Han Che, Tao Chen, Juan Tian, Yong Li, Xuan Huang, Xuekang Zhang.
      Intestinal damage following interrupted blood flow and its return (intestinal ischemia/reperfusion injury) is a serious medical problem occurring in various clinical situations. While the death of intestinal epithelial cells is a key factor, the precise reasons behind this cell death are not fully known. In this study, we identified significant downregulation of an E3 ubiquitin ligase TRIM2 in mouse models of this injury and in cells mimicking the condition. Genetic deletion of TRIM2 promotes intestinal apoptosis and worsens injury severity in studies using only male mice. We discovered that TRIM2 directly interacts with the pro-apoptotic protein Bcl2-interacting protein 3 (BNIP3) and mediates K48-linked polyubiquitination of BNIP3 at lysine 130 (K130), leading to its proteasomal degradation. Mutation of BNIP3 at K130 to arginine (K130R) abolished TRIM2-mediated ubiquitination, increased BNIP3 stability, and led to increased cell death after oxygen deprivation and restoration (hypoxia/reoxygenation). Increasing BNIP3 levels counteract the protective effect of boosting TRIM2 in intestinal epithelial cells, while lowering BNIP3 mimics the protection seen with more TRIM2. Therefore, TRIM2 protects against intestinal injury by inhibiting apoptosis through the ubiquitination and degradation of BNIP3. Targeting this TRIM2-BNIP3 axis offers possibilities for developing future treatments for intestinal ischemia/reperfusion injury.
    DOI:  https://doi.org/10.1038/s42003-025-08708-2
  88. Stroke. 2025 Sep 02.
    MFN2 and BAG6 Synergistically Protect Against Cerebral Reperfusion Injury by Regulating ROS Levels and Autophagic Flux.
    Dongting Lu, Yukun Yang, Guodong Huang, Qinlian Ye, Xingyun Quan, Britta Kaltwasser, Yanfen Liu, Dirk M Hermann, Ulf Brockmeier, Ya-Chao Wang.
       BACKGROUND: MFN2 (mitofusin-2), a transmembrane dynamin-like protein located on the outer mitochondrial membrane, plays a key role in regulating mitochondrial fusion and autophagy. In vitro studies suggested that MFN2 may exert neuroprotective effects postischemia. In gain-of-function and loss-of-function experiments, we investigated MFN2's roles in regulating neuronal ischemia/reperfusion injury in vivo and in vitro.
    METHODS: MFN2 was knocked down by neuron-specific conditional knockout or siRNA-mediated knockdown and overexpressed by adeno-associated viral vectors or plasmid vectors in C57BL/6 mice of both sexes (10-12 weeks) exposed to middle cerebral artery occlusion and SY5Y cells exposed to oxygen-glucose deprivation/reoxygenation. Neurological deficits were examined using a 48-point score and rotarod tests. Infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining. A RealTime Apoptosis and Necrosis Assay was used to measure apoptotic and necrotic cell death. Reactive oxygen species (ROS) formation and autophagic flux were analyzed by functional assays. Protein expression and interaction were evaluated using Western blots, immunoaffinity chromatography, mass spectrometry, and immunoprecipitation analysis. To assess the role of MFN2's interaction partner BAG6, BAG6 was overexpressed in middle cerebral artery occlusion mice and overexpressed or knocked down in SY5Y cells.
    RESULTS: Neuron-specific MFN2 deletion exacerbated cerebral ischemia/reperfusion injury, while MFN2 overexpression reduced it. MFN2 deficiency elevated mitochondrial ROS levels and inhibited autophagy, whereas MFN2 overexpression decreased ROS levels. In immunoprecipitation studies, we found a direct interaction between MFN2 and BAG6. Of note, BAG6 overexpression mimicked the effect of MFN2 overexpression on cerebral ischemia/reperfusion injury. Combined MFN2 and BAG6 overexpression synergistically reduced ischemia/reperfusion injury by drastically decreasing cerebral ROS levels, stabilizing mitochondrial function, and modulating autophagy.
    CONCLUSIONS: Our study suggests that MFN2 enhances stroke outcome through 2 pathways: by decreasing ROS levels and modulating autophagy via interaction with BAG6. BAG6 potentiates the ROS-lowering, cytoprotective MFN2 actions. The MFN2-BAG6 axis represents a promising target for stroke therapy.
    Keywords:  autophagy; glucose; infarction, middle cerebral artery; ischemic stroke; triphenyltetrazolium
    DOI:  https://doi.org/10.1161/STROKEAHA.125.052689
  89. Res Sq. 2025 Aug 18. pii: rs.3.rs-3136613. [Epub ahead of print]
    Mitochondrial protein import stress augments α-synuclein aggregation and neural damage independent of bioenergetics.
    Xin Jie Chen, Liam Coyne, Arnav Rana, Xiaowen Wang, Sanaea Bhagwagar, Yumiko Umino, Eduardo Solessio, Frank Middleton.
