bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–11–30
78 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial Quality Control and Cell Death.
  2. Canonical and non-canonical functions of proteins regulating mitochondrial dynamics in mammalian physiology.
  3. Selenoprotein H targets MTCH2 to regulate MFN2-dependent mitochondrial quality control to alleviate acute kidney injury.
  4. Regulation of mitochondrial dynamics and function by melatonin type 1 receptor in parkinson's disease.
  5. Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
  6. Tank-Binding Kinase 1 protects against MASH progression via mitochondrial quality control.
  7. C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.
  8. Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.
  9. Mitochondrial protein TOMM7 alleviates diabetic kidney disease by regulating mitophagy via intracellular redistribution of phospholipase PLA2G6.
  10. Inhibition of SIRT1/PGC-1α Axis Exacerbates Fluorine and Aluminium Induced Neurotoxicity via Drp1-dependent Aggravated Mitochondrial Fission.
  11. APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.
  12. Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration.
  13. Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
  14. Timosaponin B-II attenuates cerebral ischemia injury by enhancing Parkin-mediated mitophagy.
  15. Serotonin-mediated regulation of mitophagy in Alzheimer's disease: mechanistic insights and therapeutic potential.
  16. Supervised machine learning identifies impaired mitochondrial quality control in β cells with development of type 2 diabetes.
  17. Starfish-Derived Extracts Enhance Mitophagy and Suppress Senescence-Associated Markers in Human Dermal Fibroblasts.
  18. Mitochondrial capacities and quality control following short- and long-term weight restoration after simulated anorexia nervosa.
  19. TFEB-nuclear translocation promotes BNIP3-mediated mitophagy and alleviates oxidative stress and ferroptosis in acute pancreatitis.
  20. Quercetin Protects Against Transmissible Gastroenteritis Virus-Induced Intestinal Inflammation by Modulating Mitophagy-Driven Mitochondrial Dysfunction.
  21. Astragalus membranaceus injection activates mitophagy and protects mitochondrial function in chronic heart failure via inhibiting AKT/mTOR pathway.
  22. Anemarrhena asphodeloides-derived small extracellular vesicle ameliorate diabetes-induced muscle atrophy via activating Pink1-mediated mitophagy.
  23. Tau-Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential.
  24. [Astragaloside IV alleviates D-GAL-induced endothelial cell senescence by promoting mitochondrial autophagy via inhibiting the PINK1/Parkin pathway].
  25. Beyond molecular chaperoning: AHA1 reprograms autophagy flux through direct ATP5A1 interaction in ischemic neuronal injury.
  26. The intersection of mitochondrial dynamics and sarcopenic phenotyping: A call for mechanistic detail.
  27. Ventral hippocampal autophagy and mitophagy dynamics shape behavioral responses to chronic mild stress in adult male rats.
  28. The intermediate filament protein GFAP regulates mitochondrial fission in astrocytes.
  29. Anandamide-Induced Neuroprotection of Cortical Neurons Relies on Metabolic/Redox Regulation and Mitochondrial Dynamics.
  30. GSTK1 suppresses HCC aggravation via L-carnitine metabolism by PGAM5/DRP1 complex-mediated mitochondrial quality control.
  31. Protein Phosphatase 1 Regulatory Subunit 17 (PPP1R17) Regulates Cerebral Ischemia and Ischemia-Reperfusion Brain Injury by Suppressing YAP1-Mediated Mitophagy.
  32. ATF5-Dependent GDF15 Expression Mediates Anesthesia-Induced Neuroprotection Against Stroke.
  33. Hypoxia-induced mitoROS triggers M1 linear ubiquitin chains and activates NF-κB signaling.
  34. Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.
  35. PPA1 promotes oxidative phosphorylation and malignant progression of colorectal cancer under glucose restriction via AMPK/ULK1/FUNDC1-mediated mitophagy.
  36. The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism.
  37. Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
  38. ANXA1 improves mitochondrial homeostasis through uncoupling protein 1 in diabetic nephropathy.
  39. Cigarette butts: A hidden toxic time bomb for aquatic metabolism and behavior.
  40. PGC1-α drives MFN2-linked mitochondrial fusion aiding glioblastoma cell survival under TMZ stress.
  41. WDR4-mediate tRNA m7G modification to promote mitophagy and browning of white adipose tissue for ameliorating obesity in male mice.
  42. The Mitochondrial F-box protein 1 and DJ-1 homolog HSP31 support cellular proteostasis during mitochondrial protein import clogging.
  43. Drosophila HS dendrites are resilient to adult-onset deficits in mitochondrial dynamics.
  44. Hyperosmolarity-Induced Oxidative Stress Leads to Senescence in Human Corneal Epithelial Cells (HCEPC) via DNA Damage, Metabolic Disturbance and Mitophagy Decline.
  45. Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.
  46. Naringenin alleviates endotoxin-induced acute kidney injury in chicken by inhibiting pyroptosis through PINK1-dependent mitophagy.
  47. Abnormal cholesterol-cholesteryl ester metabolism impairs mouse oocyte quality during ovarian aging.
  48. Upregulated astrocytic HDAC7 induces depression-like disorders via deacetylating PINK1 and inhibiting mitophagy.
  49. ATG7-driven mitophagy in BMSC@CS hydrogel reprograms metabolism to boost bone regeneration.
  50. Pumpkin Polysaccharide Ameliorates Type 2 Diabetes in Mice via Inhibition of p38 MAPK, Activation of PINK1-PRKN Mitophagy, and Gut Microbiota Modulation.
  51. FGF2 Attenuated Inflammation-Mediated Cardiac Damage: A Novel Mechanistic Insight into the AMPK-FUNDC1-Mitophagy.
  52. A Small-Molecule Mitofusin 1 Agonist Enhances Islet Survival Under Hypoxic Conditions In Vitro and Improves Transplantation Outcomes.
  53. Regulation of UBC12 expression and protein neddylation by PINK1 suggests a primate-specific function.
  54. [Qingre Lidan Jiedu Recipe improves high copper load-induced cognitive dysfunction in rats by regulating mitophagy].
  55. New insights into mitochondrial segregation from the Doubly Uniparental Inheritance system in bivalves.
  56. Activation of RXRα mitigates maternal separation-induced hippocampal neurodevelopmental impairment in mice by inhibiting oxidative stress and restoring mitochondrial homeostasis.
  57. Low dose ionising radiation elicits MPTP comparable alterations in locomotor Function, oxidative balance and mitochondrial homeostasis in zebrafish embryos.
  58. Extracellular vesicles from Yiguanjian-primed bone-marrow mesenchymal stem cells ameliorate chronic liver fibrosis via miR-7045-5p.
  59. Oxymatrine Alleviates Cerebral Ischemia/Reperfusion Injury By Targeting HDAC1 to Regulate Mitochondria-Related Autophagy and Oxidative Stress.
  60. Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.
  61. A Sirtuin-1-Targeted Gene-Activating Tetrahedral DNA Attenuates Bladder Fibrosis by Restoring Mitophagy in Fibroblasts via the SIRT1-FOXO3-BNIP3 Axis.
  62. Photodynamic Anticancer Efficacy of meso-tris-p-Carboxyphenylporphyrin-Fullerene Dyads: Apoptosis Induction and Mitochondrial Deregulation in Glioblastoma Therapy.
  63. Ailanthone restrains hepatocellular carcinoma progression by inducing ferroptosis and disrupting mitochondrial homeostasis.
  64. Nrf2 Activated by PD-MSCs Attenuates Oxidative Stress in a Hydrogen Peroxide-Injured Retinal Pigment Epithelial Cell Line.
  65. Mitochondrial Dysfunction in Cardiomyopathy and Heart Failure: From Energetic Collapse to Therapeutic Opportunity.
  66. mTORC1-USP30-LEF1 Cascade Regulates Cancer Stemness and Malignant Progression Through Mitonuclear Crosstalk.
  67. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
  68. Neuroprotective Role of Piperine-Encapsulated Casein Micelles in Mitigating Intracellular Dyshomeostasis in Alzheimer's Disease Pathology.
  69. Olivomycin A Targets Epithelial-Mesenchymal Transition, Apoptosis, and Mitochondrial Quality Control in Renal Cancer Cells.
  70. Caenorhabditis Elegans Ortholog of TNF Alpha-Induced Protein 1 is Upregulated by TOL-1 and Exacerbates Amyloid-Beta-Associated Pathology.
  71. Mitochondrial Dynamics in Aging Heart.
  72. Mitochondrial Network Fragmentation Leads to Dysfunction of Macrophages During Echinococcus multilocularis Protoscoleces Infection.
  73. Coenzyme Q10 ameliorates obesity by promoting white adipose tissue browning and preserving mitochondrial dynamics in ovariectomized rats fed a high-fat diet.
  74. Obestatin treatment links mitochondrial homeostasis and skeletal muscle repair in Duchenne muscle dystrophy.
  75. Mitochondrial involvement in PC: improving therapeutic strategies.
  76. Ultrasensitive Biocoded SERS Immunoassay for Tracing Molecular Gatekeeper Mfn2 Expression within Single Cells during Stem Cell Differentiation.
  77. Gram-scale synthesis of the thiazolidinedione-based mitoNEET ligand NL-1 using a Hantzsch ester reduction.
  78. Portioning organelles for autophagic clearance.
  1. Int J Mol Sci. 2025 Nov 16. pii: 11084. [Epub ahead of print]26(22):
    Mitochondrial Quality Control and Cell Death.
    Zurui Zhang, Mengyuan Zhang, Hongchi Jin, Shuang Lv, Yilei Li, Yanru Li.
      Mitochondrial quality control includes mitochondrial biogenesis, fusion, fission (to maintain mitochondrial function), and mitochondrial autophagy (for removing damaged mitochondria). This is a highly delicate and complex process involving many molecules. Mitochondrial quality control is crucial for maintaining mitochondrial homeostasis and function, preserving energy supply, eliminating damaged mitochondria to prevent cytotoxicity, promoting mitochondrial regeneration and repair, protecting cells from oxidative stress and senescence, and facilitating cellular communication and material exchange. In this review, we introduce the structure and function of mitochondria, the mechanisms of quality control, and the relationship between mitochondrial quality control and cellular processes such as pyroptosis, apoptosis, and ferroptosis. We also summarize the proteins, enzymes, and their molecular mechanisms involved in these processes and propose a "spatiotemporal-threshold" model for the mitochondrial quality control-cell death axis.
    Keywords:  apoptosis; ferroptosis; mitochondrial autophagy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; pyroptosis
    DOI:  https://doi.org/10.3390/ijms262211084
  2. J Physiol. 2025 Nov 22.
    Canonical and non-canonical functions of proteins regulating mitochondrial dynamics in mammalian physiology.
    Rémi Chaney, Vincent Marcangeli, Krystel Desjardins, Shima Taherkhani, Gilles Gouspillou.
      Mitochondria are dynamic and multifunctional organelles central to cellular bioenergetics and metabolism and acting as vital signalling hubs. Their morphology is finely regulated by the opposing processes of fusion and fission, predominantly controlled by four key GTPases: mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (DRP1). In humans, mutations in their genes are linked to a broad range of pathological disorders. In animal models, both loss- and gain-of-function manipulations of these proteins lead to diverse physiological outcomes. Recent research has uncovered that, beyond their canonical roles in shaping mitochondrial morphology, these GTPases also participate in a variety of non-canonical cellular functions, impacting broader aspects of cell physiology. In this review, we examine the established functions of these GTPases in mitochondrial dynamics alongside their emerging roles beyond shaping mitochondrial morphology. We also provide an in-depth overview of how alterations in their expression or activity influence mammalian health and physiology. By highlighting the multifaceted roles and broad physiological impact of mitochondrial fusion and fission proteins, we aim to underscore their complex biology and promote further investigation into their broader physiological significance.
    Keywords:  GTPases; Mitofusins; dynamin‐related protein 1; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; optic atrophy 1
    DOI:  https://doi.org/10.1113/JP287149
  3. J Adv Res. 2025 Nov 26. pii: S2090-1232(25)00955-5. [Epub ahead of print]
    Selenoprotein H targets MTCH2 to regulate MFN2-dependent mitochondrial quality control to alleviate acute kidney injury.
