bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–07–06
68 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Diethylhexyl phthalate exposure promotes mitophagy through Drp1-mediated mitochondrial fission in neural crest cells of chick embryos.
  2. Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.
  3. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  4. SHMT2 overexpression improves glaucoma by enhancing mitophagy in retinal ganglion cells through promoting the phospho of PINK1.
  5. Role of mitochondrial dynamics in mouse preimplantation embryonic development and its molecular mechanisms.
  6. Protective Effect of Lycopene on Ifosfamide-Induced Mitophagy through Pink, Parkin, and LC3-I/II Pathway in Testicular Tissue.
  7. Targeting SIRT3 to regulate mitophagy-dependent ferroptosis for preventing glucocorticoid-induced osteoporosis.
  8. CDK12 Inactivation Attenuates Prostate Cancer Progression by Inhibiting BNIP3-Mediated Mitophagy.
  9. The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
  10. L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice.
  11. CaM promotes cardiomyocyte mitophagy in myocardial ischemia-reperfusion injury involving in the regulation of the IP3R3-GRP75-VDAC1 complex.
  12. Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy.
  13. ATF7-PINK1 Axis Governs Mitophagy and Intestinal Inflammation in Ulcerative Colitis.
  14. TRPV1 Inhibits Ferroptosis and Mitophagy to Alleviate Heart Failure by Activating SFXN2.
  15. Study on the regulation of gastric cancer cell apoptosis by LACTB through mitochondrial autophagy pathway.
  16. L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy.
  17. C/EBP-α Promotes Mitochondrial Fission and Inhibits the Activation of Hepatic Stellate Cells via YAP-Drp1 Pathway.
  18. Circadian gene BMAL1 ameliorates renal ischaemia-reperfusion injury in diabetic mice by enhancing mitophagy via the HIF-1/BNIP3 pathway.
  19. RAB7 protects against ischemic heart failure via promoting non-canonical TUFM mitophagy pathway.
  20. Transcription factor EB improves hypoxic pulmonary hypertension in fetal rats by suppressing NLRP3 inflammasome activation via induction of mitophagy.
  21. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
  22. Decrease in Mitochondrial Oxidative Respiratory Function in Liver of Cricetulus barabensis Under Long and Short Photoperiods: The Role of Mitochondrial Fission and Apoptosis.
  23. Prolonged sepsis triggers abnormal mitochondrial dynamics in the limb muscles and diaphragm.
  24. The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.
  25. A constricted mitochondrial morphology formed during respiration.
  26. Ubp2 modulates DJ-1-mediated redox-dependent mitochondrial dynamics in Saccharomyces cerevisiae.
  27. Aryl hydrocarbon receptor (AhR) alleviates the LPS-induced inflammatory responses in IPEC-J2 cells by activating PINK1/Parkin-mediated mitophagy.
  28. Pink1/Parkin Mediated Mitophagy - Friend or Foe in Hypoxia-induced Pulmonary Vascular Remodeling?
  29. Narciclasine mitigates sepsis-induced cardiac dysfunction by enhancing BNIP3-mediated mitophagy and suppressing ferroptosis.
  30. Identification of mitophagy-related biomarkers with immune cell infiltration in psoriasis.
  31. Mitophagy: A key regulator in the pathophysiology and treatment of spinal cord injury.
  32. TFIIB-related factor 2 inhibits lung squamous carcinoma cell apoptosis through SLC8A3-mediated mitochondrial homeostasis.
  33. CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release.
  34. Treatment with mitochondrial targeting antibiotics improves survival outcomes after Flock House virus infection in young and aged Drosophila melanogaster.
  35. Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
  36. Dynorphin B induces mitochondrial fragmentation in NSCLC through the PKD/DRP-1 signaling pathway.
  37. Increased eosinophils after oral corticosteroid treatment for asthma exacerbation correlated with longer ER stays and persisting thymic stromal lymphopoietin and increased Park2.
  38. Effects of echinacoside on the regulation of mitochondrial fission induced by TBK1/Drp1 in rheumatoid arthritis.
  39. Cancer stem cells: mitochondria signalling pathway and strategies for therapeutic interventions.
  40. [Icariside Ⅱ Inhibits Hepatitis B Virus and Modulates Mitochondrial Fission in vitro].
  41. Corrigendum to "Evaluation of GFM1 mutations pathogenicity through in silico tools, RNA sequencing and mitophagy pathway in GFM1 knockout cells" [Int. J. Biol. Macromol. Volume 304, Part 2, April 2025, 140970].
  42. Identification of mitophagy-related genes with diagnostic value in acute rejection following kidney transplantation using bioinformatics analysis.
  43. Cross-talk between mitophagy pathways in pre-eclampsia and gestational diabetes mellitus: a systematic analysis of shared molecular mechanisms.
  44. Modulating mitochondrial dynamics in CMT2A: a multifaceted platform for drug discovery and evaluation.
  45. Exogenous SPD inhibits trastuzumab-mediated cardiomyocyte pyroptosis through SIRT3-regulated mitochondrial quality control.
  46. FL3 mitigates cardiac ischemia-reperfusion injury by promoting mitochondrial fusion to restore calcium homeostasis.
  47. Small extracellular vesicles derived from mesenchymal stromal cells loaded with β-nicotinamide mononucleotide activate NAD+/SIRT3 signaling pathway-mediated mitochondrial autophagy to delay skin aging.
  48. Mechanistic Interactions Driving Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration: A Multi-Axial Perspective of Mechanical, Immune, and Metabolic Pathways.
  49. CD81 Aggravates Ovarian Cancer Progression via p-Cresyl Sulfate-Mediated Mitophagy in Tim4+ Tumour-Associated Macrophages.
  50. Mitochondrial transcription factor a as a guardian of mitochondrial integrity and emerging therapeutic target in human diseases: A review.
  51. Naringin alleviates fluoride-induced neurodevelopmental disorders by modulation of SIRT1, autophagy, mitochondrial fission, and ROS generation.
  52. Mechanistic Study of the Novel Peroxidase Mimetic DhHP-6 in Metabolic Cataracts.
  53. The NLRP3 Mediates Masticatory Muscle Atrophy by Pyroptosis and Mitophagy.
  54. Phosphorylation of the fission protein Drp1 contributes to the impact of the curcuminoid 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one on mitochondrial and cellular processes.
  55. BNIP3 induced by hypoxia supports the survival of mesenchymal stromal cells (MSCs) after intravenous cell transplantation.
  56. Deficits in mitochondrial dynamics and iron balance result in templated insertions.
  57. Gpbar1-mediated SIRT1-PGC-1α axis maintains mitochondrial homeostasis and mitigates renal injury in obstructive jaundice.
  58. Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
  59. You are what you eat: autophagy guides CD8+ T cell function through metabolism.
  60. RHOA-dependent regulation of mitochondrial remodeling and cell motility in hypoxia-exposed gastric epithelial cells.
  61. Alterations of Mitophagy (BNIP3), Apoptosis (CASP3), and Autophagy (BECN1) Genes in the Frontal Cortex in an Ischemic Model of Alzheimer's Disease with Long-Term Survival.
  62. Mitochondrial metabolic regulation of macrophage polarization in osteomyelitis and other orthopedic disorders: mechanisms and therapeutic opportunities.
  63. A novel isoquinoline mitophagy inducer ameliorates paclitaxel-induced peripheral neuropathy in Drosophila and mouse models.
  64. The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
  65. HSV-1 hijacks mitochondrial dynamics: potential molecular mechanisms linking viral infection to neurodegenerative disorders.
  66. The novel amino-artemisinin derivative WHN-11 disrupts mitochondria and protein homeostasis, and induces autophagy and apoptosis in cancer cells.
  67. Exploring novel protective role of semaglutide in 5-fluorouracil-induced hepatotoxicity: Insights into phosphorylated CREB, PINK1/Parkin-mediated mitophagy, and NF-κB/NLRP3 pathways.
  68. Powering Up the Brain: Intercellular Mitochondrial Quality Control and Its Implication in Stroke.
  1. Poult Sci. 2025 Jun 26. pii: S0032-5791(25)00735-7. [Epub ahead of print]104(9): 105491
    Diethylhexyl phthalate exposure promotes mitophagy through Drp1-mediated mitochondrial fission in neural crest cells of chick embryos.
    Yi Li, Fan Yang, Chenghong Xing, Penghui Liu, Yike Zhang, Caiying Zhang, Jirong Chen, Huabin Cao, Xueyan Dai.
      Di(2-ethylhexyl) phthalate (DEHP) has been used commonly in industrial production and has endocrine disrupting ability. DEHP has potential adverse effects on the development of fetal programming, but the toxic effects and mechanism study in neural crest cells is not enough understood. To investigate DEHP's effects on neural tube closure injury, the chicken embryos and primary cranial neural crest (CNC) cells model of DEHP-treatment was established. Here, we show that the development of neural tube is disrupted by DEHP, which causes an observed decrease in levels of HNK1 and Pax7 and increase in levels of adhesion molecules and extracellular matrix. This led to inhibit the migration and epithelial-mesenchymal transition (EMT) mechanism in neural crest cells, which cause dysraphism in chicken embryos. Furthermore, DEHP exposure also disrupts mitochondrial function accompanied by the elevation of Drp1 and FIS1 level, and the decrease of MFN1, MFN2, and OPA1 level, causing excessive mitochondrial fragmentation, mitophagy and apoptosis, eventually decreasing the MMP levels and ATP concentration in chicken embryos. Conversely, the addition of Drp1 inhibitor dramatically alleviate the mitochondrial fragmentation and mitophagy induced by DEHP in primary CNC cells. Our results reveal the mechanism of DEHP-induced mitophagy in neural crest cells was regulated by excessive activation of Drp1-mediated mitochondrial fission. These findings deepen the research of reproductive toxicology of DEHP and guide its application in different areas, especially in the agricultural field.
    Keywords:  Di(2-ethylhexyl) phthalate; Drp1; Embryotoxicity; Mitochondrial fission; Mitophagy
    DOI:  https://doi.org/10.1016/j.psj.2025.105491
  2. Int J Biol Sci. 2025 ;21(9): 4252-4269
    Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.
    Zhiwei Xu, Xiangzheng Gao, Dade Rong, Jingyao Wang, Liangliang Gao, Mingzhu Tang, Yiguan Chen, Yichi Zhang, Liming Xie, Liming Wang, Guang Lu, Jia-Hong Lu, Wei Liu, Han-Ming Shen.
      Mitophagy is a selective form of autophagy for the clearance of damaged and dysfunctional mitochondria via the autophagy-lysosome pathway. As mitochondria are the most important metabolic organelles, the process of mitophagy is tightly regulated by glucose metabolism. At present, it is known that glucose is required for the mitophagy process, while the underlying mechanisms remain to be further elucidated. In this study, we establish a novel regulatory role of glucose metabolism in mitophagy via protein O-GlcNAcylation. First, we found that acute mitochondrial damage enhanced glucose uptake and promoted protein O-GlcNAcylation. Second, we provided evidence that protein O-GlcNAcylation promotes PINK1-Parkin-dependent mitophagy. Next, we attempted to illustrate the molecular mechanisms underlying the regulation of O-GlcNAcylation in mitophagy by focusing on PTEN-induced kinase 1 (PINK1). One important observation is that PINK1 is O-GlcNAcylated upon acute mitochondrial damage, and suppression of O-GlcNAcylation impairs PINK1 protein stability and its phosphorylated ubiquitin, leading to impaired mitophagy. More importantly, we found that glucose metabolism promotes mitophagy via regulating O-GlcNAcylation. Taken together, this study demonstrates a novel regulatory mechanism connecting glucose metabolism with mitophagy via O-GlcNAcylation of PINK1. Therefore, targeting the O-GlcNAcylation may provide new strategies for the modulation of mitophagy and mitophagy-related human diseases.
    Keywords:  HBP; O-GlcNAcylation; PINK1; glucose metabolism; mitophagy
    DOI:  https://doi.org/10.7150/ijbs.112672
  3. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  4. Diagn Pathol. 2025 Jul 02. 20(1): 79
    SHMT2 overexpression improves glaucoma by enhancing mitophagy in retinal ganglion cells through promoting the phospho of PINK1.
    Liying Cui, Baojun Wang.
       BACKGROUND: Glaucoma is a major eye disease that causes blindness. The loss of retinal ganglion cells (RGCs) due to mitophagy impairment is a key driver of glaucoma. SHMT2 depletion leads to an increase in reactive oxygen species (ROS), but its role in regulating mitophagy remains unclear. This study aims to investigate the mechanism by which SHMT2 contributes to glaucoma through the regulation of RGC mitophagy.
    METHODS: The role of SHMT2 in glaucoma was evaluated through hematoxylin and eosin (H&E) staining and immunofluorescence (IF) staining of acute ocular hypertension (AOH) mouse eyeballs. Mitophagy was assessed by measuring LDH release, apoptosis, mitochondrial membrane potential, lipid ROS, and the protein levels of mitophagy-related proteins in RGCs. The underlying mechanism was investigated using co-immunoprecipitation, IF staining, and Western blot analysis.
    RESULTS: Results showed that SHMT2 expression was decreased in the AOH mouse model. NMDA inhibited mitophagy in RGCs, which was restored by SHMT2 overexpression. Moreover, SHMT2 overexpression stabilized PINK1 expression by enhancing the phosphorylation of PINK1. In vivo experiments suggested that SHMT2 overexpression increased the thickness of the retinal ganglion cell-inner plexiform layer.
    CONCLUSION: This study confirmed that SHMT2 overexpression alleviated glaucoma by enhancing mitophagy in RGCs through the upregulation of PINK1 phosphorylation, suggesting that SHMT2 may serve as a potential therapeutic target for glaucoma.
    Keywords:  Glaucoma; Mitophagy; PINK1; Retinal ganglion cells; SHMT2
    DOI:  https://doi.org/10.1186/s13000-025-01675-6
  5. Sci Rep. 2025 Jul 01. 15(1): 21751
    Role of mitochondrial dynamics in mouse preimplantation embryonic development and its molecular mechanisms.
    Xiaoyan Sun, Qingyang Li, Bo Chen.
      This study investigated the impact of mitochondrial dynamics on mouse preimplantation embryonic development and its underlying molecular mechanisms. Using pharmacological and genetic approaches, we demonstrated that balanced mitochondrial fusion and fission are essential for optimal embryonic development. Disruption of mitochondrial dynamics significantly impaired blastocyst formation, altered cell lineage allocation, and compromised energy metabolism. Our findings revealed that mitochondrial dynamics regulate gene expression through epigenetic modifications and influence cell survival through the modulation of apoptotic pathways. We also identified key metabolic intermediates and signaling pathways that mediate the effects of mitochondrial dynamics on embryonic development. These results provide new insights into the molecular mechanisms linking mitochondrial function to early embryonic development and suggest potential strategies for improving assisted reproductive technologies.
    Keywords:  Apoptosis; Cell fate; Energy metabolism; Epigenetic modification; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mouse embryo; Preimplantation embryonic development; Reproductive biology
    DOI:  https://doi.org/10.1038/s41598-025-05622-9
  6. Int J Fertil Steril. 2025 May 14. pii: 719395. [Epub ahead of print]19(3): 319-325
    Protective Effect of Lycopene on Ifosfamide-Induced Mitophagy through Pink, Parkin, and LC3-I/II Pathway in Testicular Tissue.
    Ali Thoulfikar A Imeer, Moona Roshanfekr Rad, Sara Abedi.
       BACKGROUND: Ifosfamide (IFO) is a widely used chemotherapeutic agent that exerts cytotoxic effects through various mechanisms, including the induction of apoptosis and oxidative stress. However, its use is associated with detrimental effects on male reproductive health, including mitochondrial dysfunction and oxidative stress-induced damage. Mitophagy, a selective autophagic process, plays a crucial role in maintaining mitochondrial homeostasis during spermatogenesis. This study aimed to investigate the potential protective effect of lycopene against IFO-induced mitophagy in testicular tissue. We evaluated the expression levels of key mitophagy regulators Pink1, Parkin, and LC3-I/ II in testicular tissue of rats treated with IFO alone or in combination with lycopene.
    MATERIALS AND METHODS: In this experimental study, 24 mature male Wistar rats (250 g ± 25) were divided into control (received normal saline), IFO-sole (received 250 mg/kg, single dose, ip), lycopene (25 mg/kg, orally), and IFO+lycopene groups. Following 60 days, the rats were euthanized and the testicles were dissected out. The expression levels of Pink1, Parkin, and LC3-I/II were evaluated using qRT-PCR and immunohistochemistry (IHC) techniques.
    RESULTS: Our findings demonstrated that IFO significantly upregulated Pink1, Parkin,, and LC3-I/II expression at both mRNA and protein levels compared to controls. Conversely, lycopene administration mitigated these increases induced by IFO, suggesting its potential to attenuate IFO-induced mitophagy. Immunohistochemistry analysis confirmed the protective effect of lycopene, showing reduced expression levels of Pink1, Parkin,, and LC3-I/II in the presence of lycopene following IFO treatment.