      Genetic and environmental factors are known to converge on mitochondria to cause Parkinson's disease (PD). However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we show that mild mitochondrial protein import stress augments neural damage independent of bioenergetics. We induce protein import stress in a mouse model of PD expressing α-synuclein(A53T). The double mutant mice demonstrate increased size of α-synuclein aggregates, increased aggregation of mitochondrial preproteins, heightened neuroinflammation and worsened motor defect relative to α-synuclein(A53T) single mutants. Importantly, we found no evidence of bioenergetic defects in any of the mutant mice. These data suggest that mitochondrial protein import stress, which can be induced by many types of mitochondrial injuries, can contribute to neural damage through cytosolic proteostatic stress and possible co-aggregation of mitochondrial and neuropathogenic proteins independent of bioenergetics.
    DOI:  https://doi.org/10.21203/rs.3.rs-3136613/v1
  90. Biomed Pharmacother. 2025 Aug 28. pii: S0753-3322(25)00684-5. [Epub ahead of print]191 118490
    Trastuzumab cardiotoxicity and drug cardioprotection in healthy and cardiac dysfunction mouse models.
    Serena L'Abbate, Matilde Masini, Giuseppina Nicolini, Sabrina Marchetti, Francesca Forini, Iacopo Fabiani, Giuseppe Vergaro, Vincenzo De Tata, Michele Emdin, Claudia Kusmic.
      Pre-existing cardiovascular disease is a recognised risk factor for cardiotoxicity in HER2-targeted therapies such as trastuzumab (TRZ), but few studies have addressed the impact of TRZ and the effects of cardioprotective drugs in pre-existing cardiac issues. This study examines the impact of TRZ-induced cardiotoxicity in pre-existing cardiac conditions and the effects of captopril and bisoprolol in mouse models with varying degrees of cardiac impairment. Adult mice models with and without baseline cardiac dysfunction ̶ healthy mice (WT), transgenic mice with cardiac hyperaldosteronism (AS) and mice with cardiac dysfunction (AS+ISO) ̶ were randomised to receive placebo, TRZ alone (6 mg/kg/week for 4 weeks), or TRZ administered concomitantly with a cardioprotective therapy based on captopril (ACEi, 20 mg/kg) and bisoprolol (BB, 5 mg/kg) (TRZ+ACEi/BB). Cardiac function was assessed one week after the final injection of TRZ, followed by myocardial tissue histopathological and ultrastructural assessments, and expression of genes associated with cardiomyocyte survival and mitochondrial homeostasis. TRZ reduced systolic function by approximately 10 % in each of the 3 populations studied, causing cellular and mitochondrial damage, regardless of pre-existing cardiac issues. The most severe effects were observed in mice with prior cardiac impairment linked to increased baseline frailty. Cardioprotective therapy improved LV systolic function in all groups to a similar degree. It also reversed the cellular and mitochondrial adverse changes, as well as the altered transcriptional signature caused by TRZ. Our findings demonstrate that the combined ACEi/BB therapy may prevent cardiac TRZ-related toxicity in mouse models with and without baseline cardiac dysfunction.
    Keywords:  Anti-cancer therapy; Bisoprolol; Captopril; Left ventricular systolic dysfunction; Mitochondrial homeostasis; Mouse model
    DOI:  https://doi.org/10.1016/j.biopha.2025.118490
  91. J Mol Cell Biol. 2025 Sep 04. pii: mjaf030. [Epub ahead of print]
    AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming.
    Hanmin Wang, Guanzhen Wang, Tao Yin, Hao Li, Hanlin Wang, Yikai Shao, Yuanyuan Li, Rong Hua, Jia Li, Yi Zang.
      The activation of hepatic stellate cells (HSCs), characterized by transdifferentiation from a quiescent state to a fibrogenic phenotype, is a core process of liver fibrosis. The metabolic reprogramming of HSCs plays a major role in this process to meet the high energy demands of myofibroblastic HSCs with multiple functions, such as extracellular matrix synthesis, migration, and proliferation. AMP-activated protein kinase (AMPK) is a gatekeeper of intracellular energy homeostasis, but its role in the activation of HSCs and the progression of liver fibrosis remains unclear. Here, we found that the phosphorylation of AMPK in HSCs was upregulated in liver tissues from metabolic dysfunction-associated steatohepatitis patients and from mice treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL). HSC-specific deletion of two catalytic α-subunits of AMPK attenuated liver fibrosis in the CCl4 or BDL mouse model. In vitro analysis demonstrated that AMPK promoted HSC activation when challenged with various profibrogenic stimuli. The activation of AMPKα-deficient HSCs was impaired due to the decreased mitochondrial oxidative phosphorylation but restored after treatment with the mitophagy inducer rapamycin. Mechanistically, both the AMPK-ULK1 and AMPK-Raptor pathways contribute to the maintenance of the mitophagy pathway and mitochondrial quality. These findings provide direct evidence of the crucial role of AMPK-mitophagy signaling in ensuring mitochondrial health and sufficient energy supply during HSC activation. In this study, AMPK was modulated in HSCs prior to activation, which is distinguished from previous investigations and thus provides new insights into the role of AMPK during distinct phases of HSC activation.
    Keywords:  AMP-activated protein kinase (AMPK); hepatic stellate cells; liver fibrosis; mitochondria; mitophagy
    DOI:  https://doi.org/10.1093/jmcb/mjaf030
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