    Dongliu Luo, Yaning Qiu, Jiahong Chu, Haodong Hu, Yanhe Zhang, Yu Xia, Fuze She, Shiwen Xu, Fating Zhu, Zhiruo Miao, Shu Li.
       INTRODUCTION: Mitochondrial dysfunction is recognized as a pivotal event in the pathogenesis of acute kidney injury (AKI). Selenoprotein (SelH), a mammalian selenoprotein, is extensively involved in regulating of diseases associated with mitochondrial dysfunction. However, its regulatory role in mitochondrial quality control during AKI remains unclear.
    OBJECTIVES: This study aims to explore the impact of SelH on AKI and potential regulatory mechanisms of SelH in AKI.
    METHODS: In vivo, a cisplatin (CP)-induced AKI model was established using SelH knockout mice to evaluate renal injury. Additionally, co-immunoprecipitation (Co-IP). combined with mass spectrometry, Co-IP assays, laser confocal microscopy, and molecular docking were employed to identify proteins interacting with SelH. In vitro, SelH/mitochondrial carrier homolog 2 (MTCH2) knockdown and overexpression models were constructed in HEK293t cells. Indicators related to oxidative stress, mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and apoptosis were analyzed.
    RESULTS: MTCH2 was identified as a potential interacting partner of SelH. Deficiency of renal SelH directly triggered oxidative stress, impaired mitochondrial biogenesis, disrupted mitochondrial dynamics, enhanced mitophagy, and promoted apoptosis. In HEK293t cells, SelH targeted MTCH2 to regulate mitofusin 2 (MFN2), thereby promoting mitochondrial fusion, alleviating mitochondrial dysfunction, maintaining mitochondrial quality control (MQC) homeostasis, and reducing renal oxidative damage and apoptosis.
    CONCLUSION: The results showed that SelH targets the MTCH2/MFN2 aixs to maintain MQC balance, alleviate oxidative stress and cell apoptosis induced by AKI. This study not only supplements kidney specific regulatory targets for the field of mitochondrial medicine but also suggests that SelH could serve as a potential molecule for proactive medicine intervention in AKI, providing experimental evidence for the early intervention of AKI.
    Keywords:  Acute kidney injury; Apoptosis; MTCH2; Restored mitochondrial homeostasis and functionality; Selenoprotein H
    DOI:  https://doi.org/10.1016/j.jare.2025.11.059
  4. Cell Mol Life Sci. 2025 Nov 25.
    Regulation of mitochondrial dynamics and function by melatonin type 1 receptor in parkinson's disease.
    Xiao-Bo Wang, Li-Li Qi, Jian-Min Wang, Yan-Rui Sun, Qian-Kun Lv, Bing-Er Cao, Shu-Min Jiang, Quan-Hong Ma, Chun-Feng Liu, Jun-Yi Liu, Fen Wang.
      Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron loss and Lewy bodies in the substantia nigra. Abnormal mitochondrial function and accumulated α-synuclein (α-syn) are key etiological factors of PD. Melatonin type 1 receptor (MT1) regulates sleep upon activation by melatonin and may be reduced in PD patients. However, the role of MT1 in PD pathogenesis remains elusive. In this study, we found knockdown of MT1 caused mitochondrial dysfunction, mitochondrial fission and mitophagy in SH-SY5Y cells. Expression of mitochondrial fission protein dynamin-related protein 1 (DRP1) was increased and expression of fusion proteins optic atrophy 1 (OPA1), mitofusin 1 (MFN1) and mitofusin 2 (MFN2) were decreased. This was probably attributed to decreased phosphorylation of DRP1 at S637 by protein kinase A (PKA) and increased phosphorylation at S616 by extracellular-regulated kinase 1/2 (ERK1/2). Loss of MT1 exacerbated mitochondrial fission without influencing mitophagy, TH expression and movement in an MPTP-induced mouse model. Neuronal MT1 deficiency aggravated preformed fibrils induced autophagy inhibition and α-syn aggregation. Overexpression of MT1 reduced mitochondrial fission, increased LC3II expression and decreased P62 accumulation to promote autophagy in HEK293T cells, thus mitigating aggregation of α-syn. This study demonstrates the function of MT1 in mitochondria and autophagy, which sheds further light on PD prevention targeting MT1.
    Keywords:  Autophagy; MPTP; Melatonin receptor MT1; Mitochondria dynamics; Parkinson’s disease; Α-synuclein
    DOI:  https://doi.org/10.1007/s00018-025-05995-0
  5. Exp Gerontol. 2025 Nov 20. pii: S0531-5565(25)00299-2. [Epub ahead of print] 112970
    Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
    Shota Uebo, Yoshiyuki Ikeda, Yoshihiro Uchikado, Yuichi Sasaki, Yuichi Akasaki, Takuro Kubozono, Mitsuru Ohishi.
      Aim Sarcopenia, a major cause of frailty in postmenopausal women, is linked to mitochondrial dysfunction, but the underlying mechanisms remain unclear. This study aimed to clarify whether mitophagy, a mitochondrial quality control mechanism, contributes to postmenopausal sarcopenia, to elucidate its underlying mechanism, and to assess whether it can be rescued.
    METHODS: C57BL/6 mice (12-week-old females) underwent ovariectomy to establish a menopause mouse model, or sham surgery, and the therapeutic effects of nicotinamide mononucleotide (NMN) were assessed. Human skeletal muscle myoblasts (HSMMs) differentiated under postmenopausal conditions with or without 17β-estradiol (E2), and Rab9 expression was modulated using CRISPR activation.
    RESULTS: Ovariectomized mice exhibited decreased muscle mass and strength. E2 deficiency in HSMMs inhibited skeletal muscle cell differentiation, promoted senescence, impaired mitochondrial function, and reduced mitophagy. However, E2 deficiency did not modulate light chain 3 and autophagy-related 7 but reduced Rab9 expression and the colocalization of Rab9 with lysosomal-associated membrane protein 2, suggesting that E2 mediates mitophagy through Rab9-dependent alternative autophagy. Furthermore, overexpression of Rab9 in E2-deficient HSMMs enhanced mitophagy, improved mitochondrial function, suppressed cellular senescence, and promoted skeletal muscle cell differentiation. The administration of NMN to ovariectomized mice increased Rab9 expression and improved sarcopenia through increased mitophagy.
    CONCLUSION: This study demonstrates that estrogen deficiency impairs mitophagy originated from Rab9-dependent alternative autophagy, leading to mitochondrial dysfunction and sarcopenia, while enhancement of Rab9 restores mitochondrial quality control and muscle function. These results identify Rab9-dependent mitophagy as a potential therapeutic target for postmenopausal sarcopenia.
    Keywords:  Alternative autophagy; Estrogen; Menopause-induced sarcopenia; Mitochondria; Mitophagy; Nicotinamide mononucleotide; Rab9
    DOI:  https://doi.org/10.1016/j.exger.2025.112970
  6. Res Sq. 2025 Oct 09. pii: rs.3.rs-7476559. [Epub ahead of print]
    Tank-Binding Kinase 1 protects against MASH progression via mitochondrial quality control.
    Jin Young Huh, Sung-Min An, Jun Hee Jang, Jin Hyun Sung, Ji Won Myung, Yong Geun Jeon, Won Taek Lee, Jin Won Jeon, Kyung Min Yim, Jae-Ho Lee, Bichen Zhang, Jong Bae Seo, Seung Soon Im, Jae Bum Kim, Alan Saltiel.
      Mitochondrial dysfunction is a critical driver of metabolic dysfunction-associated steatotic liver disease (MASLD) progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here, we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1 knockout (LTKO) mice, we show that TBK1 loss leads to the accumulation of depolarized, ROS-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal acidification. Therapeutic restoration of TBK1 expression via AAV8 delivery enhanced mitophagy, reduced mitochondrial burden, and ameliorated liver fibrosis. Notably, both human samples and murine steatohepatitis models exhibited a significant decline in TBK1 kinase activity. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH.
    DOI:  https://doi.org/10.21203/rs.3.rs-7476559/v1
  7. Cells. 2025 Nov 11. pii: 1765. [Epub ahead of print]14(22):
    C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.
    Francesca Sironi, Paola Parlanti, Cassandra Margotta, Jessica Cassarà, Valentina Bonetto, Caterina Bendotti, Massimo Tortarolo, Valentina Cappello.
      The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS.
    Keywords:  amyotrophic lateral sclerosis; atrogenes; autophagy; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.3390/cells14221765
  8. FEBS Open Bio. 2025 Nov 23.
    Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.
    Chatnapa Panusatid, Rapasviranda Soiyangsuk, Maneeluck Tanadjindarat, Chayanon Peerapittayamongkol.
      Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder caused by mitochondrial DNA mutations in complex I of the respiratory chain, leading to impaired ATP production, mitochondrial fragmentation, and oxidative stress that contribute to vision loss. This study investigated the potential repurposing of metformin, a widely used antidiabetic drug, in fibroblasts from LHON patients carrying the m.11778G>A mutation. Fibroblasts from LHON patients and healthy individuals were treated with metformin, and mitochondrial function was assessed using high-content imaging, biochemical assays, immunoblotting, immunofluorescence, and Seahorse analysis. Metformin reduced mitochondrial fragmentation, increased network length, stabilized mitochondrial membrane potential, enhanced ATP production, and lowered ROS accumulation under oxidative stress. Metformin significantly increased mitophagy and autophagic flux, as shown by LC3B puncta quantification with and without chloroquine, and activated AMPK signaling through increased AMPKα1/2 phosphorylation and AMPKβ1 Ser182 phosphorylation. In addition, metformin promoted PGC-1α nuclear translocation, indicating stimulation of mitochondrial biogenesis, while maintaining mtDNA copy number and supporting oxidative phosphorylation. These findings suggest that metformin, at clinically relevant concentrations, enhances mitochondrial health and function in LHON fibroblasts, supporting its potential as an affordable and safe therapeutic option to mitigate vision loss in LHON.
    Keywords:  AMPK activation; Leber's hereditary optic neuropathy; Metformin; Mitochondrial dynamics; Mitophagy; Primary fibroblasts
    DOI:  https://doi.org/10.1002/2211-5463.70165
  9. Kidney Int. 2025 Nov 21. pii: S0085-2538(25)00882-8. [Epub ahead of print]
    Mitochondrial protein TOMM7 alleviates diabetic kidney disease by regulating mitophagy via intracellular redistribution of phospholipase PLA2G6.
    Yi-Hui Wang, Dong-Yuan Chang, Yi-Yang Zhao, Sydney Chi-Wai Tang, Ming-Hui Zhao, Min Chen.
       INTRODUCTION: Accumulating evidence indicates that kidney tubular injury is central to the pathogenesis of diabetic kidney disease (DKD). Mitophagy plays a pivotal role in maintaining mitochondrial homeostasis, particularly in kidney tubular cells since they are enriched with mitochondria. However, the molecular mechanisms regulating mitophagy in DKD remain poorly understood. Here, we investigated the role of translocase of outer mitochondrial membrane 7 (TOMM7), a key regulator of protein kinase/ubiquitin ligase PINK1/Parkin-mediated mitophagy, in the progression of DKD.
    METHODS: Kidney tissue from patients with DKD and db/db mice, and high glucose/palmitic acid-treated HK-2 cells were employed to investigate TOMM7 expression and mitophagy activity. Regulatory mechanisms involving phospholipase PLA2G6 redistribution and zinc finger protein ZBTB12-mediated transcriptional repression were further explored, and a lithocholic acid-conjugated Zbtb12 small interfering (si)RNA was developed for targeted kidney therapy.
    RESULTS: Expression of TOMM7 was significantly downregulated in kidney tissue of patients with DKD, db/db mice and high glucose/palmitic acid treated kidney tubular cells accompanied by impaired PINK1/Parkin-mediated mitophagy. Tomm7 overexpression in db/db mice significantly alleviated injury and restored PINK1/Parkin-mediated mitophagy. Mechanistically, TOMM7 regulated PINK1/Parkin recruitment by modulating the intracellular redistribution of PLA2G6 between the nucleus and mitochondria in kidney tubular cells. Moreover, we identified ZBTB12 as a transcription repressor of TOMM7 and developed a tubular cells targeted siRNA for Zbtb12 to achieve specific upregulation of TOMM7 in the kidney. Furthermore, treatment with lithocholic acid-conjugated Zbtb12 siRNA attenuated tubular injury and enhanced mitophagy by increasing TOMM7 expression in db/db mice.