    CONCLUSION: These results underscore lycopene's role as a potent protective agent that can mitigate IFO-induced mitophagy in testicular tissue. Further research into the underlying mechanisms of lycopene's protective effects will be crucial for developing therapeutic strategies to preserve male fertility during IFO treatment.
    Keywords:  Ifosfamide; Lycopene; Mitophagy; Testicles
    DOI:  https://doi.org/10.22074/ijfs.2024.2036627.1740
  7. Int J Surg. 2025 Jul 02.
    Targeting SIRT3 to regulate mitophagy-dependent ferroptosis for preventing glucocorticoid-induced osteoporosis.
    Yunhao Hu, Hongduo Lu, Hanjun Fang, Benlu Chen, Zhiwen Chen, Mengyu Jiang, Yuehui Zhou, Ziyuan Li, Shihua Gao, Zeqing Huang, Chi Zhou, Yuhao Liu, Zhenqiu Chen, Yinuo Fan.
       BACKGROUND: Compelling evidence has implicated osteoblast ferroptosis as a critical contributor to the pathogenesis of (GIOP), However, the underlying regulatory mechanisms remain poorly understood.
    METHODS: In the glucocorticoids (GCs)-induced GIOP rat model, both osteoblast dysfunction and ferroptosis markers were assessed. Ferroptosis was inhibited with deferoxamine (DFO). Transcriptomic profiling was performed to analyze the correlation between mitophagy and SIRT3 levels. In MC3T3-E1 cells exposed to GCs, we examined key mitophagy markers PINK1 and PARKIN, mitochondrial function, and SIRT3 expression. Treatments included DFO, mitophagy inhibitors (Mdivi-1), and SIRT3 agonists (Nicotinamide riboside chloride).
    RESULTS: In the GIOP rat model, significant osteoblast dysfunction and elevated ferroptosis markers were observed. Although DFO treatment inhibited ferroptosis, it failed to restore osteogenesis, suggesting the involvement of additional regulatory mechanisms in osteogenic function regulation. Transcriptomic profiling highlighted a robust correlation between mitophagy and SIRT3 levels in glucocorticoid-induced osteoporosis (GIOP). In GC-exposed MC3T3-E1 cells, key mitophagy markers PINK1 and PARKIN were upregulated, mitochondrial function was impaired, and SIRT3 expression was significantly reduced. Notably, while DFO treatment did not restore mitochondrial homeostasis, the application of Mdivi-1 (mitophagy inhibitor) and Nicotinamide riboside chloride (SIRT3 agonists) effectively alleviated ferroptosis and restored mitochondrial function.
    CONCLUSIONS: SIRT3 regulates ferroptosis by inhibiting excessive mitophagy in osteoblasts, providing a novel mechanistic pathway for mitigating GIOP. These findings suggest that SIRT3 represents a critical regulator of mitophagy-dependent ferroptosis and a potential therapeutic target for GIOP.
    Keywords:  SIRT3; ferroptosis; glucocorticoid-induced osteoporosis; mitophagy
    DOI:  https://doi.org/10.1097/JS9.0000000000002783
  8. Cell Prolif. 2025 Jul 02. e70091
    CDK12 Inactivation Attenuates Prostate Cancer Progression by Inhibiting BNIP3-Mediated Mitophagy.
    Mengjun Huang, Hanqi Lei, Tongyu Tong, Hailin Zou, Binyuan Yan, Fei Cao, Yiting Wang, Qiliang Teng, Bin Xu, Juan Luo, Yupeng Guan, Shaohong Lai, Peng Li, Jun Pang.
      Mitochondrial stress-induced mitophagy plays a critical role to maintain cellular homeostasis; however, in cancer cells, this process may also contribute to drug resistance. Our previous work identified CDK12 as a critical regulator of prostate cancer (PCa) cell survival under sustained enzalutamide exposure, though the precise mechanism remains to be elucidated. In this study, we hypothesize that CDK12 plays a key role in mitophagy regulation under mitochondrial stress, potentially modulating PCa cell resistance to enzalutamide, the first-line clinical medication in PCa therapy. Utilising multiple in vitro PCa cell models, we demonstrate that both CDK12 knockdown and pharmacological inhibition with THZ531 impaired mitophagy following treatment with enzalutamide and mitophagy inducer CCCP. Mechanistically, our finding reveal that CDK12 inhibition disrupts FOXO3-induced BNIP3 transcription, thereby preventing receptor-mediated mitophagy and sensitising PCa cells to enzalutamide. This study identifies the CDK12-FOXO3-BNIP3 pathway as a novel regulatory mechanism governing mitophagy under mitochondrial stress. Importantly, these results underscore CDK12's role in preserving mitochondrial function and promoting PCa cell survival during enzalutamide treatment. These findings highlight the therapeutic potential of targeting the CDK12-BNIP3-mitophagy axis in combination with antiandrogen therapies, offering a promising strategy to overcome drug resistance in PCa and improve clinical outcomes.
    Keywords:  BNIP3; CDK12; enzalutamide treatment; mitophagy; prostate cancer
    DOI:  https://doi.org/10.1111/cpr.70091
  9. Nat Commun. 2025 Jul 01. 16(1): 5996
    The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
    Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, Ruteja A Barve, John A Collins, Makarand V Risbud.
      Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age-dependent disc degeneration, osteoarthritis, and vertebral osteopenia. RNA-Sequencing of Opa1cKO NP tissue revealed dysregulation of metabolism, autophagy, cytoskeletal reorganization, and extracellular matrix and shared strong thematic similarities with a subset of human degenerative NP samples. Our findings underscore that maintenance of mitochondrial dynamics and multi-organelle cross-talk is critical in preserving metabolic homeostasis of disc and cartilage.
    DOI:  https://doi.org/10.1038/s41467-025-60933-9
  10. Brain Dev. 2025 Jul 01. pii: S0387-7604(25)00070-1. [Epub ahead of print]47(4): 104388
    L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice.
    Junxia Li, Wenjuan Wu, Guang Ji, Hui Dong, Hongran Wu, Xueqin Song.
       BACKGROUND: This study investigates mitophagy in Duchenne muscular dystrophy (DMD, OMIM #310200), focusing on how nitric oxide synthase (NOS) inhibition improves muscle tissue pathology by affecting mitophagy, which is implicated in muscle weakness due to dystrophin deficiency and may affect DMD-related cardiomyopathy and respiratory problems.
    METHODS: Histopathological analysis, immunofluorescence staining, Western blot were used to study the mitophagy status of the tibialis anterior muscle in mdx mice without treatment or mdx mice administered L-NAME (L-NG-nitro arginine methylester), an inhibitor of NOS. For in vitro experiment, the effect of S-nitrosylation enzyme, N6022, on mitophagy in C2C12 cells was assessed using TEM (transmission electron microscopy), and Western blot.
    RESULTS: Mdx mice showed dystrophic muscle pathology and elevated LC3 (microtubule-mssociated protein 1 light chain) and VDAC (voltage-dependent anion channel) expression, indicating increased mitophagy. Reduced PINK1 (PTEN-induced putative kinase 1) and PARKIN (E3 ubiquitin ligase PARK2) levels suggested incomplete mitochondrial clearance. L-NAME treatment improved muscle morphology and reduced necrosis, partially restoring mitophagy by increasing LC3 without matching VDAC upregulation. However, PINK1 and PARKIN were further reduced, suggesting mitophagic inefficiency. In C2C12 cells, GSNOR(S-nitrosoglutathione reductase) inhibition via N6022 elevated nitrosylation, impaired mitophagy, and caused mitochondrial accumulation with increased PINK1 but unchanged PARKIN, highlighting a critical role of nitrosylation balance in mitophagy regulation.
    CONCLUSIONS: NOS inhibition may serve as a key point for further research on the progression of DMD disease and as a potential therapeutic target for this incurable disease.
    Keywords:  Duchenne muscular dystrophy; GSNOR; L-NAME; Mitophagy; PINK1-PARKIN pathway; S-nitrosylation
    DOI:  https://doi.org/10.1016/j.braindev.2025.104388
  11. Sci Rep. 2025 Jul 01. 15(1): 22379
    CaM promotes cardiomyocyte mitophagy in myocardial ischemia-reperfusion injury involving in the regulation of the IP3R3-GRP75-VDAC1 complex.
    Bi-Ying Liu, Zhao-Hui Dai, Li Mao, Ling-Zhi Guo, Zhong-Bao Yang.
      The pathogenesis of myocardial ischemia-reperfusion injury (MIRI) is not fully clear. This study aims to investigate the role of mitochondrial-associated endoplasmic reticulum membrane (MAM)-related calcium overload in mitophagy. In vitro and in vivo models were established to simulate MIRI. Cellular injury, apoptosis and mitophagy were measured and gene expression was analysized. The expression levels of glucose-regulated protein 75 (GRP75), receptor for inositol 1,4,5-trisphosphate (IP3R3), voltage-dependent anion-selective channel 1 (VDAC1), and calmodulin (CaM) and the mitochondrial calcium content, mitophagy and apoptosis were significantly increased in MIRI or hypoxia/reoxygenation (H/R) cells when compared to controls, but the mitochondrial membrane potential and ATP significantly decreased. GRP75 knockdown significantly inhibited CaM expression, mitochondrial calcium overload and mitophagy of H9C2 cells, whereas had no significant effect on IP3R3 and VDAC1 expression. CaM knockdown had no significant effect on the expression of GRP75, IP3R3 and VDAC1, and on mitochondrial calcium concentration, ATP levels and mitochondrial membrane potential of H9C2 cells, but significantly inhibited mitophagy and apoptosis. Collectively, these data suggest that the IP3R3-GRP75-VDAC1/CaM axis plays an important role in mitochondrial autophagy injury during myocardial ischemia-reperfusion and that it is a potential target for MIRI treatment.
    Keywords:  CaM; IP3R3-GRP75-VDAC1 complex; Mitochondrial calcium overload; Mitophagy; Myocardial ischemia reperfusion injury (MIRI)
    DOI:  https://doi.org/10.1038/s41598-025-07977-5
  12. Sci Rep. 2025 Jul 01. 15(1): 22207
    Homocysteine promotes cardiomyocyte hypertrophy through inhibiting β-catenin/ FUNDC1 mediated mitophagy.
    Yanping Lei, Hengjing Hu, Huifang Tang, Hui Sun, Rui Liu, Yue Zhao.
      Homocysteine can cause damage to cardiomyocytes. However, Mitophagy is essential for preserving homeostasis in cardiomyocytes. So, we focused on investigating the impact of homocysteine on cardiomyocyte mitophagy and cardiac hypertrophy through the β-catenin/FUNDC1 pathway. Mice were administered water containing homocysteine (1.8 g/L) to induce hyperhomocysteinemia for 4 weeks. The overexpression of specific genes, including β-catenin and FUNDC1, were performed by gene delivery mediated with adeno-associated virus. In vitro, cardiomyocytes were exposed to homocysteine (1 mmol/L) and then transfected with plasmids to overexpress β-catenin and FUNDC1, respectively. The duration of cell experiments was 48 h. Western blotting was employed to assess the expression levels of β-catenin, active β-catenin, FUNDC1, LC3, p62, α-actin, and β-MHC. Immunohistochemistry and immunofluorescence techniques were applied to measure β-catenin and FUNDC1 in cardiomyocytes. Cell viability was assessed using a CCK-8 assay kit, and mitophagy was observed under transmission electron microscopy. The interaction between β-catenin protein and the promoter of the FUNDC1 gene was examined using ChIP assay and dual-luciferase reporter gene assay. Homocysteine inhibited β-catenin signaling and the FUNDC1-mediated mitophagy in the cardiomyocytes, simultaneously promoting cardiac hypertrophy in vitro and in vivo. Elevated β-catenin signaling promoted FUNDC1 expression, then restored the normal level of mitophagy, and consequently inhibited homocysteine-induced cardiac hypertrophy. Similarly, overexpression of FUNDC1 restored mitophagy and protected cardiomyocytes from hypertrophy. In addition, FUNDC1 served as a target gene of β-catenin. In summary, homocysteine induces cardiomyocyte hypertrophy by inhibiting β-catenin signaling and suppressing FUNDC1-mediated mitophagy.
    Keywords:  Cardiomyocyte hypertrophy; FUNDC1; Homocysteine; Mitophagy; β-catenin
    DOI:  https://doi.org/10.1038/s41598-025-06772-6
  13. FASEB J. 2025 Jul 15. 39(13): e70792
    ATF7-PINK1 Axis Governs Mitophagy and Intestinal Inflammation in Ulcerative Colitis.
    Yidong Chen, Xiaopeng Zhang, Junrong Li, Fang Liu, Qi Yu, Jiamin Li, Liangru Zhu.
      Ulcerative colitis (UC), a chronic inflammatory bowel disease, is marked by sustained inflammation and excessive apoptosis of intestinal epithelial cells (IECs). Despite progress in understanding UC pathogenesis, the role of activating transcription factors (ATFs) in disease progression remains elusive. Here, we profile the expression of ATF family members (ATF1-ATF7) in the colonic mucosa of UC patients and identify ATF7 as a critical regulator of mitophagy through its control of PTEN-induced kinase 1 (PINK1). Expression levels of ATF1-ATF7 were quantified in colonic mucosal samples from UC patients (n = 219) and healthy controls (n = 105) via quantitative PCR. Using IEC-specific ATF7 knockout mouse models and human CCD 841 CoN colonic epithelial cells, we employed ChIP-seq, dual-luciferase assays, transmission electron microscopy, and immunofluorescence to elucidate their roles in mitophagy and disease progression. Clinical correlation between ATF7 expression and disease severity was assessed using the Mayo score. ATF7 expression was significantly reduced in UC patients and inversely correlated with disease severity. Mechanistically, ATF7 was identified as a direct transcriptional activator of PINK1, a key mitophagy regulator. Loss of ATF7 or PINK1 disrupted mitophagy, exacerbating mitochondrial dysfunction, IEC apoptosis, and colonic inflammation in vivo and in vitro. Our findings uncover a pivotal ATF7-PINK1 axis that governs mitophagy and limits UC progression. The inverse correlation between ATF7 expression and UC severity highlights its potential as a therapeutic target, offering new avenues for intervention in this debilitating disease.
    Keywords:  ATF7; PINK1; mitophagy; ulcerative colitis
    DOI:  https://doi.org/10.1096/fj.202500813R
  14. Front Biosci (Landmark Ed). 2025 Jun 25. 30(6): 37052
    TRPV1 Inhibits Ferroptosis and Mitophagy to Alleviate Heart Failure by Activating SFXN2.
    Pan Liu, Shiguang Wang, Liya Li, Ruihua Li, Minming Fan, Jingjing Kong, Bing Gao, Jing Wang, Ran Xia.
       BACKGROUND: Heart failure (HF) continues to represent a significant global public health concern. Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a calcium-permeable channel that has been linked to cardiac disease and function. However, its significance in HF and underlying processes is unknown. This study aims to determine the regulatory role of TRPV1 in mitochondrial autophagy in HF.
    METHODS: AC16 cardiomyocytes were exposed to angiotensin II (Ang II) to simulate pathological conditions, and changes in oxidative stress were assessed. Transverse aortic constriction (TAC) was used to create a pressure overload-induced HF mouse model, and cardiac-specific TRPV1 overexpression was achieved by Adeno-associated virus 9 (AAV9). RNA sequencing and bioinformatics analysis were performed to identify TRPV1-related mitochondrial genes. Finally, the effects of TRPV1 overexpression and sideroflexin 2 (SFXN2) knockdown on markers related to mitophagy and ferroptosis were analyzed.
    RESULTS: In vitro, TRPV1 overexpression drastically decreased intracellular Ca2+ levels, lessened oxidative stress, and reduced Ang II-induced cell death (p < 0.05). Bioinformatics analysis identified seven mitochondrial genes associated with TRPV1, among which SFXN2 showed a strong correlation with TRPV1 (p < 0.05). Overexpressing cardiac-specific TRPV1 in the TAC model led to improved cardiac function, higher fractional shortening and ejection fraction, and reduced levels of mitophagy markers (p < 0.05). Mechanistically, TRPV1 activated SFXN2, increasing glutathione peroxidase 4 (GPX4) expression and antioxidant capacity (glutathione (GSH), superoxide dismutase (SOD)) while decreasing malondialdehyde (MDA) and ferrous iron (Fe2+) levels (p < 0.05). These protective effects were removed by SFXN2 knockdown. Furthermore, the TRPV1-SFXN2 axis suppressed mitophagy by modulating the PTEN-induced kinase 1 (PINK1)-Parkin-sequestosome 1 (SQSTM1) axis.
    CONCLUSION: Our results show that TRPV1 overexpression alleviates Ang II-induced myocardial injury in HF. This protective effect is mediated through SFXN2-dependent mitophagy and ferroptosis, highlighting TRPV1 as a potential therapeutic target for HF.
    Keywords:  SFXN2; TRPV1; ferroptosis; heart failure; mitophagy
    DOI:  https://doi.org/10.31083/FBL37052
  15. Sci Rep. 2025 Jul 02. 15(1): 23273
    Study on the regulation of gastric cancer cell apoptosis by LACTB through mitochondrial autophagy pathway.
    Wei Nie, Lihua Hu, Zhiqiang Yan, Qian Wang, Shui He, Xiaoqiang Gao, Fang Yang.
      This study aimed to determine whether β-lactamase-like protein (Lactamase-β, LACTB) influences apoptosis in gastric cancer cells by modulating mitochondrial autophagy through the PTEN-induced putative kinase 1 (PINK1) or Parkin pathway. Firstly, the expression level of LACTB in gastric cancer tissues was detected by immunohistochemistry, and the survival data of patients were used to explore the relationship between LACTB expression level and patient prognosis. Secondly, LACTB overexpression (+ LACTB) and knockdown (sh-LACTB) AGS gastric cancer cell lines were constructed; flow cytometry and other experiments were used to detect the effect of LACTB on AGS cell apoptosis; Western Blot was used to detect the expression of PINK1/Parkin mitochondrial autophagy pathway-related proteins and lysosome-related proteins in + LACTB and sh-LACTB gastric cancer cells; kits and electron microscopy were used to detect changes in the number of reactive oxygen species (ROS) and autophagosomes. Finally, Western blot was used to detect the expression of apoptotic proteins Bcl-2 associated x protein (Bax) and B-cell lymphoma-2 (Bcl-2) in + LACTB and sh-LACTB gastric cancer cells treated with mitochondrial autophagy inhibitor 3-methyladenine (3-MA). Immunohistochemistry analysis revealed that LACTB expression in gastric cancer tissues was higher than in adjacent non-cancerous tissues, for patients with tumor diameters exceeding 4.5 cm, high LACTB expression was associated with a poor prognosis (P < 0.05). LACTB overexpression reduced apoptosis in gastric cancer cells. It downregulated the pro-apoptotic protein Bax, while LACTB knockdown promoted apoptosis, upregulated Bax, the expression of pro-apoptotic protein Bax, and downregulated the expression of anti-apoptotic protein Bcl-2. In LACTB overexpressing cell lines, protein sequestosome 1 (P62) protein levels were elevated, lysosomal-associated membrane protein 2 (LAMP2) expression was decreased, Reactive oxygen species (ROS) levels remained significantly stable, and autophagosome counts were reduced. Conversely, LACTB knockdown cells, PINK1, Parkin, protein light chain 3II/I (LC3II/I), LAMP2, cathepsin B (CTSB), continuous traumatic stress disorder (CTSD), and other related proteins, downregulated P62 expression, increased ROS accumulation, and higher number of autophagosomes. In LV-LACTB and sh-LACTB gastric cancer cells treated with the mitochondrial autophagy inhibitor 3-methyladenine (3-MA), apoptotic protein Bax is downregulated, and anti-apoptotic protein Bcl-2 is upregulated. In summary, the LACTB protein may regulate the apoptosis in gastric cancer cells by modulating mitochondrial autophagy through the PINK1/Parkin pathway.
    Keywords:  Apoptosis; Gastric cancer; Mitophagy; PINK1/Parkin pathway; β-lactamase-like protein
    DOI:  https://doi.org/10.1038/s41598-025-06047-0
  16. Mol Med. 2025 Jun 30. 31(1): 250
    L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy.
    Ying Sun, Lingli Cai, Bowei Yu, Haojie Zhang, Ziteng Zhang, Xiaoqin Xu, Yuefeng Yu, Jiang Li, Chi Chen, Fangzhen Xia, Yingli Lu, Kun Zhang, Ningjian Wang.
       BACKGROUND: L-Phenylalanine (L-Phe) levels are elevated in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether L-Phe induces liver steatosis and the underlying mechanism remain unknown. This study aimed to investigate the mechanism through which L-Phe promotes liver steatosis.
    METHODS: We utilized human data from the UK Biobank and SPECT-China studies. Plasma/serum samples were collected for metabolomic testing to measure L-Phe levels. A rat model with L-Phe in the drinking water was established to investigate changes in hepatic lipid metabolism. In addition, BNIP3 was overexpressed both in vitro and in vivo to validate the role of L-Phe in BNIP3-mediated mitophagy associated with liver steatosis.
    RESULTS: In both populations, elevated L-Phe quartiles were associated with increased body mass index, triglyceride, and transaminase levels and increased odds of MASLD (all p < 0.05). Rats exposed to L-Phe had increased hepatic lipid deposition and decreased mitophagy in the liver. Differentially expressed proteins were enriched in the PPARα and fatty acid β-oxidation signalling pathways, with downregulation of the mitophagy marker BNIP3. Mitophagy was activated by rapamycin and then inhibited by L-Phe, indicating that elevated L-Phe promoted lipid accumulation by suppressing mitophagy. BNIP3 overexpression effectively mitigated L-Phe-induced hepatic steatosis by restoring mitophagy. Moreover, L-Phe regulates the BNIP3-mediated PPARα and AMPK/mTOR signalling pathways to promote hepatic steatosis.
    CONCLUSIONS: Our study revealed the role of L-Phe in regulating lipid metabolism and promoting liver steatosis via BNIP3-mediated mitophagy. These findings provide novel insights into the link between L-Phe and liver steatosis, suggesting potential nutritional intervention strategies for preventing MASLD.
    Keywords:  BNIP3; L-Phenylalanine; Liver steatosis; Mitophagy
    DOI:  https://doi.org/10.1186/s10020-025-01303-5
  17. Cell Biol Int. 2025 Jul 03.
    C/EBP-α Promotes Mitochondrial Fission and Inhibits the Activation of Hepatic Stellate Cells via YAP-Drp1 Pathway.
    Chenjian Hou, Yajun Yan, Ying Su, Meili Wang, Ju Yang, Xiaoli Liu, Xuefeng Zhai, Yuxiang Wang, Xiuping Liu.
      The activation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. However, the activation of HSCs requires energy from mitochondria-highly dynamic organelles. In our previous studies, we have confirmed that CCAAT/enhancer binding protein α (C/EBP-α) can inhibit the activation of HSCs, but whether it can affect the activation of HSCs by regulating mitochondrial dynamics is still unclear. In this study, we characterized the roles and mechanisms of C/EBP-α-mediated mitochondrial fission in regulating HSCs activation. We found that C/EBP-α upregulates Drp1 expression through inhibiting YAP expression, thus promoting mitochondrial fission and suppressing the activation of HSCs. In addition, in the HSCs with C/EBP-α overexpression, the epistatic roles of YAP and Drp1 in regulating mitochondrial biology and HSCs activation were interrogated with their respective inhibitors/agonists. Thus, we propose that mitochondrial fission plays an important role in the activation of HSCs and fibrosis that is regulated by a C/EBP-α-YAP-Drp1 axis.
    Keywords:  C/EBP‐α; YAP; activation; hepatic stellate cells; mitochondrial fission
    DOI:  https://doi.org/10.1002/cbin.70058
  18. Sci Rep. 2025 Jul 02. 15(1): 23001
    Circadian gene BMAL1 ameliorates renal ischaemia-reperfusion injury in diabetic mice by enhancing mitophagy via the HIF-1/BNIP3 pathway.
    Xinqi Deng, Yan Leng, Yonghong Xiong, Wenyuan Li, Wu Chen, Yuhang Yang, Bihan Wang, Siyuan Gong, Yunhao Wang, Baichuan Yang, Wei Li.
      Diabetic kidneys are particularly vulnerable to ischemia/reperfusion injury (I/RI). Although previous research has suggested that the circadian gene brain and muscle ARNT-like 1 (BMAL1) plays a role in regulating renal function, the exact functions and mechanisms of BMAL1 in diabetic renal I/RI remain elusive. In this study, bilateral renal artery ligation and release were performed in non-diabetic (db/+) and diabetic (db/db) mice. In diabetic kidneys, experimental findings demonstrated a significant decrease in BMAL1 expression, along with the inhibition of the HIF-1α/BNIP3 signaling pathway and compromised mitophagy. BMAL1 overexpression alleviated cell damage and apoptosis under high glucose and hypoxia/reoxygenation stimulation. Inhibition of the Hypoxia-inducible factor-1α (HIF-1α)/ B-cell lymphoma-2 interacting protein 3 (BNIP3) pathway by the HIF-1α inhibitor PX-478 intensified cellular damage and reduced the protective effect of BMAL1 overexpression in TCMK-1 cells. These results indicate that BMAL1 regulates mitophagy in diabetic renal I/RI through the HIF-1α/BNIP3 pathway, providing valuable insights for the development of targeted therapies for diabetic renal I/RI.
    Keywords:  BMAL1; Diabetes; HIF-1α; Ischemia/reperfusion injury; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-025-03515-5
  19. Theranostics. 2025 ;15(14): 6753-6767
    RAB7 protects against ischemic heart failure via promoting non-canonical TUFM mitophagy pathway.
    Yuling Sun, Wei Wang, Mingyan Li, Wen Guan, Zhimin Gao, Luping Wang, Guanlan Lou, Ao Shen, Jiangbin Wu, Xiyong Yu, Panxia Wang, Xiaoqian Wu.
      Rationale: Cardiomyocyte apoptosis critically contributes to ischemic heart failure (IHF) progression. While the endosome-lysosome system governs cellular homeostasis, the functional significance of its master regulator RAB7 in cardiac pathophysiology remains unexplored. Methods: Using myocardial infarction (MI) models via left anterior descending coronary artery ligation in cardiomyocyte-specific RAB7 knockout mice and adeno-associated virus-mediated RAB7 overexpression models, we assessed cardiac function and adverse remodeling through echocardiography and pathophysiological assessment. Mitophagy flux was quantified using mt-Keima mice and confocal imaging. Molecular mechanisms were dissected through immunoprecipitation coupled with mass spectrometry (IP-MS) analysis and molecular experiment validation. Results: RAB7 expression decreased in ischemic myocardium. Cardiomyocyte-specific RAB7 ablation exacerbated while RAB7 overexpression attenuated post-MI cardiac dysfunction and maladaptive remodeling. RAB7 enhanced mitophagic clearance of damaged mitochondria, reducing cardiomyocyte apoptosis under ischemic stress both in vitro and in vivo. Mechanistically, TUFM, a mitochondrial translation elongation factor, was identified as a novel effector of RAB7. RAB7 facilitated the recruitment of TUFM and LC3 to damaged mitochondria, thereby enhancing mitophagy. TUFM knockdown significantly diminished the protective effects of RAB7 on mitophagy and cardiomyocyte survival. Finally, administration of ML-098, a chemical RAB7 activator, promoted mitophagy and mitigated IHF progression in mice. Conclusion: We identify RAB7 as a novel coordinator of cardioprotective mitophagy through TUFM-mediated machinery assembly. The RAB7-TUFM axis represents a therapeutic target for IHF that warrants further clinical evaluation.
    Keywords:  RAB7; TUFM; mitophagy; myocardial infarction
    DOI:  https://doi.org/10.7150/thno.104124
  20. Sci Rep. 2025 Jul 02. 15(1): 20356
    Transcription factor EB improves hypoxic pulmonary hypertension in fetal rats by suppressing NLRP3 inflammasome activation via induction of mitophagy.
    Chaohong Chen, Zaoye Xie, Dang Ao, Yinhui Chen, Ling Liu, Chengyan Li.
      Persistent pulmonary hypertension of the newborn (PPHN) represents a life-threatening cardiopulmonary condition characterized by hypoxia-driven pulmonary vascular remodeling. While transcription factor EB (TFEB), a master regulator of cellular adaptation to hypoxia, has been implicated in vascular pathologies, its mechanistic role in PPHN remains undefined. This study elucidates the molecular interplay of TFEB in hypoxia-induced PPHN pathogenesis. Fetal rat models of hypoxia-induced PPHN, including untreated hypoxic models and hypoxic models treated with the TFEB inhibitor Eltrombopag (EO), as well as a hypoxia-induced human pulmonary artery endothelial cell (HPAEC) model, were established. Multimodal assessments, including histopathology, qRT-PCR, JC-1 staining, immunofluorescence, flow cytometry, and Western blotting, were employed to evaluate the effects of TFEB on mitophagy and NLRP3 inflammasome. In the hypoxia group, significant thickening of the pulmonary arterioles and right ventricular wall was observed. Immunostaining revealed a significant increase in the relative staining density of TFEB-positive, NLRP3-positive, and LC3-positive cells, alongside elevated expression of mitophagy-proteins and NLRP3 inflammasome-related proteins. TFEB inhibition downregulated the expression of PINK1, TOMM20, COX IV, P62, and LC3II/I ratio, impairing mitophagy, while upregulating eNOS, NLRP3, and GSDMD, thereby enhancing NLRP3 activation and pyroptosis. In the EO group, fetal rats exhibited more pronounced pulmonary arteriole thickening, intensified fluorescence signals for NLRP3, caspase-1, and GSDMD, reduced mitophagy-related protein expression, and further elevated NLRP3 inflammasome-related protein and GSDMD expression. TFEB exerts a protective effect in PPHN by inhibiting NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy, highlighting TFEB's potential as a therapeutic target for hypoxia-induced PPHN.
    Keywords:  Hypoxic pulmonary hypertension; Mitophagy; NLRP3 inflammasome; PINK1/Parkin; Transcription factor EB
    DOI:  https://doi.org/10.1038/s41598-025-07068-5
  21. J Clin Invest. 2025 Jul 01. pii: e185000. [Epub ahead of print]135(13):
    Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
    Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph T Bass, Tamas L Horvath.
      Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide-expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
    Keywords:  Behavior; Cell biology; Metabolism; Mitochondria; Neuroscience; Synapses
    DOI:  https://doi.org/10.1172/JCI185000
  22. Clin Exp Pharmacol Physiol. 2025 Aug;52(8): e70054
    Decrease in Mitochondrial Oxidative Respiratory Function in Liver of Cricetulus barabensis Under Long and Short Photoperiods: The Role of Mitochondrial Fission and Apoptosis.
    Jin-Hui Xu, Lu-Fan Li, Yi-Man Liu, Xin-Yi Song, Le Chen, Ming-Di Wang, Li-Na Jiang, Zhe Wang.
      The photoperiod is a crucial factor affecting the seasonal rhythms of mammals. Under the seasonal rhythms, the growth and development of the body are closely related to the oxidative respiratory function of mitochondria, but the influence of the single seasonal factor photoperiod on it remains unclear. In this study, mitochondrial dynamics and associated regulatory mechanisms were investigated in the livers of striped dwarf hamsters (Cricetulus barabensis) exposed to three distinct photoperiod regimes: short photoperiod (SP), moderate photoperiod (MP) and long photoperiod (LP). Results indicated that: (1) Liver mass responses to photoperiod varied with changes in body weight. (2) ATP synthase activity was significantly decreased under LP, whereas citrate synthase activity (CS) was selectively diminished under SP. (3) The Bcl2 associated X protein (bax) to b cell lymphoma 2 (bcl2) ratio increased under both SP and LP. (4) Dynamin-related protein 1 (DRP1) protein abundance increased under both LP and SP conditions, while mitochondrial fission factor (MFF) decreased under LP, signifying divergent remodelling of mitochondrial fission signalling. (5) Caspase3 activity unchanged under SP. In conclusion, under LP and SP treatment, the oxidative respiratory function of liver mitochondria in striped dwarf hamsters may be weakened, potentially due to increased mitochondrial membrane permeability, as indicated by an elevated bax/bcl2 ratio. Compared to long photoperiod treatment, the upregulation of the liver mitochondrial fission signalling and the lower level of apoptosis under short photoperiod conditions may help facilitate thermogenic adaptation to increased energetic demands in winter.
    Keywords:   Cricetulus barabensis ; apoptosis; liver; mitochondria; photoperiod
    DOI:  https://doi.org/10.1111/1440-1681.70054
  23. Mol Cell Biochem. 2025 Jul 01.
    Prolonged sepsis triggers abnormal mitochondrial dynamics in the limb muscles and diaphragm.
    Chao Xiong, Fasheng Guan, Jianguo Feng, Jing Jia, Jumei Zhang, Rui Tu, Jie Li, Jun Zhou, Jianglin Wang, Li Liu.