    CONCLUSIONS: Our findings highlighted that TOMM7 enhanced PINK1/Parkin-mediated mitophagy through regulating intracellular redistribution of PLA2G6 in tubular cells in DKD models. Zbtb12 siRNA may be a potential treatment strategy targeting kidney tubular cells in DKD.
    Keywords:  PINK1; PLA2G6; TOMM7; ZBTB12; diabetic kidney disease; mitophagy
    DOI:  https://doi.org/10.1016/j.kint.2025.10.009
  10. Mol Neurobiol. 2025 Nov 26. 63(1): 177
    Inhibition of SIRT1/PGC-1α Axis Exacerbates Fluorine and Aluminium Induced Neurotoxicity via Drp1-dependent Aggravated Mitochondrial Fission.
    Liu Yang, Xiaoling Qian, Hongshuang Jiang, Chun Xie.
      Both fluorine (F) and aluminium (Al) exhibit neurotoxic effects. Fluorine and aluminium (FA) coexist in naturally and artificially polluted environments and potentially affect human cognitive functions. However, the mechanism through which FA exposure impairs spatial learning and memory of the second-generation offspring (F2) rats remains unknown. Mitochondria are critical for brain function and are responsible for energy production. Excessive mitochondrial fission can cause dysfunction and neuron damage. In this study, SD rats were exposed to FA, while NG108-15 cells were pretransfected with peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) siRNA or the silent information regulator1 (SIRT1) siRNA or treated with mitochondrial division inhibitor-1 (Mdivi-1), and then exposed to FA. FA exposure led to histopathological and mitochondrial structural abnormalities in the cerebral cortex; reduced GAP-43 and Ng protein expression; induced mitochondrial dysfunction; increased dynamin-related protein1 (Drp1), fission protein1 (Fis1) and mitochondrial fission factor (MFF) expression; and inhibited expression of proteins involved in the p-Drp1 (Ser637) and SIRT1/PGC-1α pathways in neurons. In vitro experiments revealed that silencing PGC-1α or SIRT1 exacerbated the FA-induced mitochondrial fission. However, treatment with Mdivi-1 suppressed mitochondrial fission and alleviated mitochondrial dysfunction caused by FA. These findings reveal that the SIRT1/PGC-1α pathway plays a role in regulating mitochondrial fission and is involved in FA-induced neurotoxicity, highlighting the protective effects of Mdivi-1 against FA-induced neurotoxicity.
    Keywords:  Aluminium; Fluorine; Mdivi-1; Mitochondria; SIRT1/PGC-1α
    DOI:  https://doi.org/10.1007/s12035-025-05400-8
  11. Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01385-1. [Epub ahead of print]243 245-259
    APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.
    Firoz Akhter, Asma Akhter, Donghui Zhu.
      APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease (AD), is closely associated with mitochondrial dysfunction, yet the mechanisms remain poorly defined. We identify a previously unrecognized failure of the Nrf2-PINK1/Parkin axis in APOE4 neurons that compromises mitochondrial quality control. Unlike APOE3, APOE4 neurons fail to activate PINK1/Parkin-dependent mitophagy under stress, a defect compounded by impaired Nrf2 signaling and weakened antioxidant defenses. In vivo, APOE4 mice show age-dependent collapse of this pathway, correlating with progressive mitochondrial dysfunction and disrupted mito-nuclear communication. Pharmacological activation of Nrf2 or PINK1 restores mitochondrial clearance, highlighting the axis as a druggable node. These findings provide a mechanistic link between APOE4 and mitochondrial failure, establishing the Nrf2-PINK1/Parkin pathway as a critical driver of neurodegeneration and a promising target for therapeutic intervention in AD.
    Keywords:  APOE4; Alzheimer's disease (AD); Mito-nuclear communication; Mitochondrial stress; Mitophagy; Nrf2-PINK/Parkin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.040
  12. Pharmacol Res. 2025 Nov 21. pii: S1043-6618(25)00468-2. [Epub ahead of print]222 108043
    Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration.
    Chenrong Jin, Juhui Qiao, Huilin Gong, Xiaorui Yu, Xinran Wang, Jiao Xi, Runying Mi, Shiting Yu, Daian Pan, Siming Wang, Xiaolin Tong, Daqing Zhao, Meichen Liu.
      Aging profoundly impacts the brain, serving as a primary driver of neurodegenerative diseases through mechanisms closely linked to mitochondrial dysfunction. Despite its clinical significance, the molecular mechanisms remain unclear, and safe, effective therapies are urgently needed. Here, leveraging ginseng's neuroprotective potential, we screened for blood-brain barrier-permeable saponins with optimal neuroprotective efficacy and identified ginsenoside Re (Re) as the predominant mitochondrially targeted neuroprotective saponin. Midlife Reintervention, temporally aligned with the natural window of mitochondrial hyperfusion, rescued age-related degenerative pathology in Drosophila. Re administration ameliorated dopaminergic neuron loss, mitigated muscles pathology, improved cognitive-motor deficits, and extended healthspan. Mechanistic studies revealed that Re directly binds to the Drp1 across multiple species via the highly conserved L94 residue, triggering robust S616 phosphorylation that drives Drp1 translocation to mitochondria, thereby restoring fission-fusion equilibrium. Re further spatiotemporally coupled fission-mitophagy through the Drp1-Atg1/ULK1 axis, enabling autophagosome initiation and ensuring efficient clearance of damaged organelles. This dual regulation enhanced bioenergetic capacity and delayed functional decline. Genetic ablation of Drp1 L94 completely abolished Re's benefits, while translational studies in mice confirmed that healthspan extension required intact Drp1-L94 functionality. Notably, Re demonstrated conserved neuroprotective efficacy in both human induced pluripotent stem cells-derived dopaminergic neurons and Drosophila Parkinson's model, indicating preservation of the Drp1-mitophagy pathway across species. Our findings establish Re as a geroprotector that targets the conserved Drp1-L94 residue to restore mitochondrial homeostasis. By spatiotemporally coupling fission to Atg1-mediated mitophagy during the critical midlife hyperfusion window, Re delays neurodegeneration, thereby establishing a molecular basis for developing therapies against age-related decline.
    Keywords:  Brain aging; Drp1 mutants; Ginsenoside Re; Mitochondrial dynamics; Mitophagy axis
    DOI:  https://doi.org/10.1016/j.phrs.2025.108043
  13. Int J Mol Sci. 2025 Nov 13. pii: 10977. [Epub ahead of print]26(22):
    Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
    Neil V Yang, Sean Rogers, Rachel Guerra, Justin Y Chao, David J Pagliarini, Elizabeth Theusch, Ronald M Krauss.
      Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy.
    Keywords:  mitochondrial dynamics; skeletal muscle; statin; translocase of outer mitochondrial membrane; transmission electron microscopy
    DOI:  https://doi.org/10.3390/ijms262210977
  14. Phytomedicine. 2025 Nov 24. pii: S0944-7113(25)01216-4. [Epub ahead of print]149 157580
    Timosaponin B-II attenuates cerebral ischemia injury by enhancing Parkin-mediated mitophagy.
    Yueyang Liu, Hanxiao Shang, Lu Zhang, Rong Fu, Yayi Li, Zhuo Wang, Yanru Zhen, Qi Zhang, Yang Zhao, Guannan Wang, Ming-Sheng Zhou.
       BACKGROUND: Ischemic stroke (IS) is linked to dysregulated mitophagy. Timosaponin B-II (TBII), a complex furostan steroid saponin extracted from Anemarrhena asphodeloides Bunge, has been demonstrated to play a crucial role in regulating autophagy. However, whether TBII exerts therapeutic effects in cerebral ischemia through the regulation of autophagy, particularly Parkin-dependent pathways remained unexplored.
    PURPOSE: The present study investigated whether TBII can alleviate cerebral ischemic injury by enhancing Parkin-dependent mitophagy.
    METHODS: We evaluated TBII's effects on cerebral ischemic injury using permanent middle cerebral artery occlusion (pMCAO) in mice and oxygen-glucose deprivation (OGD)-treated neurons. Mitophagy and mitochondrial function were assessed by Western blot, transmission electron microscopy (TEM), and immunofluorescence techniques. Parkin knockdown (shPrkn lentivirus) and the mitophagy inhibitor Mdivi-1 were employed to validate TBII' mechanisms.
    RESULTS: Intragastrical (i.g.) administration of TBII (10, 20, 40 mg/kg) for 7 days significantly reduced cerebral infarction volume, brain water content, and neurological deficits in pMCAO mice, while attenuating neuronal death in vivo and in vitro. Molecular docking, cellular thermal shift assays (CETSA), drug affinity responsive target stability (DARTS), and molecular dynamics simulations confirmed that TBII specifically binds and stabilizes to Parkin, suggesting its potential to enhance mitophagy. TBII mitigated the impairment of mitophagy by upregulating Parkin and p-Parkin (Ser65), promoting the ubiquitination of mitochondria, the degradation of autophagy substrate SQSTM1 and damaged mitochondria after IS. TBII also preserved mitochondrial membrane potential (MMP), suppressed oxidative stress, and restored mitochondrial function and ultrastructure. These benefits were reversed by the mitophagy inhibitor Mdivi-1 and Parkin knockdown.
    CONCLUSION: The present study demonstrates that TBII reduces oxidative stress, preserves mitochondrial function, and ultimately attenuates ischemic brain injure by enhancing Parkin-dependent mitophagy. Our study provides the first evidence supporting TBII as a promising therapeutic agent for IS.
    Keywords:  Ischemic stroke; Mitophagy; Oxidative stress; Parkin; Timosaponin B-II
    DOI:  https://doi.org/10.1016/j.phymed.2025.157580
  15. Ageing Res Rev. 2025 Nov 25. pii: S1568-1637(25)00303-4. [Epub ahead of print] 102957
    Serotonin-mediated regulation of mitophagy in Alzheimer's disease: mechanistic insights and therapeutic potential.
    Omme Fatema Sultana, Madhuri Bandaru, Mst Anika Bushra, P Hemachandra Reddy, Arubala P Reddy.
      This review delves into the intricate relationship between serotonin signaling, mitophagy and mitochondrial dysfunction in Alzheimer's disease (AD), with a focus on the mechanistic pathways that link these processes and their potential therapeutic implications. A neurodegenerative condition called Alzheimer's disease is marked by cognitive deterioration. It is increasingly recognized as being influenced by impaired mitochondrial function and mitophagy, the selective degradation of damaged mitochondria. Serotonin, a neurotransmitter traditionally known for its role in mood regulation, has emerged as a critical modulator of mitochondrial dynamics and quality control through its interaction with key pathways such as the PINK1-Parkin and cAMP/PKA signaling pathways. In AD, alterations in serotonin levels and receptor function are associated with disruptions in mitophagy, leading to the accumulation of dysfunctional mitochondria, increased oxidative stress, and subsequent neuronal damage. This review synthesizes current evidence that links serotonin dysregulation to mitochondrial pathology in AD, exploring how impaired serotonin signaling exacerbates mitochondrial dysfunction and contributes to amyloid-beta (Aβ), phosphorylation of Tau (p-Tau) accumulations, and increased neuroinflammation. Additionally, we assessed the therapeutic potential of serotonin-targeting agents, particularly selective serotonin reuptake inhibitors (SSRIs), in restoring mitophagy, enhancing mitochondrial integrity, and attenuating neurodegeneration. By highlighting existing knowledge gaps and key controversies, this review underscores the promise of serotonin-mitochondria pathways as novel therapeutic targets and advocates for focused investigation into receptor-specific, mitophagy-centered interventions for AD.
    Keywords:  Alzheimer's disease; PINK1-Parkin pathway; mitochondrial dysfunction; mitophagy; selective serotonin reuptake inhibitors (SSRIs); serotonin
    DOI:  https://doi.org/10.1016/j.arr.2025.102957
  16. bioRxiv. 2025 Oct 23. pii: 2025.10.22.683335. [Epub ahead of print]
    Supervised machine learning identifies impaired mitochondrial quality control in β cells with development of type 2 diabetes.
    Mirza Muhammad Fahd Qadir, Charles Dana, Paul Mauvais-Jarvis, Nazmul Haque, Theodore Dos Santos, Patrick E MacDonald, Franck Mauvais-Jarvis.