      Mitochondrial dysfunction is considered as a major trigger of sepsis-induced intensive care unit-acquired weakness (ICU-AW), but the precise role of impaired mitochondrial dynamics in sepsis-induced ICU-AW remains unclear. The cecal ligation and puncture (CLP) model was used to induce sepsis in mice. Fluid resuscitation and antibiotic treatment were used to establish a 5-day duration sepsis model, with sham-operated animals serving as controls. The muscle function of the diaphragm (DM) and tibialis anterior (TA) was assessed individually. Transmission electron microscopy (TEM) was used to observe changes in mitochondrial ultrastructure and measure the morphological parameters. Western blot analysis and quantitative real-time polymerase chain reaction were used to examine the expression of mitochondrial fusion and fission proteins and genes in DM and TA muscles. Additionally, inflammation and apoptosis were assessed in these muscles by measuring the level of pro-inflammatory cytokines and apoptotic DNA degradation, respectively. Mice subjected to CLP developed severe sepsis. Limb muscle dysfunction was more severe than that of the DM, as indicated by a greater reductions in compound muscle action potential, strength, fatigue index, and muscle fiber cross-sectional area. TEM analysis revealed sepsis-induced intermyofibrillar mitochondrial fragmentation and accumulation of injury. Both muscles showed reduced levels of Opa1 and Mfn2 mRNA and protein, and increased levels of Fis1 mRNA and protein. Correlation analysis revealed significant associations between muscle strength and Opa1, Mfn2, and Opa1/Drp1 at 5 days post-sepsis. Surviving mice at 5 days showed persistent inflammation, injury, and apoptosis in both muscles, but were more pronounced in the TA muscle. Prolonged sepsis leads to an impairment in mitochondrial dynamics, resulting in skeletal muscle weakness and atrophy, which may be one of the possible mechanisms of sepsis-induced ICU-AW.
    Keywords:  Chronic critical illness; Intensive care unit-acquired weakness; Mitochondrial dynamics; Sepsis; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11010-025-05338-4
  24. Cell Death Dis. 2025 Jul 05. 16(1): 494
    The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.
    Katlynn J Emaus, Garrett M Fogo, Joseph M Wider, Thomas H Sanderson.
      Stroke and cardiac arrest claim the lives of millions worldwide each year emphasizing the importance of understanding this injury cascade. These pathologies present as a 'two hit' injury termed ischemia/reperfusion (I/R) injury. The primary injury is the initial disruption of blood flow and ischemic state while the secondary injury, paradoxically, being the return of blood flow and oxygen availability. The injury caused by reperfusion presents a viable window for therapeutic intervention, stressing the importance of understanding this injury pathology. Constantly undergoing fission and fusion, mitochondria are dynamic organelles that play a vital role in maintaining cell health and are highly susceptible to I/R injury. Following I/R injury, disrupted mitochondrial dynamics and quality control ultimately lead to a dysfunctional mitochondrial network, energy depletion and eventually cell death. While mitochondrial dynamics and quality control have been studied extensively in the realm of I/R injuries, the role of mitochondrial lipids is emerging as an important component of injury progression. The inner mitochondrial membrane lipid, cardiolipin has been demonstrated to play an integral role in maintaining mitochondrial quality control, dynamics and energy production. In response to oxidative stress, cardiolipin has been shown to interact with several important proteins involved in mitochondrial dynamics while also contributing to integral signaling cascades. This review will highlight the role of cardiolipin in mitochondrial dynamics and quality control in response to neuronal I/R injury.
    DOI:  https://doi.org/10.1038/s41419-025-07786-8
  25. Nat Commun. 2025 Jul 01. 16(1): 5314
    A constricted mitochondrial morphology formed during respiration.
    Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  26. PLoS Genet. 2025 Jul 03. 21(7): e1011353
    Ubp2 modulates DJ-1-mediated redox-dependent mitochondrial dynamics in Saccharomyces cerevisiae.
    Sananda Biswas, Patrick D'Silva.
      Mitochondrial integrity is a crucial determinant of overall cellular health. Mitochondrial dysfunction and impediments in regulating organellar homeostasis contribute majorly to the pathophysiological manifestation of several neurological disorders. Mutations in human DJ-1 (PARK7) have been implicated in the deregulation of mitochondrial homeostasis, a critical cellular etiology observed in Parkinson's disease progression. DJ-1 is a multifunctional protein belonging to the DJ-1/ThiJ/PfpI superfamily, conserved across the phylogeny. Although the pathophysiological significance of DJ-1 has been well-established, the underlying molecular mechanism(s) by which DJ-1 paralogs modulate mitochondrial maintenance and other cellular processes remains elusive. Using Saccharomyces cerevisiae as the model organism, we unravel the intricate mechanism by which yeast DJ-1 paralogs (collectively called Hsp31 paralogs) modulate mitochondrial homeostasis. Our study establishes a genetic synthetic interaction between Ubp2, a cysteine-dependent deubiquitinase, and DJ-1 paralogs. In the absence of DJ-1 paralogs, mitochondria adapt to a highly tubular network due to enhanced expression of Fzo1. Intriguingly, the loss of Ubp2 restores the mitochondrial integrity in the DJ-1 deletion background by modulating the ubiquitination status of Fzo1. Besides, the loss of Ubp2 in the absence of DJ-1 restores mitochondrial respiration and functionality by regulating the mitophagic flux. Further, Ubp2 deletion makes cells resistant to oxidative stress without DJ-1 paralogs. For the first time, our study deciphers functional crosstalk between Ubp2 and DJ-1 in regulating mitochondrial homeostasis and cellular health.
    DOI:  https://doi.org/10.1371/journal.pgen.1011353
  27. Inflamm Res. 2025 Jun 30. 74(1): 98
    Aryl hydrocarbon receptor (AhR) alleviates the LPS-induced inflammatory responses in IPEC-J2 cells by activating PINK1/Parkin-mediated mitophagy.
    Mengfei Ma, Jianxun Guo, Xiaoying Su, Baocai Ma, Xiufen Wang, Mingyu Wangshao, Kai Zhong, Yueying Wang, Guoyu Yang, Yingqian Han.
       OBJECTIVE: This study investigates the role of the aryl hydrocarbon receptor (AhR) in lipopolysaccharide (LPS)-induced inflammatory responses in IPEC-J2 cells.
    METHODS: Inflammatory responses were triggered in IPEC-J2 cells using 5 μg/ml LPS. AhR was activated with tryptophan or FICZ and knocked down via RNA interference. PINK1/Parkin-mediated mitophagy was activated using CCCP and inhibited by PINK1 knockdown. Inflammatory mediators and pathway proteins were analyzed through ELISA, RT-qPCR, western blot, and immunofluorescence. Mitochondrial function was assessed by measuring ROS, ATP, and mitochondrial membrane potential. The interaction between AhR and PINK1 was examined using dual-luciferase reporter assays.
    RESULTS: The IDO1/AhR signaling axis was activated in LPS-stimulated IPEC-J2 cells. AhR activation was found to attenuate LPS-induced inflammatory responses, whereas AhR knockdown exacerbated these responses. Mechanistic investigations demonstrated that AhR activation alleviated LPS-induced mitochondrial damage. Activating PINK1/Parkin-mediated mitophagy successfully countered the increased inflammatory response in IPEC-J2 cells after AhR knockdown. Moreover, blocking PINK1 reversed the anti-inflammatory effects of FICZ. Dual-luciferase reporter assays revealed that AhR acts as a crucial transcription factor by directly binding to the promoter region, thereby initiating PINK1 transcription.
    CONCLUSIONS: AhR reduces LPS-induced inflammatory response in IPEC-J2 cells by activating PINK1/Parkin-mediated mitophagy, with AhR directly engaging the PINK1 promoter to enhance its transcription. Targeting AhR may present a novel strategy for the prevention and management of Escherichia coli-induced diarrhea in piglets.
    Keywords:  Aryl hydrocarbon receptor; IPEC-J2 cell; Inflammatory response; Lipopolysaccharide; PINK1/Parkin-mediated mitophagy
    DOI:  https://doi.org/10.1007/s00011-025-02063-y
  28. Am J Respir Cell Mol Biol. 2025 Jun 30.
    Pink1/Parkin Mediated Mitophagy - Friend or Foe in Hypoxia-induced Pulmonary Vascular Remodeling?
    Oleg Pak, Natascha Sommer.
      
    DOI:  https://doi.org/10.1165/rcmb.2025-0272ED
  29. Free Radic Biol Med. 2025 Jun 26. pii: S0891-5849(25)00800-7. [Epub ahead of print]238 220-234
    Narciclasine mitigates sepsis-induced cardiac dysfunction by enhancing BNIP3-mediated mitophagy and suppressing ferroptosis.
    Rong Tang, Minghe Jiang, Xiao Tang, Shengkui Chen, Hao Xu, Yudan Pan, Bifu Lin, Xiawei Wei, Qile Ye, Minsheng Wu, Pingping Qi.
      Sepsis-induced myocardial dysfunction (SIMD) remains a major contributor to sepsis-related mortality, driven by overwhelming inflammation, oxidative damage and impaired mitochondrial quality control. Narciclasine (Narc), a plant-derived diterpenoid, has demonstrated antioxidant and anti-inflammatory properties in various disease models. Here, we investigated whether Narc attenuates SIMD by inhibiting ferroptosis and promoting mitophagy. In both lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) mouse models, prophylactic administration of Narc markedly improved 72-h survival and restored left ventricular ejection fraction (LVEF), fractional shortening (FS) and cardiac output in a dose-dependent manner. Biochemical assays revealed that SIMD hearts displayed iron overload, lipid peroxidation (elevated malondialdehyde) and glutathione depletion-hallmarks of ferroptosis-while Narc treatment replenished glutathione, reduced malondialdehyde levels, downregulated transferrin receptor (TFRC) and upregulated GPX4 and HO-1 expression. In neonatal rat cardiomyocytes challenged with LPS or the ferroptosis inducer erastin, Narc dose-dependently preserved cell viability, inhibited lipid peroxidation (BODIPY-C11 staining) and maintained intracellular glutathione. Concurrently, Narc ameliorated mitochondrial dysfunction: Seahorse analysis showed enhanced basal and maximal respiration, JC-1 staining demonstrated stabilized membrane potential, and immunofluorescence confirmed increased PINK1/PARK2 recruitment and LC3-ATP5B colocalization, indicating BNIP3-dependent mitophagy. Network pharmacology and molecular docking identified BNIP3 as a central target; siRNA-mediated BNIP3 knockdown abolished Narc's anti-ferroptotic and pro-mitophagic effects in vitro, and AAV9-driven BNIP3 silencing negated its survival and functional benefits in vivo. Together, these data establish that Narc mitigates SIMD by suppressing ferroptosis and preserving mitochondrial integrity through BNIP3-mediated mitophagy. This dual mechanism highlights Narc as a promising candidate for therapeutic intervention in sepsis-related cardiac injury.
    Keywords:  BNIP3; Ferroptosis; Mitophagy; Narciclasine; Sepsis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.051
  30. BMC Med Genomics. 2025 Jul 01. 18(1): 110
    Identification of mitophagy-related biomarkers with immune cell infiltration in psoriasis.
    Shanshan Yu, Fangyuan Long, Hui Yan, Yongfang Xu, Jun Li, Zhimin Hao.
       BACKGROUND: Psoriasis is an inflammatory disorder characterized by scaly erythematous plaques and significant comorbidities. Recent studies have suggested that impaired mitophagy, the cellular mechanism for removing dysfunctional mitochondria, may contribute to the pathogenesis of psoriasis.
    METHODS: In this study, we analyzed bulk RNA sequencing data from 167 healthy individuals and 177 patients with psoriasis obtained from the Gene Expression Omnibus database (GSE30999 and GSE54456). Mitophagy-related genes were isolated using weighted gene co-expression network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed and protein-protein interaction networks were constructed for the functional enrichment of genes associated with mitophagy. The correlations between genes associated with mitophagy, signaling pathways, and immune cell infiltration were analyzed. The potential diagnostic value of genes associated with mitophagy was evaluated using receiver operating characteristic (ROC) curves, which were validated in imiquimod-induced psoriatic skin lesions in mice.
    RESULTS: We identified 3,839 differentially expressed genes between healthy individuals and patients with psoriasis, and 23 genes were selected as hub genes showing a high correlation with mitophagy in psoriasis. GO and KEGG analyses revealed that hub and associated genes were significantly correlated with skin functions, such as epidermal development and keratinocyte differentiation. In addition, mitophagy-related genes were negatively associated with pro-inflammatory and pro-proliferation pathways in psoriasis. Among the immune cells, CD4+ T cells were most significantly affected by mitophagy-related genes. ROC analysis demonstrated that mitophagy-related genes, especially ACER1, C1ORF68, CST6, FLG2, GJB3, GJB5, GPRIN2, KRT2, and SPRR4 were potential biomarkers of psoriasis for use in diagnosis or treatment.
    CONCLUSIONS: Mitophagy-related genes play crucial roles in psoriasis and have potential use as biomarkers, providing insights into disease mechanisms and therapeutic targets. Further research may lead to the development of new strategies for psoriasis management.
    Keywords:  Biomarkers; Gene expression analysis; Immune cell infiltration; Mitophagy; Psoriasis
    DOI:  https://doi.org/10.1186/s12920-025-02176-7
  31. Neural Regen Res. 2026 Apr 01. 21(4): 1396-1408
    Mitophagy: A key regulator in the pathophysiology and treatment of spinal cord injury.
    Qiuyang Gu, Shengye Yuan, Yumei An, Wenyue Sun, Mingyuan Xu, Mengchun Xue, Xianzhe Li, Chao Liu, Haiyan Shan, Mingyang Zhang.
      Mitophagy is closely associated with the pathogenesis of secondary spinal cord injury. Abnormal mitophagy may contribute significantly to secondary spinal cord injury, leading to the impaired production of adenosine triphosphate, ion imbalance, the excessive production of reactive oxygen species, neuroinflammation, and neuronal cell death. Therefore, maintaining an appropriate balance of mitophagy is crucial when treating spinal cord injury, as both excessive and insufficient mitophagy can impede recovery. In this review, we summarize the pathological changes associated with spinal cord injury, the mechanisms of mitophagy, and the direct and indirect relationships between mitophagy and spinal cord injury. We also consider therapeutic approaches that target mitophagy for the treatment of spinal cord injury, including ongoing clinical trials and other innovative therapies, such as use of stem cells, nanomaterials, and small molecule polymers. Finally, we highlight the current challenges facing this field and suggest potential directions for future research. The aim of our review is to provide a theoretical reference for future studies targeting mitophagy in the treatment of spinal cord injury.
    Keywords:  ATP production disorders; cell death; mitochondria; mitophagy; neuroinflammation; neuroprotection; oxidative stress; secondary injury; spinal cord injury; treatment
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01029
  32. Cell Death Dis. 2025 Jul 03. 16(1): 491
    TFIIB-related factor 2 inhibits lung squamous carcinoma cell apoptosis through SLC8A3-mediated mitochondrial homeostasis.
    Shen Yi, Xing Qi, Fei Luo, Dingxin Wang, Zitong Feng, Luyuan Ma, Wenhao Yu, Cong Wang, Hui Tian, Ming Lu.
      Lung cancer is the most common cancer and the leading cause of cancer-related deaths. Developing therapies for lung cancer is challenging, and new targets are urgently required. TFIIB-related factor 2 (BRF2) plays a crucial role in the development and progression of various tumors. However, the potential role of BRF2 in lung squamous carcinoma (LUSC) is unclear. Therefore, the aim of this study was to elucidate the mechanism of BRF2 regulation in LUSC development. Flow cytometry, protein blotting, and in vivo experiments were performed to assess the function of BRF2 in LUSC. Transmission electron microscopy imaging and mitochondrial membrane potential (MMP) measurements were used to determine the effect of BRF2 on mitochondria in LUSC. The impact of the downstream molecule SLC8A3 was predicted using bioinformatics analysis, and the mechanism was investigated by analyzing quantitative reverse transcription-polymerase chain reaction and immunoprecipitation (IP) assays, which were confirmed through rescue experiments. BRF2 expression was upregulated in squamous carcinoma cells, which increased SLC8A3 protein expression, promoted mitochondrial autophagy, stabilized MMP, and reduced apoptosis. In addition, SLC8A3 overexpression inhibited PTEN-induced putative kinase 1 (PINK1) binding to TIMM23 to promote mitochondrial autophagy and stabilize the MMP, which counteracted BRF2 knockdown-induced apoptosis. BRF2 mediated SLC8A3 expression to reduce apoptosis in LUSC cells by maintaining mitochondrial homeostasis. These findings provide novel selective therapeutic targets and ideas for the treatment of LUSC.
    DOI:  https://doi.org/10.1038/s41419-025-07813-8
  33. Acta Biochim Biophys Sin (Shanghai). 2025 Jul 02.
    CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release.
    Yajing Liu, Pengcheng Ye, Cijun Tang, Meiru Jiang, Yiru Shen, Xiangrui Wang, Lei Hou, Yupeng Zhao.
      Accumulating evidence suggests that NLRP3-mediated alveolar macrophage (AM) pyroptosis and subsequent high mobility group box protein 1 (HMGB1) secretion play significant roles in the pathogenesis of acute respiratory distress syndrome (ARDS). Nrf2 has been shown to be individually involved in regulating pyroptosis. In this study, we investigate the ability of CDDO-imidazolide, a potent Nrf2 activator, to regulate AM pyroptosis and HMGB1 secretion in sepsis-associated ARDS, along with its underlying mechanism. The in vitro alveolar macrophage (AM) pyroptosis model, established by stimulating J774A.1 cells with LPS and ATP, was treated with CDDO-imidazolide or utilized Nrf2-knockout cells. The mice are intraperitoneally administered with CDDO-imidazolide before the in vivo sepsis-associated ARDS model is constructed via caecal ligation perforation and the Nrf2 inhibitor, ML385. In vitro studies reveal that the use of 3-MA to prohibit PINK1/Parkin-dependent mitophagy aggravates NLRP3-mediated pyroptosis and HMGB1 release in J774A.1 cells via LPS and ATP exposure. CDDO-imidazolide also significantly prevents NLRP3-mediated pyroptosis and HMGB1 release to increase PINK1/Parkin-dependent mitophagy, but these effects are not detected in Nrf2-knockout macrophages. Most importantly, CDDO-imidazolide significantly alleviates NLRP3 inflammasome protein expression in the lung tissues of septic mice and HMGB1 protein levels in the serum and bronchoalveolar lavage fluid (BALF), which can be reversed by ML385. Taken together, our results demonstrate that CDDO-imidazolide prominently protects the lungs by promoting Nrf2 activation and enhancing PINK1/Parkin mitophagy to inhibit AM pyroptosis and HMGB1 release. These findings provide novel insights for therapeutic strategies for sepsis-associated ARDS.
    Keywords:  CDDO-imidazolide; HMGB1; Nrf2; mitophagy; pyroptosis
    DOI:  https://doi.org/10.3724/abbs.2025092
  34. Res Sq. 2025 Jun 10. pii: rs.3.rs-6816306. [Epub ahead of print]
    Treatment with mitochondrial targeting antibiotics improves survival outcomes after Flock House virus infection in young and aged Drosophila melanogaster.
    Dean Bunnell, Madelyn Buhl, Justin McGee, Grace Milas, Stanislava Chtarbanova.
      Aged organisms are more susceptible to infectious diseases, including infections with RNA viruses. Mitochondrial dysfunction is one of many hallmarks of aging that could affect this increased susceptibility, as the relationship between immunity and metabolism is crucial to manage infections. Using Drosophila melanogaster- Flock House virus (FHV) host-virus interactions model system, previous work has identified differences in young and aged flies' ability to modulate oxygen consumption rates (OCR). Here, we hypothesized that interventions that reduce OCR could improve survival of FHV, as observed in young flies. Tetracycline (TTC) and rifampicin (RIF) antibiotics disrupt mitochondrial translation and transcription respectively because of mitochondria's bacterial ancestry. The mitochondrial unfolded protein response (UPRmt) is activated by mitochondrial stressors, including reactive oxygen species, defects in oxidative phosphorylation, and mitonuclear protein imbalance. UPRmt activation initiates retrograde signaling to the nucleus, prompting transcription, translation, and import of nuclear proteins to resolve stress. We showed TTC or RIF treatment extended survival in young and aged flies after FHV infection, independently of virus load modulation. Furthermore, we demonstrate that bacterial loads are not significantly different between FHV-infected flies and controls, and that the protective effect of TTC likely occurs independently of its antimicrobial properties. We observed increased expression of genes involved in the UPRmt, glycolysis, and oxidative stress response with TTC treatment. Our results suggest perturbing mitonuclear protein balance with TTC or RIF could activate the UPRmt and improve outcomes of virus infection.
    Keywords:  Drosophila melanogaster; aging; antibiotics; innate immunity; mitochondrial unfolded protein response; virus infection
    DOI:  https://doi.org/10.21203/rs.3.rs-6816306/v1
  35. Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]
    Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
    Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.
      Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.
    Keywords:  NAD; glycolysis; mitophay; neuron; organismal wellbeing
    DOI:  https://doi.org/10.1016/j.tem.2025.05.005
  36. Neuropeptides. 2025 Jun 25. pii: S0143-4179(25)00035-6. [Epub ahead of print]112 102535
    Dynorphin B induces mitochondrial fragmentation in NSCLC through the PKD/DRP-1 signaling pathway.
    Yunxiao Li, Bin Zhou, Yuenan Yang, Kexin Liu, Shichao Zhou.
      Mitochondrial fragmentation and impairment are essential targets for therapeutic approach for non-small cell lung cancer (NSCLC), given their significant contributions to the persistence and progression of malignant cells. Dynorphin B (Dyn B), an endogenous opioid peptide, has been demonstrated for its involvement in an extensive array of cellular activities; however, its specific functions and mechanisms within the context of cancer remain largely undefined. To address this, we employed NCI-H2087 NSCLC cells treated with Dyn B (0.01-100 μM) and utilized lactate dehydrogenase (LDH) release and γ-glutamyl transpeptidase (GPT) activity assays to evaluate cytotoxicity. Mitochondrial function was assessed via Complex I activity assays, adenosine triphosphate (ATP) production measurements, and MitoSOX Green staining for reactive oxygen species (ROS). MitoTracker Red staining with ImageJ quantification characterized mitochondrial morphology, while Western blot analysis probed phosphorylation of dynamin-related protein 1 (DRP1) and protein kinase D (PKD). Lentiviral shRNA-mediated PKD silencing was used to validate functional rescue of mitochondrial dynamics. This investigation reveals that Dyn B induces cytotoxic effects in NCI-H2087 NSCLC cells by facilitating mitochondrial dysfunction and fragmentation. Treatment with Dyn B resulted in a significant augmentation of LDH and elevated GPT activity, indicating cellular injury. Additionally, Dyn B compromised mitochondrial functionality by reducing Complex I activity, diminishing ATP synthesis, and promoting mitochondrial ROS generation. Mechanistically, Dyn B triggered mitochondrial fragmentation through activation of DRP1 and PKD, without affecting protein kinase C (PKC). Silencing of PKD reversed Dyn B-induced mitochondrial fragmentation and restored mitochondrial functionality. These findings underscore the promising role of Dyn B as a prospective therapeutic agent in NSCLC, targeting mitochondrial dynamics via the PKD-DRP1 signaling pathway.
    Keywords:  DRP-1; Dyn B; Mitochondrial dysfunction; Mitochondrial fragmentation; NSCLC; PKD
    DOI:  https://doi.org/10.1016/j.npep.2025.102535
  37. Sci Rep. 2025 Jul 03. 15(1): 23755
    Increased eosinophils after oral corticosteroid treatment for asthma exacerbation correlated with longer ER stays and persisting thymic stromal lymphopoietin and increased Park2.
    Kittipong Maneechotesuwan, Jirawat Assawabhumi, Jirabhorn Chankham, Kanda Kasetsinsombat, Khin Su Su Htwe, Ian M Adcock.
      TSLP-regulated Park2 and mitophagy may be critical underlying driver of asthma exacerbations, as well as eosinophil responses to oral corticosteroids (OCS). However, detailed molecular knowledge of the molecular mechanisms involved is lacking. In a prospective cohort study at ED Siriraj Hospital, 28 consecutive patients with an acute asthma exacerbation were administered OCS treatment for one week. Serum levels of TSLP, Park2, Mul1, related cytokines, mitochondrial DNA (mtDNA), and oxidative stress were measured. The effects of TSLP, inhaled corticosteroids, NLRP3 inflammasome inhibitor, and mitochondrial-targeted antioxidant on mitophagy, mtDNA release, Park2, and Mul1 were examined in blood monocytes and in a human bronchial epithelial cell line (HBEC). Two distinct eosinophil responses to OCS treatment were observed: reduced (RE) and increased absolute blood eosinophil levels (IE). Following OCS treatment, participants with IE demonstrated stable TSLP levels and a significant rise in Park2. The IE group exhibited markedly higher baseline oxidative stress levels than the RE group at an exacerbation episode and further increase in oxidative stress after OCS treatment. TSLP augmented the induction of Park2 while inhibiting mitophagy, resulting in increased release of mtDNA from blood monocytes and human bronchial epithelial cells and stimulating inflammasome activation. Corticosteroids did not effectively suppress oxidative stress-mediated TSLP effects. The present study demonstrated potential inflammatory mechanisms in acute asthmatics with rising eosinophil counts following OCS treatment including a possible role of TSLP in suppressing mitophagy and inducing mtDNA release with concomitant inflammasome activation, and Park2 expression.
    Keywords:  Asthma exacerbation; Mitochondrial DNA; Mitophagy; Park2; Thymic stromal lymphopoietin
    DOI:  https://doi.org/10.1038/s41598-025-07102-6
  38. Adv Clin Exp Med. 2025 Jul 02.
    Effects of echinacoside on the regulation of mitochondrial fission induced by TBK1/Drp1 in rheumatoid arthritis.
    Xiaoyan Wang, Zhufeng Chen, Shanshan Wu, Xuemei Fan.
       BACKGROUND: Dysregulated mitochondrial fission in synovial tissue is a key contributor to the progression of rheumatoid arthritis (RA), and echinacoside (ECH) has been shown to modulate this process in a mouse model of RA.
    OBJECTIVES: This study aimed to investigate the effects of echinacoside (ECH) on the proliferation and inflammatory response of human fibroblast-like synoviocytes (MH7A cells), and to elucidate the potential underlying mechanisms.
    MATERIAL AND METHODS: The expression and co-localization of TANK-binding kinase 1 (TBK1) and phosphorylated dynamin-related protein 1 (p-Drp1) in synovial tissues from patients with and without RA were analyzed. MH7A cells were exposed to either ECH or 0.1% dimethyl sulfoxide (DMSO). Cell proliferation was detected using Cell Counting Kit-8 (CCK-8) assay and reactive oxygen species (ROS) expression was detected with dichlorofluorescin (DCFH) staining. The levels of interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), cyclooxygenase (COX)-2, IL-1β, TANK-binding kinase 1 (TBK1), and Drp1 and the oxidative stress markers NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) were measured using quantitative real-time polymerase chain reaction (qPCR). The mitochondrial morphology was detected with transmission electron microscopy (TEM), and the expression levels of p-TBK1 (S172), TBK1, p-Drp1 (S616), p-Drp1 (S637), and Drp1 were assessed using western blotting.
    RESULTS: Compared to tissue from non-RA patients, RA synovial tissue exhibited higher expression and co-localization of TBK1 and phosphorylated Drp1 (p-Drp1). Following ECH treatment, MH7A cell proliferation and inflammatory cytokine secretion were reduced, while the expression of antioxidant stress markers was significantly increased. Furthermore, ECH treatment led to reduced levels of ROS, mitochondrial fragmentation and dysregulated mitochondrial fission in MH7A cells, along with decreased expression of p-TBK1 (Ser172) and p-Drp1 (Ser616), while p-Drp1 (Ser637) levels were increased.
    CONCLUSIONS: Echinacoside regulates abnormal mitochondrial fission via the TBK1/Drp1 pathway, reducing the proliferation and inflammatory response of MH7A cells.
    Keywords:  echinacoside; mitochondrial fission; rheumatoid arthritis
    DOI:  https://doi.org/10.17219/acem/199920
  39. Mol Biol Rep. 2025 Jul 03. 52(1): 671
    Cancer stem cells: mitochondria signalling pathway and strategies for therapeutic interventions.
    Ee Wern Tan, Sachin Kumar Singh, Kamal Dua, Gaurav Gupta, Wai Leng Lee, Rebecca Shin Yee Wong, Kuan Onn Tan, Bey Hing Goh.
      Cancer stem cells (CSCs) play a critical role in tumor initiation, progression, and resistance to therapy, making them a major hurdle in effective cancer treatment. Unlike bulk cancer cells, CSCs exhibit remarkable adaptability, allowing them to survive under metabolic stress and evade conventional therapies. Mitochondria, as central regulators of cellular metabolism and apoptosis, are integral to CSC function. They facilitate metabolic reprogramming, redox balance, and stress adaptation, thereby enhancing CSC survival, self-renewal, and resistance to treatment. Dysregulated mitochondrial dynamics, including alterations in biogenesis, degradation, and signaling pathways, contribute to CSC maintenance and therapeutic resistance. Furthermore, mitochondrial membrane integrity and oxidative stress regulation determine CSC fate, influencing their ability to withstand chemotherapy and radiotherapy. Recent advances have identified mitochondrial-targeted strategies as promising approaches to impair CSC function and sensitize them to treatment. These include disrupting mitochondrial metabolism, inducing oxidative stress, and modulating mitochondrial quality control mechanisms. By understanding the intricate relationship between mitochondria and CSCs, new therapeutic strategies can be developed to selectively target CSCs, ultimately improving cancer treatment outcomes and preventing disease recurrence. This review provides an in-depth analysis of mitochondrial mechanisms in CSCs and their potential as therapeutic targets.
    Keywords:  Cancer stem cells; Metabolic reprogramming; Mitochondrial dynamics; Mitochondrial-targeted therapy; Therapeutic resistance
    DOI:  https://doi.org/10.1007/s11033-025-10748-0
  40. Sichuan Da Xue Xue Bao Yi Xue Ban. 2025 Mar 20. 56(2): 382-388
    [Icariside Ⅱ Inhibits Hepatitis B Virus and Modulates Mitochondrial Fission in vitro].
    Zhengyun Liu, Juan Wen, Guoli Chen, Wan Yu, Guo Luo, Qihai Gong, Huan Wang.
       Objective: To investigate the in vitro anti-hepatitis B virus (HBV) effects of icariside Ⅱ (ICS Ⅱ) and its impact on mitochondrial fission.
    Methods: HBV-positive hepatocellular carcinoma HepAD38 cells were used as the cellular model. The cytotoxicity of ICS Ⅱ was assessed via CCK8 assay. The secretion levels of HBV surface antigen (HBsAg) and HBV e antigen (HBeAg), as well as HBV DNA copy numbers, were measured by ELISA and qPCR after treatment with ICS Ⅱ alone or ICS Ⅱ in combination with entecavir (ENT). The effects of ICS Ⅱ on mitochondrial morphology and motility were observed using confocal laser scanning microscopy and transmission electron microscopy (TEM). After ICS Ⅱ treatment, Western blot was performed to analyze the expression levels of key proteins involved in mitochondrial dynamics. Additionally, intracellular reactive oxygen species (ROS) production was evaluated via fluorescence staining.
    Results: The CCK8 assay results showed that ICS Ⅱ treatment at 25 μmol/L had no significant effect on cell proliferation after 72 h. ICS Ⅱ significantly inhibited the secretion levels of HBsAg and HBeAg, with the respective inhibition rates reaching 54.90% and 39.65% (P < 0.05). Additionally, ICS Ⅱ alone reduced HBV DNA copy numbers by 15.19%, while ENT alone achieved a 34.11% inhibition rate. Notably, ICS Ⅱ in combination with ENT reduced HBV DNA copy numbers by 55.81% (P < 0.05). Furthermore, ICS Ⅱ induced mitochondrial shortening and enhanced mitochondrial motility in HepAD38 cells (P < 0.05). ICS Ⅱ significantly increased the expression levels of mitochondrial motility-related proteins, including Mfn1, Fis1, and phosphorylated Drp1 (ser 616) (P < 0.05), while no significant changes were observed in the expression levels of Mfn2, total Drp1, or Drp1 (ser 637) (P > 0.05). Additionally, ICS Ⅱ significantly suppressed the production of intracellular ROS in HepAD38 cells (P < 0.05).
    Conclusion: ICS Ⅱ inhibits HBV replication in HepAD38 cells, and the underlying mechanism may be associated with the promotion of mitochondrial fission and suppression of ROS production.
    Keywords:  Epimedium herb; Hepatitis B virus; Mitochondria
    DOI:  https://doi.org/10.12182/20250360107
  41. Int J Biol Macromol. 2025 Jun 28. pii: S0141-8130(25)06102-1. [Epub ahead of print] 145547
    Corrigendum to "Evaluation of GFM1 mutations pathogenicity through in silico tools, RNA sequencing and mitophagy pathway in GFM1 knockout cells" [Int. J. Biol. Macromol. Volume 304, Part 2, April 2025, 140970].
    Bashir Ahmad, John Sieh Dumbuya, Wen Li, Ji-Xin Tang, Xiuling Chen, Jun Lu.
      
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145547
  42. Sci Rep. 2025 Jul 01. 15(1): 20797
    Identification of mitophagy-related genes with diagnostic value in acute rejection following kidney transplantation using bioinformatics analysis.
    Jianan Ma, Dawei Wu, Xinyuan An, Yongrui Zhang, Haijian Wei.
      Acute rejection (AR) after kidney transplantation, is a common and serious complication that occurs when the recipient's immune system attacks the graft, and the specific genes and molecular mechanisms underlying the role of mitophagy are still unclear. This study integrated two transcriptomic datasets (GSE129166 and GSE25902) from the GEO database. Thirty differential mitophagy-related genes were identified by intersecting differentially expressed genes, module genes obtained through weighted gene co-expression network analysis and mitophagy-related genes. Functional enrichment analysis uncovered several biological processes and signaling pathways associated with these genes. Four candidate genes including CCND1, ZC3H15, RPL38, and ARPC4, were further identified through Random Forest and Support Vector Machine with recursive feature elimination. Internal, external datasets and a nomogram confirmed they could effectively predict AR. Moreover, these genes significantly correlated with the infiltration of multiple immune cells. Differential expressions of the four genes were also validated in patient's peripheral blood and AR mice. These four mitophagy-related genes may be novel biomarkers for predicting the occurrence and diagnosis of AR.