      In type 2 diabetes (T2D), molecular pathways driving β cell failure are difficult to resolve with standard single cell analysis. Here we developed an interpretable, supervised machine learning framework that couples sparse rule-based classification (SnakeClassifier), pathway constrained modelling (BlackSwanClassifier), and β cell mitochondrial fitness stratification (Kolmogorov-Arnold Neural Networks KANN), linking and integrating them into disease mechanisms in single cell RNA sequencing (scRNA-seq) from 52 human donors. SnakeClassifier trained on 50 genes accurately predicted T2D at single cell resolution, outperforming classical ensemble machine learning classifier models, and yielded donor level diabetes scores that correlated with chronic hyperglycemia. The clustering of β cell populations (β1-4) revealed a resilient non-diabetic (ND) β1 subtype characterized by preserved β cell identity genes and lower disease risk, whereas T2D β2-4 subtypes exhibited upregulation of genes involved in cellular and mitochondrial stress and suppression of genes promoting oxidative phosphorylation and insulin secretion. Mitophagy emerged as the dominant program linked to T2D and a mitophagy focused BlackSwanClassifier nominated PINK1, BNIP3 , and FUNDC1 as key regulators. PINK1 was enriched in ND β1, decreased with T2D disease score and connected sex stratified mitophagy. We generated a KANN derived mitochondrial fitness index (MFI) integrating mitophagy, mitochondrial proteostasis, biogenesis and oxidative phosphorylation into a single interpretable score (R 2 = 0.934 vs module-based mitochondria quality index), which identified mitophagy PINK1, SQSTM1, PRKN and BNIP3 as top contributors to T2D progression. These transparent models unify prediction with T2D disease mechanism and identify the mitophagy receptor PINK1 as a central determinant of β cell metabolic fitness.
    DOI:  https://doi.org/10.1101/2025.10.22.683335
  17. Mar Drugs. 2025 Oct 27. pii: 418. [Epub ahead of print]23(11):
    Starfish-Derived Extracts Enhance Mitophagy and Suppress Senescence-Associated Markers in Human Dermal Fibroblasts.
    Hyun Jung Lee, Junhee Kim, Bada Won, Dong Hun Lee, Ok Sarah Shin.
      While the starfish species Asterias pectinifera (Ap) and Asterias amurensis (Aa) are considered ecological threats to marine environments and the fishing industry, recent studies have identified them as rich sources of highly water-soluble, non-toxic collagen peptides. Mitochondrial dysfunction is a key driver of cellular senescence and skin aging, yet the therapeutic potential of marine-derived extracts in modulating mitophagy remains largely unexplored. In this study, we investigated whether starfish-derived extracts could mitigate senescence-associated phenotypes in human dermal fibroblasts (HDFs) through the modulation of mitophagy. Treatment with Ap- or Aa-derived extracts led to reduced senescence-associated β-galactosidase (SA-β-gal) activity, decreased expression of matrix metalloproteinase-1 (MMP-1), and suppression of pro-inflammatory cytokines including interleukin-6 (IL-6) and interleukin-8 (IL-8). Ap- or Aa-derived extracts significantly increased mitophagy in HDFs stably expressing mitochondrial-targeted Keima (HDF-mtKeima), while knockdown of PINK1, the essential regulator of mitophagy, abolished the mitophagy-inducing effects of Ap- or Aa-treatment, indicating that Ap- or Aa-derived extracts activate PINK1/Parkin-dependent mitophagy pathways. Importantly, PINK1 knockdown reversed starfish-induced suppression of MMP-1 and p21, demonstrating its crucial role in regulating senescence-associated gene expression. Additionally, Ap or Aa treatments significantly reduced reactive oxygen species (ROS) accumulation, improved mitochondrial function, and enhanced both basal and maximal respiratory capacity in senescent HDFs. These findings highlight that extracts derived from starfish promote mitophagy through PINK1-dependent mechanisms, exhibiting significant anti-senescence effects in HDFs. This suggests their potential application in the development of novel cosmeceuticals with skin-protective and rejuvenating properties.
    Keywords:  human dermal fibroblasts; mitophagy; senescence; skin aging; starfish-derived extracts
    DOI:  https://doi.org/10.3390/md23110418
  18. Exp Physiol. 2025 Nov 29.
    Mitochondrial capacities and quality control following short- and long-term weight restoration after simulated anorexia nervosa.
    Megan E Rosa-Caldwell, Toby L Chambers, Lauren Breithaupt, Ruqaiza Muhyudin, Patience Salvalina Okoto, Sadie R Thompson, Emily E Rothacker, Claire Greenhill, Katie A Wood, Kevin A Murach, Sarah H White-Springer, Ursula B Kaiser, Seward B Rutkove.
      Anorexia nervosa (AN) is a psychiatric disorder characterized by prolonged caloric restriction and skeletal muscle atrophy. Mitochondrial health is a key mediator of muscle function, yet the role of mitochondria during AN and following weight regain has not been investigated. The objective of this study was to evaluate mitochondrial capacities and quality control mechanisms in a rodent model of AN, spanning the acute underweight phase and multiple recovery periods. Through a series of experiments, 8-week-old female Sprague-Dawley rats underwent a 30-day simulated AN protocol, followed by different durations of weight recovery via ad libitum feeding. Following designated interventions, muscle performance on a submaximal fatiguing protocol and components of mitochondrial function were evaluated. AN resulted in 23%-25% lower muscle performance compared to healthy controls, and these alterations remained even after short-term weight gain. AN rats had 23% lower contribution of complex I to maximal mitochondrial electron transfer as well as alterations to genes important for mitochondrial translation and dynamics, many of which were not resolved with short-term recovery. With long-term recovery, muscle performance and mRNA content of genes related to mitochondrial translation were similar to healthy controls. However, genes related to mitochondrial fission were greater than healthy controls. AN results in reduced muscle performance during a fatiguing protocol, reliance on mitochondrial complex I and genes related to mitochondrial quality control. Many alterations persist with short-term weight recovery; however, given sufficient time, many facets of mitochondrial health appear to normalize following AN, though there still may be long-term consequences to mitochondrial dynamics.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial translation; mitophagy; muscle fatigability; starvation
    DOI:  https://doi.org/10.1113/EP093325
  19. Free Radic Biol Med. 2025 Nov 23. pii: S0891-5849(25)01390-5. [Epub ahead of print]243 398-413
    TFEB-nuclear translocation promotes BNIP3-mediated mitophagy and alleviates oxidative stress and ferroptosis in acute pancreatitis.
    Haoyu Zhang, Yuchen Jia, Zheng Wang, Jie Li, Xiaozhou Xie, Yixuan Ding, Feng Cao, Fei Li.
      Mitophagy, oxidative stress, and ferroptosis are critical processes in the development of acute pancreatitis (AP). Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, plays a central role in the pathogenesis of AP. However, its specific regulatory mechanisms within the mitophagy-oxidative stress-ferroptosis network remain incompletely understood. This study investigated the therapeutic potential of ginkgetin (GK), a natural TFEB activator, in AP. The results demonstrated that GK activated TFEB and subsequently significantly alleviated pathological damage in AP in vivo and effectively inhibited acinar cell death in vitro. Further mechanistic studies revealed that TFEB activation markedly improved impaired autophagic flux in AP, enhanced mitophagy, and simultaneously suppressed ferroptosis and oxidative stress. Specifically, TFEB upregulated the expression of the lysosomal marker LAMP1 to restore autophagy-lysosome function and induced the expression of BNIP3, a key mitophagy receptor, thereby enhancing mitochondrial quality control, restoring mitochondrial function, and ultimately mitigating oxidative stress and ferroptosis. Functional experiments confirmed that TFEB exerts its protective effects through nuclear translocation. When nuclear translocation was blocked by a C270S mutation-a mutation that disrupts TFEB dissociation from 14-3-3 proteins and subsequent nuclear localization-TFEB's regulatory roles in autophagy, mitophagy, ferroptosis, and oxidative stress were significantly inhibited. This study elucidates that TFEB, through nuclear translocation, not only restores basal autophagy but also enhances mitophagy, thereby collectively inhibiting oxidative stress and ferroptosis and alleviating the progression of AP. These findings provide a novel therapeutic strategy for AP.
    Keywords:  Acute pancreatitis; Ferroptosis; Ginkgetin; Mitophagy; Oxidative stress; TFEB
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.045
  20. Int J Biol Sci. 2025 ;21(15): 6559-6578
    Quercetin Protects Against Transmissible Gastroenteritis Virus-Induced Intestinal Inflammation by Modulating Mitophagy-Driven Mitochondrial Dysfunction.
    Kang Wang, Zhentao He, Yan Li, Bing Yu, Yuheng Luo, Xiangbing Mao, Hui Yan, Aimin Wu, Junqiu Luo, Jun He.
      Transmissible gastroenteritis virus (TGEV), an enteropathogenic α-coronavirus, causes severe disruption of the intestinal epithelium and diarrhea in neonatal piglets. Despite growing evidence linking mitochondrial dysfunction to coronavirus-induced inflammation, the role of mitophagy-mediated mitochondrial regulation in TGEV pathogenesis remains largely unclear. Here, we conducted a screening of a series of natural plant compounds in TGEV-infected porcine intestinal epithelial cells and identified quercetin, a plant-derived flavonoid, as a potent antiviral candidate. Quercetin significantly alleviated TGEV-induced cytopathic effects and reduced viral load, without directly inactivating viral particles. Interestingly, TGEV infection triggered excessive activation of PINK1/Parkin-mediated mitophagy, leading to mitochondrial membrane potential loss, mitochondrial reactive oxygen species (mtROS) accumulation, and suppression of respiratory chain components, which subsequently activated the NF-κB and JAK/STAT signaling pathways. However, quercetin restored mitochondrial function by suppressing mitophagy overactivation, preserving mitochondrial membrane potential and mtDNA levels, and attenuating oxidative stress. Moreover, functional interference assays revealed that the anti-inflammatory efficacy of quercetin was dependent on its ability to maintain mitochondrial homeostasis and inhibit pathological mitophagic flux. These findings were validated in a TGEV-infected piglet model, where excessive mitophagy correlated closely with intestinal inflammation signaling activation. Collectively, our results not only indicated a novel mechanism of mitophagy-driven mitochondrial dysfunction in TGEV pathogenesis, but also suggested that quercetin may serve as a potential mitochondria-targeted natural compound for mitigating coronavirus-induced intestinal inflammation.
    Keywords:  Inflammation; Intestinal epithelial cells; Mitochondrial dysfunction; Mitophagy; Quercetin; Transmissible gastroenteritis virus
    DOI:  https://doi.org/10.7150/ijbs.116855
  21. Sci Rep. 2025 Nov 28. 15(1): 42770
    Astragalus membranaceus injection activates mitophagy and protects mitochondrial function in chronic heart failure via inhibiting AKT/mTOR pathway.
    Sinai Li, Juju Shang, Wenlong Xing, Mingxue Zhou, Shenglei Qiu, Weihong Liu, Lei Zhang, Haoyue Shi, Huanning Niu, Songtao Kuang, Tong Wu, Mengting Liu, Hongxu Liu.
      To investigate the effects and mechanisms of Astragalus Membranaceus Injection (AMI) on mitophagy and mitochondrial function in chronic heart failure (CHF) based on phosphoproteomic and network pharmacology analysis. Primary neonatal mouse cardiomyocytes were isolated and hypertrophy cardiomyocyte model was induced by phenylephrine (PE) stimulation. AMI's effects on cell size, apoptosis, mitophagy, and mitochondrial function in hypertrophic cardiomyocytes were assessed. A pressure-overload CHF model was established via transverse aortic constriction (TAC) surgery in C57BL/6N mice. Echocardiography and histopathology were employed to evaluate AMI's effects on cardiac function and structural remodeling. Transmission electron microscope (TEM) and immunofluorescence were used to detect the distribution of autophagosomes and mitochondria. Phosphorylation-antibody microarray and network pharmacology were employed to explore AMI's cardioprotective mechanisms. The AKT/mTOR pathway's involvement was verified through Western blotting of AKTSer473 and mTORSer2481 phosphorylation and pharmacological validation using SC79 (AKT/mTOR activator) and GSK-690693 (AKT/mTOR inhibitor) in gain/loss-of-function experiments. In vitro, AMI dose-dependently suppressed pathological hypertrophy, attenuated apoptosis, restored mitochondrial function, and enhanced mitophagic flux. In vivo, AMI treatment significantly improved left ventricular ejection fraction while attenuated cardiac hypertrophy and interstitial fibrosis in TAC-induced CHF mice. Besides, AMI treatment increased the number of mitochondria and elevated autophagy in TAC mice. Phosphoproteomic screening and network pharmacology analysis identified the PI3K/AKT/mTOR axis as the primary regulatory pathway mediating AMI's cardioprotection. Pharmacological activation of AKT/mTOR signaling using SC79 significantly suppressed mitophagic flux, whereas AMI treatment mirrored the effects of the AKT/mTOR inhibitor GSK-690693, effectively restoring mitophagy and mitochondrial homeostasis. AMI exerts its cardioprotective effects through inhibition of the AKT/mTOR pathway, thereby ameliorating maladaptive remodeling and mitochondrial dysfunction in CHF.