    Keywords:  Acute rejection; Gene signature; Immune cells; Kidney transplantation; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-025-09143-3
  43. Eur J Med Res. 2025 Jul 03. 30(1): 568
    Cross-talk between mitophagy pathways in pre-eclampsia and gestational diabetes mellitus: a systematic analysis of shared molecular mechanisms.
    Lidan He, Lin Lu, Xia Zhang, Xiuyan Wu, Feng Zhan, Jianbo Wu.
       BACKGROUND: Mitophagy plays a crucial role in both pre-eclampsia (PE) and gestational diabetes mellitus (GDM); however, the molecular mechanisms connecting these conditions remain unclear. This study employs bioinformatics approaches to investigate shared mitophagy-related gene signatures in PE and GDM.
    METHODS: We analyzed RNA sequencing data from PE and GDM patients to identify mitophagy-related differentially expressed genes (MRDEGs). Diagnostic models were constructed using RandomForest, LASSO and Nomogram, with validation through decision curve analysis (DCA) and calibration curves. Functional enrichment and regulatory networks involving MRDEGs, miRNAs and transcription factors (TFs) were constructed. Expression of key genes was subsequently validated in placental tissues through quantitative analysis.
    RESULTS: A total of 11 MRDEGs were identified. The LASSO model demonstrated promising diagnostic potential, achieving AUC values of 0.646 for PE and 0.721 for GDM. Eight key MRDEGs were closely associated with oxidative phosphorylation and reactive oxygen species (ROS) signaling pathways. Immune infiltration analysis revealed significant alterations in immune cell infiltration levels in both PE and GDM placental tissues, particularly manifesting as notable decreases in activated CD4 T cells and activated dendritic cells. These MRDEGs interacted with 80 TFs and 101 miRNAs in comprehensive regulatory networks. Finally, validation in placental tissues from control (n = 24) and disease groups (PE: n = 18, GDM: n = 20) confirmed significant differential expression of five key genes (MRPS5, PNPO, ARRB2, UBE2M, and PRAGC; all P < 0.01).
    CONCLUSIONS: This study highlights key MRDEGs as potential diagnostic biomarkers for PE and GDM, with their differential expression substantiated in placental tissues. Mitophagy likely contributes to disease pathogenesis through immune regulation and oxidative stress mechanisms, offering novel perspectives on potential therapeutic targets.
    Keywords:  Bioinformatics analysis; Gestational diabetes mellitus; Mitophagy; Oxidative stress; Pre-eclampsia
    DOI:  https://doi.org/10.1186/s40001-025-02823-w
  44. Biophys Rep. 2025 Jun 30. 11(3): 143-155
    Modulating mitochondrial dynamics in CMT2A: a multifaceted platform for drug discovery and evaluation.
    Yang Liu, Chen Yan, Borui Cao, Dejun Kong, Jiaqi Li, Wenlei Li, Yingjie Guo, Zhongyang Yuan, Yumiao Gao, Yubo Zhang, Ran Sui, Guo Chen, Xiaojiang Hao, Quan Chen.
      Mitochondrial dynamics, encompassing fusion and fission processes, plays a crucial role in regulating mitochondrial distribution, motility, and material exchange within cells, particularly in the nervous system. Mitofusin-2 (MFN2), a GTPase localized to the outer mitochondrial membrane, mediates mitochondrial fusion through dimerization and conformational changes. Mutations in MFN2 are causal for Charcot-Marie-Tooth disease type 2A (CMT2A), an inherited peripheral neuropathy for which no curative treatment currently exists. Herein, we have developed a comprehensive mitochondrial drug-screening and evaluation platform to facilitate the identification of potential therapeutic candidates. This work builds upon our previous research with S89, a small molecule agonist derived from spiramine alkaloids that promotes mitochondrial fusion by interacting with endogenous MFN1 and effectively mitigates axonal degeneration in CMT2A patient-derived motor neurons. This platform integrates three sequential stages of assessment: (1) initial screening in Mfn knockout mouse embryonic fibroblasts (MEFs) to identify compounds capable of reversibly rescuing mitochondrial fragmentation; (2) evaluation in primary neuronal cultures derived from CMT2A mouse dorsal root ganglia and cortex to assess the compounds' efficacy in restoring mitochondrial morphology, axonal transport, and neurite outgrowth; and (3) final assessment in CMT2A patient-derived induced pluripotent stem cell (iPSC)-differentiated motor neurons to determine the candidates' therapeutic potential in human peripheral nervous system cells. This multi-tiered approach facilitates rapid compound screening with increasing physiological relevance, enhancing the efficiency and translational potential of identifying therapeutic candidates for CMT2A.
    Keywords:  CMT2A neuronal system; Charcot-Marie-Tooth disease type 2A (CMT2A); Mitochondrial fusion; Mitofusin-2 (MFN2); Screening and evaluation platform; Small molecule compounds
    DOI:  https://doi.org/10.52601/bpr.2024.240037
  45. Int J Biol Sci. 2025 ;21(9): 4027-4050
    Exogenous SPD inhibits trastuzumab-mediated cardiomyocyte pyroptosis through SIRT3-regulated mitochondrial quality control.
    Xue Yu, Yan Yang, Tianzuo Chen, Qianbing Wang, Zitong Wang, Xi Gao, Qianxue Wang, Jinxiang Guo, Yuqin Wang, Yajie Zhao, Shilin Wang, Wei Lu, Xing Luo, Tielei Gao, Jiayuan Kou, Hong Li, Liming Yang.
      Trastuzumab (TRZ) is an anti-HER2 monoclonal antibody associated with significant survival benefits; however, its clinical utility is restricted by trastuzumab-induced cardiotoxicity (TIC). While the inhibition of HER2 induces mitochondrial dysfunction in cardiomyocytes, it is unclear whether mitochondrial quality control participates in trastuzumab-mediated cardiomyocyte pyroptosis. This study demonstrated that TRZ leads to a reduction in left ventricular systolic function, myocardial pyroptosis, and mitochondrial oxidative stress; alterations in the mitochondrial membrane potential; changes in mitochondrial permeability; mitochondrial dysfunction; and a decrease in mitochondrial biosynthesis in the murine heart. Supplementation with exogenous spermidine inhibits myocardial oxidative stress and mitochondrial dysfunction, and promotes mitochondrial biosynthesis in mice, thereby protecting cardiac function. Additionally, SIRT3 plays a protective role in TRZ-induced myocardial injury. In SIRT3 knockout mice, TRZ-induced cardiac injury was exacerbated, and mitochondrial damage was aggravated. In conclusion, these findings reveal the pathogenic mechanism underlying trastuzumab-induced cardiomyopathy and suggest a novel therapeutic target for preventing cardiotoxicity in HER2+ breast cancer treatment.
    Keywords:  mitochondrial biosynthesis; pyroptosis; spermidine; trastuzumab
    DOI:  https://doi.org/10.7150/ijbs.110580
  46. Cell Death Discov. 2025 Jul 03. 11(1): 304
    FL3 mitigates cardiac ischemia-reperfusion injury by promoting mitochondrial fusion to restore calcium homeostasis.
    Zikan Zhong, Yutong Hou, Changzuan Zhou, Jiahui Wang, Longzhe Gao, Xiaoyu Wu, Genqing Zhou, Shaowen Liu, Yingjie Xu, Wen Yang.
      This study aims to investigate the therapeutic potential of Flavagline3 (FL3) in mitigating myocardial ischemia-reperfusion (IR) injury, with a specific focus on its regulatory effects on mitochondrial fusion, mitochondrial-endoplasmic reticulum (ER) interactions, and calcium homeostasis in cardiomyocytes. Using a well-established myocardial IR injury model in mice and primary cardiomyocytes treated with FL3, the study assessed its impact on mitochondrial dynamics and intracellular signaling processes. The results demonstrated that FL3 effectively reduced myocardial apoptosis, infarct size, and cardiac dysfunction caused by IR injury. Mechanistically, FL3 promoted mitochondrial fusion in a mitofusin1 (MFN1)-dependent manner, preserving mitochondrial function under stress conditions and enhancing cellular resilience. Furthermore, FL3 facilitated mitochondrial-ER crosstalk, which played a critical role in modulating intracellular calcium levels by optimizing the transfer of calcium ions between these two organelles. This balanced regulation of mitochondrial dynamics and calcium homeostasis was associated with improved survival and functionality of cardiomyocytes following IR injury. These findings suggest that FL3 exerts robust cardioprotective effects through its ability to promote mitochondrial fusion, enhance mitochondrial-ER interactions, and maintain calcium homeostasis. As a result, FL3 holds promise as a potential therapeutic agent for reducing myocardial damage and dysfunction associated with IR injury, offering valuable insights into novel approaches for cardioprotection.
    DOI:  https://doi.org/10.1038/s41420-025-02575-w
  47. Stem Cell Res Ther. 2025 Jul 01. 16(1): 339
    Small extracellular vesicles derived from mesenchymal stromal cells loaded with β-nicotinamide mononucleotide activate NAD+/SIRT3 signaling pathway-mediated mitochondrial autophagy to delay skin aging.
    Zixuan Sun, Jiali Li, Yuzhou Zheng, Jiaxin Zhang, Wenhuan Bai, Xinyi Deng, Zhijing Wu, XueZhong Xu, Wei Ding, Hui Qian, Yulin Tan.
       BACKGROUND: Recently, the beneficial effects of human umbilical cord mesenchymal stromal cell (hucMSC)-derived small extracellular vesicles (sEVs) in mitigating skin aging through multiple mechanisms have been widely reported. β-Nicotinamide mononucleotide (NMN) is an iconic anti-aging drug that increases NAD+ levels in the body to slow down, ameliorate, and prevent various phenotypes associated with aging, but its high water solubility, low permeability, and instability limit its clinical application. Based on this, we applied electroporation to construct NMN-loaded hucMSC-sEVs (NMN-sEVs) to improve their stability and efficacy and to enhance their potential for translational application in medical aesthetics and anti-aging.
    METHODS: D-galactose was applied to construct a mouse skin aging model, based on which comparative analyses of topical and nano-microneedle administration were performed to determine the optimal delivery method of sEVs in vivo experiments. After constructing NMN-sEVs by electroporation, high-performance liquid chromatography was applied to detect the loading efficiency, and the effects of NMN-sEVs on delaying skin aging were assessed by histological analysis. In addition, the defense effects of NMN-sEVs against cellular senescence were verified by reactive oxygen species assay, β-galactosidase staining, qRT-PCR, Western blot, and cellular immunofluorescence. Finally, the roles of NMN-sEVs in remodeling mitochondrial function and delaying cellular senescence through mitochondrial autophagy were assessed by mitochondrial mass, function, and autophagy level assays.
    RESULTS: Our data suggested that NMN-sEVs could improve skin aging in mice, delay cellular senescence, and restore cellular mitochondrial dysfunction. Notably, NMN-sEVs treatment increased intracellular NAD+ levels and SIRT3 expression, as well as rescued the inhibition of senescence-induced mitochondrial autophagy, suggesting a role for NMN-sEVs in the remodeling of mitochondrial function through mitochondrial autophagy. Additionally, the use of the SIRT3 inhibitor 3-TYP suppressed the positive effects of NMN-sEVs on cellular senescence, mitochondrial function, and mitochondrial autophagy while restoring senescence-associated characteristics.
    CONCLUSION: Overall, our findings revealed a mechanism by which NMN-sEVs attenuated mitochondrial dysfunction and rescued cellular senescence by promoting NAD+/SIRT3 pathway-mediated mitophagy and might provide a promising strategy for anti-aging pharmaceuticals.
    Keywords:  HucMSC-sEVs; Mitochondrial autophagy; NMN; SIRT3; Skin aging
    DOI:  https://doi.org/10.1186/s13287-025-04460-w
  48. JOR Spine. 2025 Sep;8(3): e70089
    Mechanistic Interactions Driving Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration: A Multi-Axial Perspective of Mechanical, Immune, and Metabolic Pathways.
    Yunbo Yang, Haoming Li, Junhui Zuo, Fei Lei.
       Background: The senescence of nucleus pulposus cells (NPCs) at the heart of the pathogenesis of intervertebral disc degeneration (IVDD), which causes low back pain. Abnormal mechanical stress causes intracellular Ca2+ overload by activating the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) channel.
    Aims: This creates a positive feedback loop of oxidative-inflammatory damage by inducing endoplasmic reticulum stress and mitochondrial reactive oxygen species (ROS) bursts, as well as directly activating the NLRP3 inflammasome/NF-кB axis to promote the release of pro-inflammatory factors like IL-1β.
    Results: Energy metabolism collapsed as a result of mechanistic cause that caused excessive activation of mitophagy via the ROS-PINK1/Parkin pathway, and SIRT1 functional suppression further compromised mitochondrial quality control. The inflammatory nucleus pulposus (NP) brought on by mechanical stimulation caused macrophages to polarize toward the M1 type, and the p38MAPK pathway was activated by the TNF-α/IL-1β released, which in turn increased senescence markers like p16/p21. Notably, ROS both triggers mitophagy and activates the p53 pathway. On the one hand, oxidative damage-induced ATM/ATR kinase activation leads to p53 phosphorylation, which triggers p21-mediated cell-cycle block. On the other hand, p53 exacerbates mitochondrial dysfunction by inhibiting SIRT1 expression, creating a triangular amplification loop of p53-ROS-mitophagy. Furthermore, p53 stimulates apoptosis by altering the Bax/Bcl-2 balance and works in concert with inflammatory substances secreted by M1-type macrophages to cause the development of senescence-associated secretory phenotype (SASP).
    Conclusion: This interaction network reveals the dynamic coupling of mechano-immune-metabolic pathways in the course of IVDD, providing a theoretical basis for the development of multi-targeted intervention strategies, such as PIEZO1 inhibitors combined with M2-type macrophage polarization modulation, which are expected to delay disease progression by blocking key nodes.
    Keywords:  intervertebral disc degeneration; macrophage polarization; mechanical stimulation; mitophagy; nucleus pulposus cell
    DOI:  https://doi.org/10.1002/jsp2.70089
  49. J Cell Mol Med. 2025 Jul;29(13): e70701
    CD81 Aggravates Ovarian Cancer Progression via p-Cresyl Sulfate-Mediated Mitophagy in Tim4+ Tumour-Associated Macrophages.
    Jiali Ni, Xiaoying Li, Yue Wu, Xiaodi Tu, Xinxin Zhang, Lu Wang, Hao Xie, Yayi Hou, Huan Dou, Shuli Zhao.
      Ovarian cancer (OC) is characterised by widespread peritoneal metastasis. Tetraspanin CD81 is predominantly located at the cellular membrane and exhibits inconsistent roles in tumour progression. However, its precise function in OC remains unclear. We found that CD81 expression was significantly elevated in tumour tissues from OC patients with poor prognosis, and it directly promoted proliferation, and migration of OC cells. Stable knock-down of CD81 expression ameliorated disease progression in a murine model of OC and induced metabolic responses in OC cells. Metabolomics and mass spectrometry identified the protein-bound toxin p-cresyl sulfate (PCS) as a key metabolite regulated by the CD81-FAK signalling axis. One aspect is that PCS promoted the growth of OC cells. Furthermore, tumour-derived PCS combined with Cdh1 to enhance Bnip3-dependent mitophagy activity of Tim4 positive tumour-associated macrophages (TAMs). Intraperitoneal injection of PCS reversed the therapeutic effects observed following CD81 knock-down; the mitophagy of reprogrammed Tim4+ TAMs was also promoted, accompanied by alterations in antitumor immunity. In summary, we elucidated CD81 prompted Tim4+ TAMs mitophagy to induce OC progression via FAK/PCS/Cdh1 pathway, deepen our understanding of OC pathogenesis.
    Keywords:  CD81; PCS; TAM; ovarian cancer
    DOI:  https://doi.org/10.1111/jcmm.70701
  50. Int J Biol Macromol. 2025 Jul 01. pii: S0141-8130(25)06261-0. [Epub ahead of print]319(Pt 4): 145706
    Mitochondrial transcription factor a as a guardian of mitochondrial integrity and emerging therapeutic target in human diseases: A review.
    Miao Yang, Le Sun, Xibin Feng, Wei Xu.
      Mitochondrial transcription factor A (TFAM) plays a central role in mtDNA transcription, replication, and nucleoid compaction, thereby maintaining mitochondrial integrity and function. As a highly conserved nuclear-encoded protein, TFAM is indispensable for mitochondrial biogenesis and influences cellular energy metabolism and mitochondrial homeostasis. Given its fundamental role in mitochondrial function, dysfunction of TFAM contributes to the pathogenesis of various diseases and has become a key focus of biomedical research. This review systematically examines recent advances in understanding the diverse biological functions and regulatory mechanisms of TFAM, specifically addresses disease progression through the perspective of TFAM dysfunction. We highlight the therapeutic potential of TFAM, aiming to provide insights into its role as a biomarker and a promising therapeutic target for mitochondrial dysfunction-related diseases, offering promising insights for future therapeutic development in mitochondrial dysfunction-related conditions.
    Keywords:  Mitochondrial homeostasis; Mitochondrial transcription factor A; Therapeutic potential
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145706
  51. Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 30.
    Naringin alleviates fluoride-induced neurodevelopmental disorders by modulation of SIRT1, autophagy, mitochondrial fission, and ROS generation.
    Vishal Chhabra, Ravindra Shantakumar Swamy, Annem Ravi Teja Reddy, Rashmi Bhushan, Smita Shenoy, Shreya Maiti, Abubakar, Sarasa Meenakshi, Krishna Murti, Nitesh Kumar.
      The present study explored the mechanism behind the fluorosis-mediated neurodevelopmental disorder and its intervention by naringin in prenatal and perinatal models in Wistar rats. Both in vitro and in vivo studies were conducted to assess autophagy, oxidative stress, neurogenesis, and impaired molecular dynamics markers. The experiment was conducted over a period of 120 days. Twelve Wistar rats were divided into four groups: control, sodium fluoride (NaF)-treated (10 ppm in drinking water), NaF + naringin-treated (50 mg/kg via oral gavage), and NaF with naringin administered to pups via breastfeeding. Treatments lasted 60 days for adults, with NaF exposure beginning 30 days pre-mating. Pups were evaluated at days 90 (prenatal) and 120 (perinatal) to assess developmental effects. Fluoride was administered by mixing NaF in drinking water at a dose of 10 ppm, and naringin was given via oral gavage at a dose of 50 mg/kg body weight. Fluoride toxicity showed altered behavior in the open field test (OFT), novel object recognition test (NORT), forced swim test (FST), and Morris Water Maze tests and impaired motor coordination in neonatal tests using nest seeking, locomotion, righting reflex, forelimb grasp reflex, cliff avoidance, and negative geotactic reflex. At the end of the experiment, prenatal and natal pups were sacrificed postweaning. Biochemical assays, fluoride concentration estimation, Western blotting, and immunohistochemistry were performed for the brain tissues. Naringin showed improvement in these behavioral studies, probably due to neuroprotection by modulation of SIRT-1, Dnm1L, and Lc3B levels, which were assessed by western blot. These findings highlight naringin as a promising therapeutic agent for mitigating fluoride-induced neurodevelopmental toxicity through pathways involving oxidative stress regulation, autophagy, and mitochondrial dynamics.
    Keywords:  Autophagy; Cognition; Drinking water; Mitochondrial dynamics; SIRT1; Sodium fluoride
    DOI:  https://doi.org/10.1007/s00210-025-04398-z
  52. Free Radic Biol Med. 2025 Jul 02. pii: S0891-5849(25)00805-6. [Epub ahead of print]
    Mechanistic Study of the Novel Peroxidase Mimetic DhHP-6 in Metabolic Cataracts.
    Zhuoya Li, Ping Gong, Yuxin Tian, Xi Wang, Hui Zhang.
      Metabolic disorders such as diabetes and high-galactose often induce oxidative damage and mitochondrial dysfunction in the lens, leading to metabolic cataracts. Although surgical intervention remains the primary treatment, its associated risks and complications underscore the need for pharmacological alternatives with multifaceted protective effects. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6), a novel microperoxidase mimetic derived from microperoxidase 11, has demonstrated potent reactive oxygen species (ROS)-scavenging activity in vivo. Our previous studies confirmed its efficacy in mitigating lens opacity and enhancing antioxidant enzyme levels in galactose-induced cataract models. To further elucidate the underlying mechanisms, we established both in vivo galactose-induced rat models and in vitro lens epithelial cell models. The results revealed that DhHP-6 significantly alleviated lens opacity by activating the NRF2/KEAP1/HO-1 pathway, thereby boosting antioxidant enzyme activity, restoring ATP levels, and inhibiting apoptotic signaling. Crucially, in vitro analyses confirmed DhHP-6's ability to maintain mitochondrial structural integrity and functional homeostasis through this pathway, thereby preventing the initiation of apoptosis cascades. These findings demonstrate that DhHP-6 attenuates metabolic cataract progression through multi-target mechanisms orchestrated by the NRF2/KEAP1/HO-1 pathway, integrating antioxidative defense, mitochondrial homeostasis restoration, and apoptosis inhibition into a unified therapeutic strategy.
    Keywords:  (5–6); DhHP-6; Metabolic cataract; apoptosis; mitochondrial dynamics; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.001
  53. J Dent Res. 2025 Jun 29. 220345251344295
    The NLRP3 Mediates Masticatory Muscle Atrophy by Pyroptosis and Mitophagy.
    Q Li, A Gao, C Wu, X Song, W Liu, Y Cheng, T Li, K Zhang, Y Chen, X Liu, Y Hong, T Wu.
      Masticatory muscle atrophy is relatively common and affects occlusal function, facial appearance, and even quality of life. The molecular mechanisms underlying changes in the masticatory muscles remain largely unknown. The Nod-like receptor protein 3 (NLRP3) inflammasome has been extensively reported to be associated with various myopathies; however, little is known about its role in masticatory muscle atrophy. Here, we investigated the function and underlying mechanisms of NLRP3 inflammasome activation in muscle atrophy models both in vitro and in vivo. First, significant atrophy of the masticatory muscles was observed after excessive orthodontic traction in rats, with NLRP3 inflammasome activation leading to increased myocyte pyroptosis. Further observations in the atrophied masticatory muscles revealed a significant reduction in mitochondrial number and overactivation of mitophagy. Conversely, inhibiting NLRP3 suppressed the expression of pyroptosis-related proteins and alleviated muscle atrophy. Moreover, blocking the activation of the NLRP3 inflammasome considerably alleviated mitochondrial dysfunction in the atrophied masticatory muscles and reduced excessive mitophagy, thereby maintaining intracellular homeostasis and preserving muscle mass. In addition, the results of the in vitro experiments confirmed that knocking down NLRP3 significantly alleviated NLRP3 agonist-induced pyroptosis and atrophy in the myotubes, improved mitochondrial damage, maintained mitochondrial membrane potential (Δψm), and decreased reactive oxygen species production. In summary, this study demonstrates that the NLRP3 inflammasome induces pyroptosis, mitochondrial dysfunction, and mitophagy, thereby becoming an important regulatory factor for masticatory muscle atrophy. Our research provides new insights into the mechanism of masticatory muscle atrophy.
    Keywords:  NLR family; atrophy; inflammasomes; mitochondrial diseases; muscle cells; muscles; orthodontics; pyrin domain-containing 3 protein
    DOI:  https://doi.org/10.1177/00220345251344295
  54. BBA Adv. 2025 ;8 100164
    Phosphorylation of the fission protein Drp1 contributes to the impact of the curcuminoid 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one on mitochondrial and cellular processes.
    Navyamol Chakkalaparambil Dileep, Chi-Wei Chiu, Ching-Tse Wu, Chuang-Rung Chang, Chih-Yu Lo.
      Curcumin and its curcuminoid derivatives extracted from turmeric have been investigated for their potential therapeutic benefits in cancer treatment. Curcuminoids 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one and bisdemethoxycurcumin can be obtained from Alpinia galangal. Despite their similar chemical structures, the effects of these curcuminoids on cellular functions and their therapeutic potential require further characterization. This study examined the impact of 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one and bisdemethoxycurcumin on human cancer cell lines and mouse embryonic fibroblasts. Our findings suggest that curcuminoids induce a shift in mitochondria dynamics toward fission. Exposure to curcuminoids resulted in attenuated mitochondrial activity, decreased mitochondrial mass, reduced reactive oxygen species (ROS) levels, and decreased membrane potential, accompanied by alterations in Drp1 phosphorylation. Notably, 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one had more pronounced effects than curcumin and bisdemethoxycurcumin. Curcuminoids derived from Alpinia galangal influence mitochondrial function and cell survival through Drp1 phosphorylation, indicating their potential for cancer therapy via the modulation of mitochondrial function.
    Keywords:  1,7-Bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one; Curcumin; Curcuminoid; Drp1; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbadva.2025.100164
  55. Regen Ther. 2025 Dec;30 224-233
    BNIP3 induced by hypoxia supports the survival of mesenchymal stromal cells (MSCs) after intravenous cell transplantation.
    Toshiyuki Takehara, Takatoshi Tsujimoto, Fumie Ikebuchi, Sayaka Miyoshi, Tatsufumi Mori, Natsumi Iwawaki, Kanae Shigi, Kei Houri, Yoshiyuki Tago, Takeshi Teramura.
       Introduction: Mesenchymal stromal cells (MSCs) are widely recognized as a valuable cell source for transplantation therapy due to their anti-inflammatory and tissue-regenerative properties in various inflammatory disorders. However, numerous studies have reported that transplanted MSCs frequently undergo cell death shortly after transplantation, leading to a limited number of surviving cells in recipient tissues.
    Methods: We found that culturing both mouse and human MSCs under 5 % oxygen conditions enhances the short-term survival rate after cell transplantation in the bleomycin treated model mice. Based on this finding, we performed transcriptomic analysis to identify the responsible genes, allogeneic and xenogeneic transplantation in mice following siRNA treatment, and measured reactive oxygen species (ROS) levels with assessment of mitophagy activity.
    Results: We identified Bnip3 as a gene that is consistently upregulated in both human and mouse MSCs under hypoxic culture conditions. Suppression of Bnip3 reduced the survival rate of MSCs cultured under hypoxic conditions, which should normally show high survival rates after transplantation. Bnip3 involved regulation of mitophagy, and we also found that preconditioning cells with hypoxic culture prior to transplantation upregulates Bnip3, conferring resistance to the transient ROS surge that occurs post-transplantation.
    Conclusion: This suggests that cell culture under hypoxia facilitates accumulation of Bnip3, a key regulator of mitophagy and confers stress tolerance to the MSCs. The findings indicate that pre-treating MSCs in hypoxic environment prior to transplantation could be a simple and effective strategy to improve cell viability in cell transplantation therapy.
    Keywords:  BCL2 interacting protein 3; Cell transplantation; Hypoxia; Mesenchymal stromal cells; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.reth.2025.06.005
  56. Nat Commun. 2025 Jul 01. 16(1): 5454
    Deficits in mitochondrial dynamics and iron balance result in templated insertions.
    Jordan Fox, Yang Yu, Yang Yu, Pilendra Thakre, Chloe Fox, Qian Li, Yunxia Wang, Adam Hughes, Xin Wang, Kaifu Chen, Grzegorz Ira.
      Mitochondrial membrane dynamics control the shape, number, and distribution of mitochondria and regulate energy production and cell health. In a screen for yeast mutants with increased levels of templated insertions (~10-1000 bp) in the nuclear genome, we identified mitochondrial fusion deficient mutants (mgm1Δ, ugo1Δ, fzo1Δ). We found that fusion mutants activate the iron regulon, have decreased iron-sulfur clusters (ISCs), and increased DNA damage, suggesting a role of iron homeostasis in preventing insertions. Consistently, a secondary screen found mutants affecting iron-sulfur cluster production (yfh1Δ, grx5Δ), vacuolar iron storage (ccc1Δ) or general iron homeostasis (aft1Δ) to exhibit high insertion levels. Treatment with iron chelators or hydrogen peroxide also increased insertions. We propose that iron dysregulation leading to oxidative DNA damage and compromised DNA repair drives insertions. These studies suggest that severe iron imbalance, associated with many human diseases and pharmacological treatments, can trigger genome instability in the form of templated insertions.
    DOI:  https://doi.org/10.1038/s41467-025-60546-2
  57. Sci Rep. 2025 Jul 01. 15(1): 21425
    Gpbar1-mediated SIRT1-PGC-1α axis maintains mitochondrial homeostasis and mitigates renal injury in obstructive jaundice.
    Mingchen Li, Kai Luo, Xu Sun, Yuting Zhao, Haiyang Chen, Courtney Quan, Caiming Xu, Guixin Zhang.
      Obstructive jaundice (OJ)-induced kidney injury has a high mortality rate, severely affecting patient prognosis. Gpbar1, a bile acid receptor, plays a key role in maintaining tissue homeostasis in organs such as the liver and pancreas during OJ. However, its role in obstructive jaundice-induced kidney injury remains unexplored. This study investigated the protective role of Gpbar1 in OJ-induced kidney injury. Sprague-Dawley rats underwent common bile duct ligation to establish an OJ model. Organ damage was evaluated by pathological examination, TUNEL staining, and liver/kidney function tests to assess both OJ model establishment and kidney injury. Mitochondrial function changes were assessed through electron microscopy, SOD, MDA, GSH and ATP detection. Immunohistochemistry and Western blot were used to assess Gpbar1, SIRT1, and PGC-1α expression. HK-2 cells were treated with deoxycholic acid to establish a renal tubular epithelial cell injury model. Lentiviral vectors were used to overexpress or knock down Gpbar1, combined with interventions using SIRT1 and PGC-1α agonists and inhibitors. The Gpbar1-SIRT1-PGC-1α axis was validated by qRT-PCR and WB. The protective role of the Gpbar1-SIRT1-PGC-1α axis in OJ-induced kidney injury was studied using CCK-8, transmission electron microscopy, ROS detection, and mitochondrial membrane potential assays. In the rat OJ model, the model group exhibited injury-related pathological changes compared to control group. Liver and kidney function markers and TUNEL-positive cells significantly increased, and structural and functional damage in the kidneys occurred. Mitochondrial structural disorder occurred in the kidneys, with significant reductions in SOD, GSH, and ATP levels, while MDA levels were significantly increased, indicating impaired antioxidant capacity and energy metabolism dysfunction. IHC, WB, and qRT-PCR revealed that protein and mRNA levels of Gpbar1, SIRT1, and PGC-1α in kidney tissues were lower in the model group. In the cellular model, DCA treatment and Gpbar1 knockdown significantly reduced cell viability, caused mitochondrial structural disorder, increased ROS levels and decreased JC-1 ratio, while Gpbar1 overexpression reversed these changes. After treatment with the SIRT1 inhibitor EX527, PGC-1α expression significantly decreased. We used SIRT1 inhibitors, activators and PGC-1α inhibitors to conduct positive and negative regulation experiments and confirmed the hierarchical regulatory effect of Gpbar1 on SIRT1-PGC-1α. Gpbar1 influences oxidative stress resistance via the SIRT1-PGC-1α axis, promotes mitochondrial functional homeostasis, and alleviates kidney injury induced by obstructive jaundice.
    DOI:  https://doi.org/10.1038/s41598-025-05022-z
  58. Sci Adv. 2025 Jul 04. 11(27): eadx4562
    Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
    Anna Pellattiero, Charlotte Quirin, Federico Magrin, Mattia Sturlese, Alberto Fracasso, Nikolaos Biris, Stéphanie Herkenne, Laura Cendron, Evripidis Gavathiotis, Stefano Moro, Andrea Mattarei, Luca Scorrano.
      The guanosine triphosphatase (GTPase) activity of the mitochondrial dynamin-related protein Optic Atrophy 1 (OPA1) regulates cristae remodeling, cytochrome c release, and apoptosis. Elevated OPA1 levels in multiple cancers correlate with reduced therapy sensitivity and poor survival, calling for specific OPA1 GTPase inhibitors. A high-throughput screening of ~10,000 compounds identified MYLS22, a heterocyclic N-pyrazole derivative as a reversible, noncompetitive OPA1 GTPase inhibitor. MYLS22 engaged with OPA1 in vitro and in cells where it induced cristae remodeling and mitochondrial fragmentation contingent on intactness of its predicted OPA1 binding site. MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy, without toxicity on noncancer cells. By MYLS22 structure-activity relationship studies, we obtained Opa1 inhibitor 0 (Opitor-0) that inhibited OPA1, promoted cytochrome c release, and restored anti-Bcl-2 therapy sensitivity more efficiently than MYLS22. These chemical probes validate OPA1 as a therapeutic target to increase cancer cell apoptosis at the mitochondrial level.
    DOI:  https://doi.org/10.1126/sciadv.adx4562
  59. Immunometabolism (Cobham). 2025 Jul;7(3): e00064
    You are what you eat: autophagy guides CD8+ T cell function through metabolism.
    Caio Loureiro Salgado, Henrique Borges da Silva.
      The differentiation of naive CD8+ T cells into effector or memory populations requires dynamic remodeling of cellular metabolism and proteome composition. In a recent study published in Nature Immunology, Sinclair et al offer critical insights into the role of autophagy, particularly mitophagy, in regulating these processes during CD8+ T cell differentiation. Autophagy, a conserved catabolic mechanism, is traditionally associated with cellular homeostasis and survival during nutrient deprivation. In contrast, Sinclair et al reveal that, in the immune system, autophagy is not simply a survival mechanism but a fine-tuned regulator of CD8+ T cell metabolism and function, fine-tuning CD8+ T cell effector vs quiescence choices.
    Keywords:  CD8+ T cells; autophagy; cytotoxic T cell; mitophagy; naive T cells
    DOI:  https://doi.org/10.1097/IN9.0000000000000064
  60. J Cell Sci. 2025 Jul 02. pii: jcs.263690. [Epub ahead of print]
    RHOA-dependent regulation of mitochondrial remodeling and cell motility in hypoxia-exposed gastric epithelial cells.