    Keywords:  AKT/mTOR pathway; Astragalus membranaceus; Chronic heart failure; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-025-27065-y
  22. Phytomedicine. 2025 Nov 20. pii: S0944-7113(25)01209-7. [Epub ahead of print]149 157573
    Anemarrhena asphodeloides-derived small extracellular vesicle ameliorate diabetes-induced muscle atrophy via activating Pink1-mediated mitophagy.
    Pingcui Xu, Yuzhen Xia, Leqian Wang, Lisha Zhao, Chao Feng, Mingli Ye, Kai Huang, Nani Wang.
       BACKGROUND: Diabetes-induced muscle atrophy, characterized by progressive loss of skeletal muscle mass and function, poses a major challenge in diabetes management. To address this, we developed a phyto-exosomal formulation derived from Anemarrhena asphodeloides small extracellular vesicle (AA-sEV) and evaluated its therapeutic potential against diabetic muscle atrophy.
    METHODS: AA-sEV were isolated by ultracentrifugation and characterized for exosomal morphology. The therapeutic efficacy of AA-sEV was assessed through in vivo studies in diabetic db/db mice and in vitro assays using C2C12 myoblasts exposed to high glucose conditions.
    RESULTS: Fluorescently labeled AA-sEV efficiently accumulated in skeletal muscle tissue and myoblasts. Oral administration of AA-sEV enhanced muscle performance, as indicated by increased grip strength and hanging endurance, restoration of myofiber cross-sectional area, and upregulation of FNDC5 expression. Transcriptomic analysis revealed that mitophagy served as the central mechanism mediating AA-sEV's therapeutic effects. Specifically, AA-sEV activated the Pink1/Parkin-dependent mitophagy pathway, reducing mitochondrial reactive oxygen species accumulation. This restoration of mitochondrial quality control promoted the MyoG/MyoD1-driven anabolic program while suppressing the MuRF1/MAFbx-mediated catabolic response. Treatment with the mitophagy inhibitor 3-methyladenine abolished the anabolic and catabolic regulatory effects of AA-sEV under hyperglycemic conditions.
    CONCLUSIONS: Our findings demonstrate that AA-sEV mitigate diabetes-induced muscle atrophy by restoring protein anabolic-catabolic balance via Pink1-mediated mitophagy. These results highlight a novel extracellular vesicle-based therapeutic strategy for managing diabetic myopathy and related complications.
    Keywords:  Anemarrhena asphodeloides; Diabetes; Mitophagy; Muscle atrophy; Small extracellular vesicle
    DOI:  https://doi.org/10.1016/j.phymed.2025.157573
  23. Cell Mol Neurobiol. 2025 Nov 25.
    Tau-Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential.
    Yaisa Castillo-Casaña, Clorinda Arias, Roberto Coria.
      Tau is a microtubule-associated protein encoded by the MAPT gene and is mainly expressed in neurons. Alternative splicing generates preferentially six isoforms differing in N-terminal inserts (0, 1, or 2N) and microtubule-binding repeats (3R or 4R). Isoform expression varies by cell type, developmental stage, and neuronal maturation. Structurally, 4R isoforms bind and stabilize microtubules more effectively than 3R isoforms, while 3R variants are more prone to oligomerization. Differences among isoforms also affect aggregation and post-translational modification patterns, yet their specific roles in tauopathies remain unclear. Beyond its role in microtubule stabilization, tau is increasingly recognized for its functions in other cellular compartments, particularly mitochondria, where it may contribute to mitochondrial dysfunction in neurodegenerative diseases. Its intrinsically disordered conformation and extensive post-translational modifications enable interactions with multiple mitochondrial components, linking tau biology to broader aspects of neuronal health and pathology. The main focus of this review is to analyze how tau protein interacts with mitochondria and disrupts their function. Literature evidence indicates that tau localizes to the outer mitochondrial membrane, intermembrane space, and matrix, where it interferes with key processes. These include disruption of electron transport chain activity, inhibition of ATP synthase, and reduced ATP production, ultimately compromising neuronal energy supply. In parallel, tau destabilizes microtubule-based trafficking, impairing axonal transport and mitochondrial distribution, while also disrupting fission and fusion dynamics that shape mitochondrial morphology. Quality control pathways are affected as well, with tau altering mitophagy and mitochondria-nucleus signaling. Moreover, tau dysregulates calcium buffering and increases reactive oxygen species production, thereby promoting synaptic dysfunction, oxidative stress, and mitochondrial damage. Collectively, these facts establish tau as a central mediator of mitochondrial impairment and neuronal vulnerability. Elucidating the mechanisms by which tau affects mitochondrial physiology underscores its importance as a therapeutic target, with strategies aimed at preserving mitochondrial integrity offering promising avenues to slow neurodegenerative progression. In the last section, we include examples of clinical applications currently in various phases of testing, some of which show promising potential for implementation.
    Keywords:  Mitochondrial bioenergetics; Mitochondrial dynamics; Mitochondrial dysfunctions; Mitochondrial transport; Mitophagy; Neurodegeneration; Tau protein; Tauopathies
    DOI:  https://doi.org/10.1007/s10571-025-01634-1
  24. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Nov 20. pii: 1673-4254(2025)11-2427-11. [Epub ahead of print]45(11): 2427-2437
    [Astragaloside IV alleviates D-GAL-induced endothelial cell senescence by promoting mitochondrial autophagy via inhibiting the PINK1/Parkin pathway].
    Ming Yi, Ye Luo, Lu Wu, Zeheng Wu, Cuiping Jiang, Shiyu Chen, Xiao Ke.
       OBJECTIVES: To explore the mechanism by which astragaloside IV (AS-IV) alleviates D-galactose (D-GAL)-induced senescence in human umbilical vein endothelial cells (HUVECs).
    METHODS: Cultured HUVECs were treated with D-GAL (40 g/L), AS-IV (200 μmol/L), D-GAL+AS-IV, or D-GAL+AS-IV+MTK458 (a mitochondrial autophagy agonist, 25 μmol/L) for 48 h, and the changes in cell proliferation, migration, and angiogenesis capacity were evaluated. Cell apoptosis, reactive oxygen species (ROS) levels, mitochondrial membrane potential, and expressions of autophagy-related proteins (LC3-II/LC3-I) and PINK1/Parkin pathway proteins in the treated cells were detected.
    RESULTS: AS-IV treatment significantly reduced the inhibitory effect of D-GAL on HUVEC viability, effectively alleviated D-GAL-induced impairment of tube-forming ability, and promoted angiogenesis and migration ability of the cells. AS-IV also significantly reduced the rate of D-GAL-induced HUVECs positive for senescence-associated β-galactosidase (SA-β-Gal) staining and inhibited the expression of senescence-related genes P21 and P53. AS-IV restored mitochondrial membrane potential and reduced intracellular ROS levels in D-GAL-induced HUVECs, and inhibited the fusion of autophagosomes and lysosomes to prevent the completion of autophagic flux. In HUVECs treated with both D-GAL and AS-IV, the application MTK458 significantly increased the number of yellow spots and enhanced the expressions of P21, P53, PINK1, Parkin, LC3, and Beclin proteins.
    CONCLUSIONS: AS-IV alleviates D-GAL-induced endothelial cell senescence by inhibiting the PINK1/Parkin pathway to regulate mitochondrial autophagy.
    Keywords:  D-galactose; PINK1/Parkin signaling pathway; astragaloside; cellular senescence; endothelial cells; mitochondrial autophagy
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.11.15
  25. Redox Biol. 2025 Nov 08. pii: S2213-2317(25)00433-1. [Epub ahead of print]88 103920
    Beyond molecular chaperoning: AHA1 reprograms autophagy flux through direct ATP5A1 interaction in ischemic neuronal injury.
    Duo Jin, Xinran Ge, Li Liu, Yujie Jia, Chang Liu, Ke Meng, Xiaowei Zhang.
       BACKGROUND: Mitochondrial dysfunction and excessive reactive oxygen species (ROS) generation play a pivotal role in ischemic neuronal injury. The Activator of 90kDa heat shock protein ATPase homolog 1 (AHSA1/AHA1) has been implicated in regulating ATP synthesis and energy metabolism. Yet, its role in neurological functional impairment and mitophagy under pathological conditions remains unclear.
    METHODS: We utilized in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse models and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) neuronal cell models. The study integrated bioinformatics, molecular biology techniques, histological analyses, behavioral tests, and genetic knockdown (siRNA) to elucidate the underlying mechanisms.
    RESULTS: Our findings demonstrate that I/R stress induces the transcription factor STAT3 to upregulate AHA1 expression. AHA1 then translocates to the mitochondria and directly interacts with the ATP synthase subunit ATP5A1. This interaction disrupts the cellular ATP/AMP ratio and increases ROS production, leading to mitochondrial damage. The resulting energy stress triggers the aberrant activation of the AMPK/mTOR/ULK1 signaling pathway, culminating in an excessive and detrimental flux of PINK1/Parkin-mediated mitophagy. Critically, silencing of AHA1 reversed these effects, suppressing pathological mitophagy, reducing infarct volume, and improving neurological outcomes.
    CONCLUSION: This study reveals a novel, non-canonical function for AHA1 as a pathological driver in ischemic stroke. By directly interacting with ATP5A1, AHA1 links transcriptional stress responses to mitochondrial bioenergetic failure and excessive autophagy. Targeting the AHA1-ATP5A1 axis represents a promising therapeutic strategy to inhibit maladaptive mitophagy and protect against neurological outcomes.
    Keywords:  AHA1; ATP5A1; Ischemic stroke; Mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2025.103920
  26. J Frailty Aging. 2025 Nov 26. pii: S2260-1341(25)00109-4. [Epub ahead of print]14(6): 100116
    The intersection of mitochondrial dynamics and sarcopenic phenotyping: A call for mechanistic detail.
    Parth Aphale, Himanshu Shekhar, Shashank Dokania.
      
    DOI:  https://doi.org/10.1016/j.tjfa.2025.100116
  27. Neurobiol Stress. 2025 Nov;39 100769
    Ventral hippocampal autophagy and mitophagy dynamics shape behavioral responses to chronic mild stress in adult male rats.
    Paola Brivio, Maria Teresa Gallo, Elena Volpari, Piotr Gruca, Magdalena Lason, Ewa Litwa, Fabio Fumagalli, Mariusz Papp, Francesca Calabrese.
      Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterized by a range of symptoms that often lead to reduced quality of life. Although chronic stress is a major risk factor for the development of MDD, only a subset of individuals exposed to stress develop depressive symptoms, while others remain resilient. Emerging evidence suggests that autophagy and mitophagy, key cellular processes involved in maintaining homeostasis and energy balance, may play a critical role in the response to stress. In this study, we investigated the impact of 6 weeks of chronic mild stress (CMS) on autophagy and mitophagy pathways in adult male rats, aiming to explore their potential association with vulnerability or resilience to stress-induced anhedonic-like behavior. By analyzing key autophagy and mitophagy markers in the dorsal (dHip) and ventral hippocampus (vHip), we describe region- and phenotype-specific alterations that may reflect distinct neurobiological adaptations to stress. In particular, we observed enhanced mitophagy alongside an overall impairment of autophagy in the vHip of vulnerable rats, while resilient animals showed preserved activity. These findings provide new insights into the molecular mechanisms associated with stress susceptibility and may inform future studies aimed at identifying novel therapeutic targets for MDD.
    Keywords:  Lysosomes; PINK1; Resilience; TFEB; Vulnerability
    DOI:  https://doi.org/10.1016/j.ynstr.2025.100769
  28. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2524111122
    The intermediate filament protein GFAP regulates mitochondrial fission in astrocytes.
    Ding Xiong, Ye Sing Tan, Fang Yuan, Yinglu Li, Kay En Low, Isabelle Bonne, Sakthikumar Mathivanan, Phil Jun Kang, Zijun Sun, Xueyan Li, Emily Abella, Albee Messing, Linghai Kong, Su-Chun Zhang.
      Mitochondrial plasticity, coordinated by fission and fusion, is crucial to ensure cellular functions. Mitochondrial fission is mediated by the GTPase Drp1 at the constriction site, which is proposed to be driven by the actin-myosin contractile force. However, the mechanism that propels constriction remains unclear, and the potential involvement of additional mechanisms in this process remains an open question. Here, using structured illumination microscopy, electron microscopy, and correlative light electron microscopy (CLEM), we show that the type III intermediate filament glial fibrillary acidic protein (GFAP) participates in mitochondria constriction and fission by interacting with Drp1. Remarkably, loss of GFAP results in hyperfused mitochondria under physiological and even Ca2+-induced mitochondrial fission conditions. Additionally, mutations in GFAP, the cause of Alexander disease, result in more Drp1 localized to GFAP and lead to significantly increased mitochondrial fissions. Taken together, these findings propose a role of type III intermediate filaments in mitochondrial division.
    Keywords:  GFAP; alexander disease; astrocyte; intermediate filament; mitochondrial fission
    DOI:  https://doi.org/10.1073/pnas.2524111122
  29. Mol Neurobiol. 2025 Nov 24. 63(1): 153
    Anandamide-Induced Neuroprotection of Cortical Neurons Relies on Metabolic/Redox Regulation and Mitochondrial Dynamics.
    Ana Laura Torres-Román, Tània Gavaldà-Vives, Samuel Simón-Sánchez, Omar Emiliano Aparicio-Trejo, José Pedraza-Chaverri, Tessy López-Goerne, Alette Ortega Gómez, Alexey A Tinkov, Michael Aschner, Ismael Galve-Roperh, Abel Santamaría.
      Mitochondrial disruption is a key mechanism in the etiology of neurodegenerative diseases. Promoting mitochondrial dynamics and renewal of the mitochondrial network can restore its function and sustain neuronal viability. Although a growing body of evidence implicates endocannabinoid signaling in the regulation of mitochondrial function, its neuroprotective role in neurodegenerative diseases remains largely unexplored. Clarifying this relationship is crucial for understanding the therapeutic efficacy of the endocannabinoid system. This study aimed to evaluate whether endocannabinoid signaling via PPARγ and CB1 receptors regulates mitochondrial biogenesis and dynamics, exerting neuroprotective actions. Primary cortical neuronal cultures were subject to energy deficiency and excitotoxicity with 3-nitropropionic acid (3NP) and quinolinic acid (QUIN). Neurons were pretreated with the endogenous cannabinoid anandamide (AEA 100 nM), and cell viability and lipid peroxidation levels were characterized. To further explore mitochondrial status, immunofluorescence, western blot, and qPCR of mitochondrial proteins or genes were carried out. The metabolic status was assessed by oxygen consumption and extracellular acidification rates. Intracellular calcium levels and PPARγ transactivation were also analyzed. 3NP + QUIN induced neuronal damage, while AEA treatment afforded a neuroprotective effect. The use of selective receptor antagonists indicated that AEA neuroprotection depends on both PPARγ and CB1 receptors. AEA also increased mitochondrial biogenesis, fission markers and OXPHOS function, while delayed Ca2+ levels and induced PPARγ transactivation. In conclusion, AEA afforded neuroprotection secondary to increased mitochondrial biogenesis and redox regulation triggered by the activation of CB1 and the nuclear receptor PPARγ.
    Keywords:  Anandamide; Cannabinoid receptors; Endocannabinoid System; Energy metabolism; Mitochondrial dynamics; PPARγ receptor
    DOI:  https://doi.org/10.1007/s12035-025-05514-z
  30. J Exp Clin Cancer Res. 2025 Nov 24.
    GSTK1 suppresses HCC aggravation via L-carnitine metabolism by PGAM5/DRP1 complex-mediated mitochondrial quality control.
    Yuze Shi, Jinyao Zhang, Bojiao Song, Haitian Zhang, Jianbo He, Ke Ding, Fei Wang, Weiwei Yu, Guangyan Zhangyuan, Kangpeng Jin, Wenjie Zhang, Beicheng Sun.
       BACKGROUND: Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality worldwide. The high recurrence rate and resistance to chemotherapy of HCC contribute to poor clinical outcomes, necessitating the development of novel therapeutic strategies. Glutathione S-transferase kappa 1 (GSTK1) is specifically localized to mitochondria and peroxisomes, participates in adiponectin secretion and insulin resistance, and inhibits the progression of non-alcoholic fatty liver disease. However, the role of GSTK1 in HCC is unknown. We aimed to determine the role of GSTK1 in HCC progression.
    METHODS: N-nitrosodiethylamine (DEN)/ carbon tetrachloride and DEN/high-fat, high-fructose, high-cholesterol diet models were used in hepatocyte-specific Gstk1 knockout and control mice to establish a murine HCC model. Human HCC cell lines with GSTK1 overexpression or knockdown were used to determine GSTK1 function in tumor growth and migration in vitro. Non-target metabolomics analysis, RNA-sequence, transmission electron microscope (TEM), immunoprecipitation (IP), liquid chromatography, and high-throughput mass spectrometry (LC-MS/MS) were used to determine the mechanism by which GSTK1 participates in HCC.
    RESULTS: GSTK1 was shown to suppress HCC in vivo and in vitro. Non-target metabolomics analysis indicated that GSTK1 participates in L-carnitine metabolism. L-carnitine supplementation inhibited proliferation and promoted apoptosis of HCC cells in vivo and in vitro. This effect was enhanced by GSTK1 overexpression. Mechanically, TEM and western blot showed that GSTK1 influences mitochondrial quality control (MQC) by promoting mitochondrial biosynthesis and mitochondrial fusion. GSTK1 was shown to inhibit mitochondrial fission and mitophagy, which was consistent with the immunofluorescence results. IP and LC-MS/LMS indicated that GSTK1 combines with PGAM5 and competes with DRP1. Additionally, GSTK1 was shown to be regulated by transcription factors (PPARα/RXRα) and the RXRα agonist, bexarotene, inhibited HCC cell proliferation.
    CONCLUSIONS: GSTK1 was shown to be a tumor suppressor via its role in MQC and L-carnitine metabolism. Bexarotene and L-carnitine supplementation may serve as potential therapeutic strategies for HCC treatment.
    Keywords:  Glutathione s-transferase kappa 1; Hepatocellular carcinoma; L-carnitine; Mitochondrial quality control; Phosphoglycerate mutase 5
    DOI:  https://doi.org/10.1186/s13046-025-03580-8
  31. Mol Neurobiol. 2025 Nov 24. 63(1): 149
    Protein Phosphatase 1 Regulatory Subunit 17 (PPP1R17) Regulates Cerebral Ischemia and Ischemia-Reperfusion Brain Injury by Suppressing YAP1-Mediated Mitophagy.
    Ming Ma, Jiahui Yang, Zheng Li, Xiaohua Shi, Zhongxin Xu.
      Stroke is a vital cause of death worldwide. Ischemic stroke, a predominant type, is characterized by a sudden blockage of blood vessels supplying the brain, causing loss of blood flow. Restoring blood flow and oxygen in ischemic areas is the principal clinical treatment for ischemic stroke. Nevertheless, this process brings cerebral ischemia-reperfusion injury, which restrains the therapeutic effect on ischemic stroke. Plumbing the pathogenesis of brain injury and ischemia-reperfusion injury induced by ischemic stroke is crucial for improving stroke treatment. In this study, we analyzed differentially expressed genes in the penumbra of ischemic and ischemia-reperfusion rat brain tissue using transcriptome sequencing and screened out a gene PPP1R17 associated with mitophagy. We found that cerebral ischemia and ischemia-reperfusion induced PPP1R17 aggravated brain injury by repressing mitophagy. Mechanistically, PPP1R17 induces YAP1 phosphorylation by limiting the phosphatase activities of PP1 and PP2A and inhibits the activation of Pink1 and Parkin transcription by YAP1 as a transcriptional coregulator. In conclusion, PPP1R17 may serve as a potential therapeutic target for ameliorating cerebral ischemia and cerebral ischemia-reperfusion induced brain injury.
    Keywords:  Brain injury; Cerebral ischemia; Cerebral ischemia–reperfusion; Mitophagy; Protein phosphatase 1 regulatory subunit 17; Yes1-associated transcriptional regulator
    DOI:  https://doi.org/10.1007/s12035-025-05488-y
  32. Adv Sci (Weinh). 2025 Nov 26. e17086
    ATF5-Dependent GDF15 Expression Mediates Anesthesia-Induced Neuroprotection Against Stroke.
    Xianshu Ju, Tao Zhang, Jianchen Cui, Yulim Lee, Suho Lee, Ho Min Kim, Boohwi Hong, Jiho Park, Chul Hee Choi, Hyon-Seung Yi, Jun Young Heo, Woosuk Chung.
      Perioperative stroke is a rare but serious complication with a rising incidence in aging populations. Although preclinical studies consistently demonstrate that anesthetics such as sevoflurane can induce neuroprotective preconditioning against ischemic injury, clinical results have remained inconclusive. In this study, it is demonstrated that sevoflurane-induced neuroprotection is associated with the upregulation of genes involved in the mitochondrial unfolded protein response (UPRmt) and mitochondrial bioenergetic metabolism. The findings emphasize the critical role of ATF5 (activating transcription factor-5) in mediating these protective effects. Sevoflurane preconditioning markedly increases ATF5 expression and its downstream target GDF15, a key regulator of mitochondrial homeostasis, in the cerebral cortex. However, this protective mechanism is not activated in the aged brain, suggesting that aging impairs the ability to mount a mitochondrial stress response. The results imply a need for age-specific strategies to reduce perioperative stroke risk, including approaches that target mitochondrial function in elderly patients.
    Keywords:  ATF5 / GDF15; anesthesia; preconditioning; stroke
    DOI:  https://doi.org/10.1002/advs.202417086
  33. bioRxiv. 2025 Nov 06. pii: 2025.11.06.686916. [Epub ahead of print]
    Hypoxia-induced mitoROS triggers M1 linear ubiquitin chains and activates NF-κB signaling.
    Kiri Tal, Jonathan Ram, Reis Noa, Maniv Inbal, Ordureau Alban, Michael H Glickman, Sulkshane Prasad.
      Mitochondria are essential organelles responsible for cellular energy production and metabolism. Hypoxia, a pathophysiological condition, impairs the electron transport chain, disrupts mitochondrial function, and produces harmful reactive oxygen species (ROS). Ubiquitin signaling regulates mitochondrial health through several mechanisms, including protein degradation and mitophagy. Here, we show that hypoxia-induced mitophagy occurs independently of ubiquitination. However, mitochondria are heavily ubiquitinated under hypoxic stress. A significant portion of these hypoxia-induced ubiquitin chains constitute a specific type: linear head-to-tail fusions (M1), which are known for their role in NF-κB activation during cytokine signaling. We demonstrate that hypoxia-induced mitochondrial ROS leads to the accumulation of these M1 chains, activating NF-κB signaling and increasing the expression of its target genes. These findings reveal a critical internal signal that helps cells adapt to mitochondrial stress and triggers an inflammatory response.
    DOI:  https://doi.org/10.1101/2025.11.06.686916
  34. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2517552122
    Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.
    Prerona Bora, Mashiat Zaman, Samantha Oviedo, Sergei Kutseikin, Nicole Madrazo, Prakhyat Mathur, Meera Pannikkat, Sophia Krasny, Rama Aldakhlallah, Alan Chu, Kristen A Johnson, Danielle A Grotjahn, Timothy E Shutt, R Luke Wiseman.
      Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth type 2A (CMT2A). These mutations can disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR)-the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2-deficient cells. These results demonstrate the potential for pharmacologic ISR activation through the OMA1-DELE1-HRI signaling pathway as a potential strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.