    Aranya Pal, Prabin Bawali, Abhisek Brahma, Smruti Ranjan Rana, Rakesh Mohapatra, Debashish Chakraborty, Indrajit Poirah, Supriya Samal, Smaran Banerjee, Duane T Smoot, Hassan Ashktorab, Asima Bhattacharyya.
      Mitochondrial appearance distinctively reflects cellular stress. Hypoxia, one of the most fundamental stressors, drives tumor progression, impacting mitochondrial structure and function. RAS homolog family member A (RHOA), a key regulator of cell motility, is frequently upregulated in response to hypoxia across cancers. However, its behavior under hypoxic condition in gastric cancer (GC) remains largely unexplored. Additionally, investigating the influence of RHOA in cell motility through mitochondrial reshaping is promising. Elevated RHOA level triggered mitochondrial shape-shifts from tubular to stress-associated lasso and donut, correlating with increased reactive oxygen species (ROS). However, RHOA-overexpressing cells experiencing hypoxia exhibited increased migration, despite reduced fission and ROS levels. RHO-associated coiled-coil kinase (ROCK) inhibition impaired mitochondrial shape changes, suggesting its role in mitochondrial remodeling. These results indicate a unique adaptive response to hypoxia, where RHOA upregulation increases motility and modulates mitochondrial plasticity in GC cells. In summary, RHOA-mediated mitochondrial reshaping may serve as a key regulator in tumor cell adaptation and migration in low-oxygen environments.
    Keywords:  Cell motility; Gastric cancer; Lasso; Mitochondrial morphology; RHOA; ROS
    DOI:  https://doi.org/10.1242/jcs.263690
  61. Curr Alzheimer Res. 2025 Jul 02.
    Alterations of Mitophagy (BNIP3), Apoptosis (CASP3), and Autophagy (BECN1) Genes in the Frontal Cortex in an Ischemic Model of Alzheimer's Disease with Long-Term Survival.
    Ryszard Pluta, Janusz Kocki, Anna Bogucka Kocka, Jacek Bogucki, Stanisław J Czuczwar.
       INTRODUCTION: Currently, there is no information on changes in the mitophagy (BNIP3), apoptosis (CASP3), and autophagy (BECN1) genes in the frontal cortex after brain ischemia with animal survival for 2 years. Furthermore, it is not known whether the BNIP3, CASP3, and BECN1 genes possess any influence on neurons in the frontal cortex due to ischemia.
    AIM: The goal of the investigation was to evaluate alterations in the behavior of BNIP3, CASP3, and BECN1 genes in the frontal cortex following ischemia with survival of 2 years.
    MATERIALS AND METHODS: Gene expression was assessed using an RT-PCR protocol at 2-30 days and 6-24-months after ischemia.
    RESULTS: BECN1 gene expression after ischemic injury was lower than the controlgroup during 7-30- days and 18 months, whereas overexpression was noted after 2 days, 6-, 12- and 24 months. In the case of BNIP3 gene expression, it was lower than the control group for 2-7 days and higher than the control throughout the remaining time after ischemia. Increased expression of the CASP3 gene was observed except on days 7-30 following ischemia when its expression was lower compared to control values.
    DISCUSSION: The data seem to indicate that the observed changes in gene expression may reflect the activation and inhibition of different mechanisms involved in the advancement of neurodegeneration after ischemia.
    CONCLUSION: Overexpression of BECN1gene is likely to be associated with the induction of neuroprotective phenomena, whereas overexpression of BNIP3 and CASP3 genes can cause harmful effects.
    Keywords:  Alzheimer’s disease; Brain ischemia; apoptosis; autophagy; frontal cortex; genes; long-term survival.; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.2174/0115672050385480250619045022
  62. Front Cell Dev Biol. 2025 ;13 1604320
    Mitochondrial metabolic regulation of macrophage polarization in osteomyelitis and other orthopedic disorders: mechanisms and therapeutic opportunities.
    Jinglin Li, Lin Zhang, Jiaze Peng, Chuntao Zhao, Wenguang Li, Yang Yu, Xianpeng Huang, Fuyin Yang, Xuan Deng, Xuxu Yang, Tao Zhang, Jiachen Peng.
      Osteomyelitis is a complex infectious bone disease involving pathogen invasion, host immune responses, and dysregulation of the local microenvironment. As a critical component of the innate immune system, macrophages play a pivotal role in inflammatory responses and tissue repair. Their polarization states (M1/M2) directly influence disease progression, while mitochondrial metabolism, as the central hub of cellular energy metabolism, has recently been shown to play a key role in macrophage polarization and functional regulation. However, how mitochondrial metabolism regulates macrophage polarization to affect the pathological mechanisms of osteomyelitis, and how to develop novel therapeutic strategies based on this mechanism, remain critical scientific questions to be addressed. This review systematically summarizes the molecular mechanisms by which mitochondrial metabolism regulates macrophage polarization and its role in osteomyelitis, with a focus on the impact of mitochondrial dynamics (fission/fusion), metabolic reprogramming, and reactive oxygen species (ROS) generation on macrophage polarization. Additionally, potential therapeutic strategies targeting mitochondrial metabolism are analyzed. For the first time, this review integrates the interplay between mitochondrial metabolism and macrophage polarization in osteomyelitis, revealing how mitochondrial dysfunction exacerbates inflammation and bone destruction through metabolic reprogramming. Based on these findings, we propose novel therapeutic strategies targeting mitochondrial metabolism, offering new perspectives and directions for understanding the pathogenesis and clinical treatment of osteomyelitis.
    Keywords:  bone repair; inflammation; macrophage polarization; mitochondrial dynamics; mitochondrial metabolism; osteomyelitis
    DOI:  https://doi.org/10.3389/fcell.2025.1604320
  63. Sci Rep. 2025 Jul 01. 15(1): 20960
    A novel isoquinoline mitophagy inducer ameliorates paclitaxel-induced peripheral neuropathy in Drosophila and mouse models.
    Sangwoo Im, Se Myeong Choi, Young Yeon Kim, Dae Jin Jeong, Jee-Hyun Um, Kang-Min Lee, Eunhee Yoo, Jong Hyun Cho, Ji Hyun Lee, Jeanho Yun.
      Chemotherapy-induced peripheral neuropathy (CIPN) resulting from neurodegeneration due to chemotherapy is a challenging complication of widely administered anticancer drugs including paclitaxel. Although CIPN is common and limits the use of chemotherapies, no curative treatment for CIPN has been developed. Recently, stimulation of mitophagy has emerged as a promising strategy for treating neurodegenerative diseases, but studies on its therapeutic effects on CIPN are limited. In this study, we examined the therapeutic effect of the recently developed mitophagy inducer ALT001 on paclitaxel-induced peripheral neuropathy model in Drosophila and mice. Importantly, ALT001 administration in a paclitaxel-induced Drosophila model of peripheral neuropathy significantly ameliorated paclitaxel-induced alterations in sensory neurons and the thermal hyperalgesia phenotype in a mitophagy-dependent manner. Moreover, we demonstrated that ALT001 administration significantly ameliorated paclitaxel-induced mechanical allodynia and the reduction in intraepidermal nerve fiber density in a mouse model. Interestingly, ALT001 did not interfere with the cytotoxic effect of paclitaxel on lung cancer or breast cancer cells. Our results suggest that ALT001 is a potential candidate for the treatment of paclitaxel-induced peripheral neuropathy and that stimulation of mitophagy is a promising strategy for CIPN treatment that does not affect the cytotoxic effect of chemotherapy.
    Keywords:  Mitophagy; Neuronal degeneration; Paclitaxel; Peripheral neuropathy
    DOI:  https://doi.org/10.1038/s41598-025-04178-y
  64. J Cell Biochem. 2025 Jun;126(6): e70050
    The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
    Sajad Ehtiati, Behzad Hatami, Seyyed Hossein Khatami, Kiarash Tajernarenj, Saeed Abdi, Majid Sirati-Sabet, Seyyed Amir Hossein Ghazizadeh Hashemi, Reyhane Ahmadzade, Nastran Hamed, Marziyeh Goudarzi, Fatemeh Namvarjah, Melika Hajimohammadebrahim-Ketabforoush, Abbas Tafakhori, Vajiheh Aghamollaii, Saeed Karima.
      Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.
    Keywords:  autophagy; beta‐hydroxybutyrate; epigenetic; mitochondrial biogenesis; therapeutic strategies
    DOI:  https://doi.org/10.1002/jcb.70050
  65. Apoptosis. 2025 Jul 01.
    HSV-1 hijacks mitochondrial dynamics: potential molecular mechanisms linking viral infection to neurodegenerative disorders.
    Siping Kuang, Zhiyang He, Jingjing Zhang, Shuli Li, Juntao Ding, Zhenghai Ma, Beibei Zhang.
      Herpes simplex virus type 1 (HSV-1), a neurotropic virus, hijacks the critical neuronal organelle-mitochondria-to establish lifelong latent infection and potentially accelerate neurodegenerative pathologies. Research indicates that HSV-1 infection disrupts mitochondrial dynamics, impairs its bioenergetic function, and compromises interorganellar communication. This disruption is primarily achieved through the degradation of mitochondrial DNA (mtDNA) and the functional alteration of key proteins, leading to excessive production of reactive oxygen species (ROS), intracellular calcium dysregulation, and abnormal energy metabolism. These alterations not only diminish cellular energy production and exacerbate oxidative damage but also readily trigger neuronal cell death. Crucially, the virus specifically interferes with mitochondrial-endoplasmic reticulum contact sites (MERCs) to evade immune surveillance while simultaneously promoting its own replication. In severe encephalitis, mitochondrial damage is closely associated with neuroinflammation. For Alzheimer's disease (AD), HSV-1 may synergize with amyloid-beta pathology through ROS and viral proteins (such as glycoprotein B (gB) and glycoprotein I (gI)), exacerbating disease progression. Paradoxically, HSV-1 also inhibits immediate cell death to sustain host cell survival, facilitating latent viral reactivation. Research elucidating how the virus exploits mitochondria for pathogenesis suggests that future therapeutic strategies could combine classical antiviral drugs with agents that protect mitochondrial function (e.g., antioxidants). This combined approach holds promise for combating acute infection and potentially mitigating the progression of associated neurodegenerative diseases.
    Keywords:  AD; HSE; HSV-1; Immune evasion; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s10495-025-02142-9
  66. Sci Rep. 2025 Jul 01. 15(1): 21604
    The novel amino-artemisinin derivative WHN-11 disrupts mitochondria and protein homeostasis, and induces autophagy and apoptosis in cancer cells.
    Deborah Kajewole, Ho Ning Wong, Alexander von Kriegsheim, Richard K Haynes, Jo-Anne de la Mare, Adrienne Lesley Edkins.
      Semi-synthetic derivatives of artemisinin exhibit anti-cancer activity in vitro and in vivo in addition to anti-malarial activity. Here, we report the anti-cancer and anti-cancer stem cell potential of novel C-10 substituted amino-artemisinin derivatives. Of these, the 4'-trifluoromethylarylurea piperazinyl derivative WHN-11 demonstrated cytotoxic activity at high nanomolar concentrations across a range of cancer cell lines. WHN-11 reduced short- and long-term survival of triple-negative breast cancer (TNBC) cells, a highly aggressive breast cancer subtype that currently lacks standardized targeted treatments. Mechanistically, WHN-11 induced a stress response and increased proteasome-mediated turnover of ubiquitinated proteins. WHN-11 promoted mitochondrial depolarization and fission, suppressing the expression of anti-apoptotic B-cell lymphoma extra-large (Bcl-xL) protein and ATP synthesis, thereby decreasing cellular energy production, and inducing apoptosis. WHN-11 treatment also increased autophagosomes, acidic vesicular organelles and lipid droplets. Activation or inhibition of autophagy synergized with the activity of WHN-11 in promoting cellular toxicity, as did increasing cellular dependence on oxidative phosphorylation. Unexpectedly, the effects of WHN-11 appear independent of substantial reactive oxygen species (ROS) production. Taken together, these data suggest that amino-artemisinins related to WHN-11 are promising candidates for anti-TNBC therapies targeting the mitochondria alone or in combination with autophagy modulators.
    Keywords:  Amino-artemisinin; Apoptosis; Autophagy; Mitochondrial fission; Reactive oxygen species (ROS); Triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1038/s41598-025-05284-7
  67. J Pharmacol Exp Ther. 2025 Jun 11. pii: S0022-3565(25)39842-3. [Epub ahead of print]392(8): 103629
    Exploring novel protective role of semaglutide in 5-fluorouracil-induced hepatotoxicity: Insights into phosphorylated CREB, PINK1/Parkin-mediated mitophagy, and NF-κB/NLRP3 pathways.
    Nermein F El Sayed, Sara A Baraka, Bassant M El-Mokadem, Heba H El Osaily, Abeer Bishr.
      Semaglutide (Sema), a potent glucagon-like peptide-1 receptor agonist, is widely used in the management of type 2 diabetes mellitus due to its glucose-lowering effects. Beyond this, Sema also exhibits antioxidative, anti-inflammatory, antiapoptotic, and autophagy-enhancing properties. However, its potential role against 5-fluorouracil (5-FU)-induced hepatic injury has not yet been investigated. Hence, our study aims to investigate the hepatoprotective role of Sema against 5-FU-induced hepatotoxicity. Rats were randomly distributed in 5 groups: group I was the control group (saline only); group II and the rest of the groups except the normal group received 5-FU (150 mg/kg i.p.) to induce hepatotoxicity; group III received Sema (0.3 mg/kg orally) + 5-FU; group IV received Sema + 5-FU + chloroquine (CQ; 10 mg/kg i.p., 10 minutes prior to 5-FU);group V received 5-FU + CQ. Our results showed that 5-FU markedly increased hepatic enzyme levels, oxidative stress, inflammatory markers, and histological injury. However, pretreatment with Sema effectively counteracted these harmful effects by suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and enhancing PINK1/Parkin-mediated mitophagy. Notably, the addition of CQ, an autophagy inhibitor, abolished the protective role of Sema in autophagic flux. Furthermore, Sema reduced proinflammatory cytokines (tumor necrosis factor-α and interleukin-6), oxidative stress markers (malondialdehyde), and apoptotic markers (caspase-3), enhanced the antioxidant activity (glutathione), and promoted the activation of the phosphorylated CREB/Nrf2/HO-1 signaling pathway. In conclusion, Sema attenuates the 5-FU-induced liver injury through a multifaceted mechanism involving suppression of inflammation, oxidative stress, and apoptosis, as well as by increasing autophagic flux by inducing the phosphorylated CREB/PINK/Parkin trajectory pathway. These findings suggest that Sema holds promise as a novel therapeutic approach for preventing chemotherapy-induced liver toxicity. SIGNIFICANCE STATEMENT: Semaglutide, a GLP-1 receptor agonist, significantly mitigates 5-fluorouracil-induced hepatotoxicity in rats, suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and reducing oxidative stress and inflammation. Semaglutide also enhances mitophagy by activating the phosphorylated CREB/PINK1/Parkin pathway, aiding in the clearance of damaged mitochondria, confirmed using chloroquine, an autophagy inhibitor.
    Keywords:  5-Fluorouracil; Chloroquine; NF-κB; Nrf2; PINK; Semaglutide
    DOI:  https://doi.org/10.1016/j.jpet.2025.103629
  68. Curr Neuropharmacol. 2025 Jun 30.
    Powering Up the Brain: Intercellular Mitochondrial Quality Control and Its Implication in Stroke.
    Xinyu Zhou, Shenzhe Wu, Tianxi Huang, Yue Li, Jianhong Yang, Zhen Gu, Xiangnan Zhang.
      Mitochondria are critical for neuronal survival and function, and their dysregulation is closely related to the incidence and prevalence of various neurological disorders, including stroke. Mitochondrial quality control (MQC) is vital for maintaining mitochondrial integrity, particularly in neurons. Under ischemic conditions, neurons evolve a range of adaptive strategies to preserve mitochondria function dynamically, either by generating functional mitochondria or by eliminating dysfunctional ones via autophagy, both of which play key roles in keeping neuronal survival under the conditions of stroke. Besides these intracellular strategies, the intercellular mechanisms underlying MQC have been observed in the nervous system. Functional mitochondria from healthy cells can be supplemented to ischemic neurons in distinct manners and thus restore the mitochondrial network of recipient cells. Conversely, injured neurons release dysfunctional mitochondria, which can be further degraded by adjacent glial cells. Alternatively, the discarded mitochondria act as a threat to surrounding cells and can disrupt the homeostasis of the nervous system. In this review, the key discoveries in intercellular MQC in the nervous system were summarized, and further discussed the implications of intercellular MQC strategies for stroke therapy.
    Keywords:  Intercellular mitochondrial quality control; intercellular mitochondrial transport; stroke.; trans mitophagy
    DOI:  https://doi.org/10.2174/011570159X388351250620065716
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