    Keywords:  drug repurposing; integrated stress response; mitochondrial dysfunction
    DOI:  https://doi.org/10.1073/pnas.2517552122
  35. Cell Death Discov. 2025 Nov 28. 11(1): 549
    PPA1 promotes oxidative phosphorylation and malignant progression of colorectal cancer under glucose restriction via AMPK/ULK1/FUNDC1-mediated mitophagy.
    Yajun Chen, Qican Deng, Zhenzhou Chen, Lei Yang, Xiang Li, Zhongxue Fu.
      Metabolic reprogramming is a hallmark of colorectal cancer (CRC). Pyrophosphatase 1(PPA1), an energy-metabolizing enzyme, has been observed to be upregulated in multiple cancers and implicated in tumorigenesis and progression. However, its specific role in metabolic rewiring of CRC and the underlying molecular mechanisms remain poorly understood. Our study revealed that PPA1 is highly expressed in CRC epithelial cells and is significantly associated with advanced tumor size, lymph node status, TNM stage, and reduced overall survival in patients. Knockdown of PPA1 suppressed CRC tumorigenesis and metastasis both in vitro and in vivo. Under glucose-restricted conditions, PPA1 depletion impaired OXPHOS in CRC cells, leading to reduced oxygen consumption, decreased ATP production, elevated mitochondrial ROS levels, and decline in mitochondrial membrane potential. Mechanistically, PPA1 promotes phosphorylation of AMPK at Thr172, thereby facilitating phosphorylation of ULK1 at Ser467 and Ser555, and subsequently enhancing FUNDC1 phosphorylation at Ser17. This phosphorylation cascade initiates mitophagy to sustain OXPHOS metabolic activity, thereby driving CRC malignant progression. In summary, PPA1 sustains OXPHOS and drives malignant progression in CRC under glucose restriction by promoting AMPK/ULK1/FUNDC1-mediated mitophagy.
    DOI:  https://doi.org/10.1038/s41420-025-02816-y
  36. Elife. 2025 Nov 26. pii: RP105541. [Epub ahead of print]14
    The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism.
    Ana Lapão, Lauren Sophie Johnson, Laura Trachsel-Moncho, Samuel J Rodgers, Sakshi Singh, Matthew Y W Ng, Sigve Nakken, Eeva-Liisa Eskelinen, Anne Simonsen.
      SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.
    Keywords:  ACC; Mitochondria; RAB27A; SYTL5; cell biology; hypoxia; mitophagy; none
    DOI:  https://doi.org/10.7554/eLife.105541
  37. bioRxiv. 2025 Oct 16. pii: 2025.10.08.681260. [Epub ahead of print]
    Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
    Katie G Vineall, Alexia Andrikopoulos, Michael J Sun, Anna Yan, Ethan R Hartanto, Danielle L Schmitt.
      Phosphatase and tensin homologue-induced kinase 1 (PINK1) is a serine/threonine kinase that plays roles in mitophagy, cell death, and regulation of cellular bioenergetics. Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity. Therefore, we sought to develop a novel PINK1 kinase activity reporter to characterize PINK1 activity. Taking advantage of the separation of phases-based activity reporter of kinase (SPARK) design, we developed a phase separation-based PINK1 biosensor (PINK1-SPARK). With PINK1-SPARK, we observe real-time PINK1 activity in single cells treated with mitochondria depolarizing agents or pharmacological activators. We then developed a Halo Tag-based PINK1-SPARK for multiplexed imaging of PINK1 activity with live-cell markers of mitochondrial damage. Thus, PINK1-SPARK is a new tool that enables temporal measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function.
    DOI:  https://doi.org/10.1101/2025.10.08.681260
  38. J Adv Res. 2025 Nov 22. pii: S2090-1232(25)00935-X. [Epub ahead of print]
    ANXA1 improves mitochondrial homeostasis through uncoupling protein 1 in diabetic nephropathy.
    Zi-Han Li, Lu Fang, Liang Wu, Dong-Yuan Chang, Manyuan Dong, Liang Ji, Qi Zhang, Ming-Hui Zhao, Sydney C W Tang, Lemin Zheng, Min Chen.
       INTRODUCTION: Diabetic nephropathy (DN) is a major public health concern. Our previous study found that annexin A1 (ANXA1) alleviated DN by improving mitochondrial homeostasis. However, the underlying mechanism is not fully clear yet.
    OBJECTIVES: This study aimed to explore mechanisms by which ANXA1 improves mitochondrial homeostasis and identify novel therapeutic targets for DN.
    METHODS: Diabetic Anxa1-/-/uncoupling protein 1 (Ucp1)-/- mice and renal Ucp1/cardiolipin synthase 1 (Crls1)-overexpressing mice were constructed. Diabetes was established using high-fat diet (HFD) plus streptozotocin (STZ). CL316243 was used to upregulate UCP1 in db/db mice. Knockdown and overexpression in proximal tubular epithelial cells (PTECs) were constructed. Metabolomics and lipidomics were applied.
    RESULTS: Transcriptomics revealed that Ucp1 was the most significantly downregulated mitochondria-associated gene in kidneys of diabetic Anxa1-KO mice. Functional validation demonstrated that local overexpression of Ucp1 in kidneys alleviated urine albumin-to-creatine ratio (uACR), kidney injuries in histopathology and mitochondrial fission in Anxa1-KO diabetic mice. In vitro, UCP1 silencing abolished the improvements of human recombinant ANXA1 on high glucose (HG)-induced inflammation, fibrosis and mitochondrial dysfunction in PTECs. Silencing/overexpression of ANXA1 reduced/increased the stability of transcription factor GATA binding protein 3 (GATA3) in HK-2 cells under HG conditions, respectively. GATA3 could bind to the proximal promoter region of UCP1, thereby enhancing its transcriptional activity. UCP1 was significantly upregulated in kidneys of DN patients and mice. UCP1 deficiency reduced renal cardiolipin and exacerbated diabetes-induced kidney injury, including aggravated uACR, interstitial inflammation and fibrosis, and enhanced mitochondrial fission. Mechanistically, UCP1 upregulated CRLS1 by modulating aristaless-related homeobox (ARX), thereby promoting cardiolipin biosynthesis and reducing mitochondrial fission. Therapeutically, pharmacological upregulation of UCP1 by CL316243 attenuated established DN in db/db mice.
    CONCLUSION: ANXA1 stabilized GATA3 to upregulate UCP1, which promoted cardiolipin biosynthesis through the ARX/CRLS1 axis, inhibited mitochondrial fission, thereby alleviated DN. This study highlighted the therapeutic potential of targeting UCP1 in DN.
    Keywords:  Annexin A1; Cardiolipin synthase 1; Diabetic nephropathy; GATA binding protein 3; Mitochondrial dynamics; Uncoupling protein 1
    DOI:  https://doi.org/10.1016/j.jare.2025.11.039
  39. Environ Pollut. 2025 Dec 15. pii: S0269-7491(25)01695-1. [Epub ahead of print]387 127321
    Cigarette butts: A hidden toxic time bomb for aquatic metabolism and behavior.
    Hairong Lian, Chuhan Xu, Pengrui Xu, Da Tong, Zhizhong Li, Xinfeng Cheng, Kai Zhang, Xianling Xiang.
      Cigarette butts (CBs) are rapidly emerging as a burgeoning threat to marine ecosystems, posing substantial risks to aquatic life. This study systematically investigated the effects of CBs fibers and leachate on the behavior, metabolism, and mitophagy of the marine rotifer Brachionus plicatilis. The results indicated that exposure to CBs significantly inhibited the motility and feeding behavior of rotifers. Further studies found that CB exposure caused metabolic stress on rotifers and significantly interfered with their energy metabolism, which was specifically manifested as a biphasic dose-effect of amylase activity (increase at low concentrations and inhibition at high concentrations) and a decrease in triglyceride and neutral lipid content. CB exposure elicited oxidative stress and disrupted mitochondrial fission-fusion homeostasis (increased in ATG3, FUNDC1, FIS1, and Mfn2; decreased in Drp1/DNM1L, VPS35, and STOML2), lowering mitochondrial membrane potential and ATP levels while activating mitophagy and culminating in mitochondrial dysfunction. Addition of the antioxidant N-acetylcysteine effectively alleviated CB-induced mitochondrial dysfunction and metabolic disorders. Notably, the study revealed that the residual ash from smoked CB exerted the most pronounced toxic effect on rotifers, with distinct mechanisms between fibers and leachates. Fiber caused chronic toxic effects through continuous contact, while leachate quickly caused acute damage by dissolving substances. Rotifer health declined dose-dependently with CB concentration, with lipid-metabolic disorder serving as the central driver of the CB toxicity network.
    Keywords:  Brachionus plicatilis; Cellulose acetate; Lipid metabolism; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.envpol.2025.127321
  40. Int J Biol Macromol. 2025 Nov 26. pii: S0141-8130(25)09849-6. [Epub ahead of print] 149292
    PGC1-α drives MFN2-linked mitochondrial fusion aiding glioblastoma cell survival under TMZ stress.
    Anirudha K Sahu, Prasanthi L Kaja, Subhashree Chatterjee, Megha Chaudhary, Bhawna Bissa, Rajdeep Chowdhury, Sudeshna Mukherjee.
      Glioblastoma Multiforme (GBM) is an extremely aggressive primary brain-tumor with a median-survival rate of <2 years. Higher risk in surgery has shifted the treatment paradigm towards combined chemotherapies. Interestingly, arduous dependency on chemotherapy has shown recurrence. Recent studies have portrayed the role of mitochondrial dynamics for survival under drug-pressure leading to recurrence. However, such studies exploring the role of mitochondria in response to drug stress in GBM are limited. Here we show that PGC1α (Peroxisome Proliferator-activated Receptor Gamma coactivator-1 Alpha) upregulates Mfn2 (Mitofusin 2) enhancing mitochondrial-fusion in GBM cells contributing to survival under profound Temozolomide (TMZ) stress. The interaction of PGC1α with SET1 compass / compass-like complex induces H3K4me3 trimethylations at the promoter regions of Mfn2 leading to an open chromatin assisting Mfn2 upregulation. The latter is further involved in inducing mitochondrial fusion, promoting oxidative phosphorylation which supports cell survival under stress. Notably, this further corroborates with our observations in the patient samples and clinical data where upregulation of Mfn2 was concurrently observed with elevated levels of PGC1α simultaneously leading to poor prognosis. Thus, this study provides critical insights into the molecular regulation of mitochondrial dynamics-dependent survival mechanisms in GBM that could further be exploited to design future therapies.
    Keywords:  Glioblastoma; Mfn2; Mitochondrial fusion; PGC1α; Temozolomide
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149292
  41. Adipocyte. 2025 Dec;14(1): 2588888
    WDR4-mediate tRNA m7G modification to promote mitophagy and browning of white adipose tissue for ameliorating obesity in male mice.
    Beisi Lin, Chaofan Wang, Yanling Yang, Zhigu Liu, Panwei Mu, Wen Xu, Yonghui Li.
       OBJECTIVE: Brown adipose tissue activation is a potential anti-obesity strategy. N7-methylguanosine (m7G) modification is a novel RNA epigenetic modification, but its role in adipose metabolism remains unexplored.
    METHODS: Male mice were fed a high-fat diet (HFD), followed by PCR array screening. Gain-of-function experiments and TRAC-seq were employed to explore WDR4 function.
    RESULT: A Mouse Epigenetic Modification Enzymes PCR Array revealed that WDR4 expression showed the most pronounced downregulation in HFD mice. Overexpression of WDR4 in 3T3-L1 cells and primary adipocytes significantly increased UCP1 expression and suppressed lipid droplet formation, and enhanced mitophagy as evidenced by mitochondrial ultrastructure, autophagic vesicles, and LC3 expression. Suppression of mitophagy using 3-MA and bafilomycin A1 attenuated WDR4-induced adipocyte browning. WDR4 overexpression enhanced translational activity and reshaped the tRNA m7G methylome in 3T3-L1 adipocytes, specifically induced 38 unique tRNA m7G modification sites, and increasing cleavage scores of multiple tRNAs. GSE229240 dataset revealed that WDR4 mutation significantly reduced translation efficiency of 195 genes enriched in the TGF-β signalling , including BMP8B. Knockdown of BMP8B partially counteracted WDR4-mediated mitophagy.
    CONCLUSION: WDR4 promotes adipocyte browning by enhancing BMP8B translation through tRNA m7G modification, revealing a novel m7G epitranscriptomic mechanism with therapeutic potential for obesity.
    Keywords:  Obesity; WDR4; brown adipose tissue; mitophagy; tRNA m7G modification
    DOI:  https://doi.org/10.1080/21623945.2025.2588888
  42. bioRxiv. 2025 Oct 14. pii: 2025.10.13.682092. [Epub ahead of print]
    The Mitochondrial F-box protein 1 and DJ-1 homolog HSP31 support cellular proteostasis during mitochondrial protein import clogging.
    Gargi Mishra, Xiaowen Wang, Eamon Fitzpatrick, Auyon Ghosh, Xin Jie Chen.
      Mitochondrial biogenesis requires the import of ∼1,000-1,500 nuclear-encoded proteins across the Translocase of Outer Membrane (TOM) and the Translocase of Inner Membrane (TIM) 22 or 23 complexes. Protein import defects cannot only impair mitochondrial respiration but also cause mitochondrial Precursor Overaccumulation Stress (mPOS) in the cytosol. Recent studies showed that specific mutations in the nuclear-encoded Adenine Nucleotide Translocase 1 (ANT1) cause musculoskeletal and neurological diseases by clogging TOM and TIM22 and inducing mPOS. Here, we found that overexpression of MFB1 , encoding the mitochondrial F-box protein 1, suppresses cell growth defect caused by a clogger allele of AAC2 , the yeast homolog of Ant1. Disruption of MFB1 synergizes with a clogger allele of aac2 to inhibit cell growth. This is accompanied by increased retention of mitochondrial proteins in the cytosol, suggesting exacerbated defect in mitochondrial protein import. Proximity-dependent biotin identification (BioID) suggested that Mfb1 interacts with several mitochondrial surface proteins including Tom22, a component of the TOM complex. Loss of MFB1 under clogging conditions activates genes encoding cytosolic chaperones including HSP31 . Interestingly, disruption of HSP31 creates a synthetic lethality with protein import clogging under respiring conditions. We propose that Mfb1 functions to maintain mitochondrial protein import competency under clogging conditions, whereas Hsp31 plays an important role in protecting the cytosol against mPOS. Mutations in DJ-1, the human homolog of Hsp31, and mitochondria-associated F-box proteins (eg., Fbxo7) are known to cause early-onset Parkinson's disease. Our work may help to better understand how these mutations affect cellular proteostasis and cause neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.10.13.682092
  43. bioRxiv. 2025 Nov 09. pii: 2025.11.07.687201. [Epub ahead of print]
    Drosophila HS dendrites are resilient to adult-onset deficits in mitochondrial dynamics.
    Hailey Q Wang, Demetria G Fortson, Eavan D Burton, Hunter S Whitbeck, Briana M Robles, Letitia Bortey, Avi J Adler, Jordan I Kalai, Giovanna Napoleone, Erin L Barnhart.
      Mitochondrial transport, fusion, and fission are necessary for neuronal development, but the role of mitochondrial dynamics in neuronal maintenance remains unclear. In this work, we employed functional in vivo imaging of neurons in the Drosophila visual system, HS ("horizontal system") cells, to determine how adult-onset deficits in mitochondrial dynamics affect mitochondrial localization, local regulation of ATP, and dendrite maintenance. In mature HS neurons, inhibition of mitochondrial transport or fusion depleted mitochondria from the dendrite over time but, surprisingly, had no effect on dendrite morphology. Moreover, adult-restricted mitochondrial mis- localization affected neither visual stimulus-driven dendritic calcium responses nor local, dynamic regulation of ATP levels. In contrast, when induced during development, the same perturbations caused mitochondrial mis-localization, loss of dendrite complexity, abrogation of stimulus-locked calcium responses and ATP fluctuations, and age-dependent dendrite degeneration. Thus, although mitochondrial dynamics are necessary during neuronal development, mature dendrites are capable of maintaining form and function in vivo in the absence of properly-positioned mitochondria.
    DOI:  https://doi.org/10.1101/2025.11.07.687201
  44. Antioxidants (Basel). 2025 Nov 19. pii: 1381. [Epub ahead of print]14(11):
    Hyperosmolarity-Induced Oxidative Stress Leads to Senescence in Human Corneal Epithelial Cells (HCEPC) via DNA Damage, Metabolic Disturbance and Mitophagy Decline.
    Yongjie Zhang, Tingjun Fan.
       BACKGROUND: Dry eye disease (DED), characterized by tear film hyperosmolarity, can lead to corneal epithelial damage. The mechanisms linking hyperosmotic stress to human corneal epithelial cell (HCEPC) damage are not fully understood.
    METHODS: A DED model was established by exposing HCEPCs to sustained hyperosmotic stress (400 mOsm/L) over multiple passages in vitro. Senescence was assessed using senescence-associated-β-galactosidase (SA-β-gal) staining, 5-ethynyl-2'-deoxyuridine (EdU) assays, p16INK4A and senescence-associated secretory phenotypes (SASP) analysis. Mechanisms were investigated by measuring reactive oxygen species (ROS), mitochondrial function, energy metabolism, DNA damage, and inflammatory signaling. The role of autophagy was probed pharmacologically.
    RESULTS: Hyperosmotic stress induced HCEPC senescence, driven by mitochondrial dysfunction, oxidative stress, DNA damage, bioenergetic crisis, and compromised autophagy (especially mitophagy). Autophagy and mitophagy play a key role in regulating senescence progression. Enhancing autophagy with LYN-1604 ameliorated oxidative stress, improved energy homeostasis, and attenuated senescence. Inhibiting autophagy exacerbated these states.
    CONCLUSION: Hyperosmolarity promotes HCEPC senescence via mitochondrial dysfunction and oxidative damage. Autophagy serves a critical protective role, and its enhancement represents a promising therapeutic strategy for DED.
    Keywords:  autophagy; cell senescence; hyperosmolarity; oxidative stress
    DOI:  https://doi.org/10.3390/antiox14111381
  45. Autophagy. 2025 Nov 23. 1-43
    Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.
    Jiayi Lu, Damian N Di Florio, Patricia Boya, Sandra Maday, Wolfdieter Springer, Charleen T Chu.
      The human brain is one of the most metabolically active tissues in the body, due in large part to the activity of trillions of synaptic connections. Under normal conditions, macroautophagy/autophagy at the synapse plays a crucial role in synaptic pruning and plasticity, which occurs physiologically in the absence of disease- or aging-related stressors. Disruption of autophagy has profound effects on neuron development, structure, function, and survival. Neurons are dependent upon maintaining high-quality mitochondria, and alterations in selective mitochondrial autophagy (mitophagy) are heavily implicated in both genetic and environmental etiologies of neurodegenerative diseases. The unique spatial and functional demands of neurons result in differences in the regulation of metabolic, autophagic, mitophagic and biosynthetic processes compared to other cell types. Here, we review recent advances in autophagy and mitophagy research with an emphasis on studies involving primary neurons in vitro and in vivo, glial cells, and iPSC-differentiated neurons. The synaptic functions of genes whose mutations implicate autophagic or mitophagic dysfunction in hereditary neurodegenerative and neurodevelopmental diseases are summarized. Finally, we discuss the diagnostic and therapeutic potentials of autophagy-related pathways.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; APP: amyloid beta precursor protein; ASD: autism-spectrum disorder; BDNF: brain-derived neurotrophic factor; BPAN: β-propeller protein associated neurodegeneration; CR: caloric restriction; ΔN111: deleted N-terminal region 111 residues; DLG4/PSD95: discs large MAGUK scaffold protein 4; ER: endoplasmic reticulum; FTD: frontotemporal dementia; HD: Huntington disease; LIR: LC3-interacting region; LRRK2: leucine rich repeat kinase 2; LTD: long-term depression; LTP: long-term potentiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMM: outer mitochondrial membrane; PD: Parkinson spectrum diseases; PGRN: progranulin; PINK1: PTEN induced kinase 1; PRKA/PKA: protein kinase cAMP-activated; PtdIns3P: phosphatidylinositol-3-phosphate; p-S65-Ub: ubiquitin phosphorylated at serine 65; PTM: post-translational modification; TREM2: triggering receptor expressed on myeloid cells 2.
    Keywords:  Biomarkers; Parkinson disease; dementia; dendritic spines; mitochondria; neurodegenerative diseases; neurodevelopmental disorders; synaptic plasticity
    DOI:  https://doi.org/10.1080/15548627.2025.2581217
  46. Phytomedicine. 2025 Oct 21. pii: S0944-7113(25)01066-9. [Epub ahead of print]149 157429
    Naringenin alleviates endotoxin-induced acute kidney injury in chicken by inhibiting pyroptosis through PINK1-dependent mitophagy.
    Xuewei Chen, Xu Shi, Xuejiao Yang, Meichen Gao, Tong Nie, Shiwen Xu.
       BACKGROUND: Lipopolysaccharide (LPS), known as endotoxin, constitutes a major component of the cell wall of Gram-negative bacteria and threatens public health. Naringenin (Nar), as a phenolic compound, has antioxidant, anti-inflammatory, and anti-bacterial function. Nevertheless, the mechanism of LPS-induced nephrotoxicity in poultry and the protective effect of Nar warrant further exploration.
    METHODS: Based on the LPS or/and Nar exposure models, the study explored the damaged mechanism of LPS-induced acute kidney injury (AKI) and the antagonistic effect of Nar through Western blot, Immunofluorescence, and Molecular docking analysis, and so on.
    RESULTS: The results showed that Nar alleviated LPS exposure-elicited kidney structural damage and oxidative damage. Further analysis revealed that LPS exposure promoted mitochondrial cristae fragmentation, decreased mitochondrial membrane potential (MMP) and mitochondrial electron transport chain (ETC) complex protein expression, induced mitochondrial-ROS (mito-ROS) accumulation, downregulated mitophagy-related proteins expression, and upregulated pyroptosis-related proteins expression in kidney. Nar mitigated these injuries caused by LPS in vivo and in vitro. Molecular docking and dynamics and Cell thermal shift assay analysis further indicated that Nar directly bound to PINK1 and promoted the protein stability. The addition of Rotenone, chloroquine (CQ) or si-PINK1 demonstrated that Nar alleviated LPS-induced nephrotoxicity by promoting mitophagy to reduce ROS/TXNIP/NLRP3-driven pyroptosis.
    CONCLUSION: This study demonstrated that Nar targeted PINK1-dependent mitophagy to alleviate ROS/TXNIP/NLRP3-driven pyroptosis, thereby mitigating AKI in chickens. The study provided a theoretical and experimental basis for LPS-induced AKI and demonstrated that Nar could reduce LPS-induced nephrotoxicity, thereby offering a reference for comparative medicine.
    Keywords:  Acute kidney injury; Lipopolysaccharide; Mitochondria damage; Naringenin; PINK1-dependent mitophagy; Pyroptosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.157429
  47. Cell Mol Biol Lett. 2025 Nov 24. 30(1): 140
    Abnormal cholesterol-cholesteryl ester metabolism impairs mouse oocyte quality during ovarian aging.
    Sainan Zhang, Bichun Guo, Junshun Fang, Shanshan Wang, Yicen Liu, Die Wu, Nannan Kang, Yang Zhang, Xin Zhen, Guijun Yan, Lijun Ding, Haixiang Sun, Chuanming Liu.
       BACKGROUND: Ovarian aging-induced decline in oocyte quality has been a main issue in women of advanced maternal age. However, the potential mechanism remains elusive, and there are no effective strategies to ameliorate aged oocyte quality. The lipid metabolism of oocytes has drawn great attention, but the intrinsic regulation of oocyte quality by metabolites, metabolic enzymes, and intracellular mediators is less well-characterized.
    METHODS: Targeted lipidomics was employed to detect the neutral lipids in oocytes during maturation. We used 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503) and Filipin to stain cholesteryl ester and free cholesterol, respectively. The Cholesterol/Cholesteryl Ester Quantification Assay kit was used further to quantify cholesterol-related metabolites. Western blotting was performed to evaluate acyl-coenzyme A: cholesterol acyltransferase 1/2 (ACAT1/2) expression. Immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR) were conducted to validate the knockdown efficiency of ACAT1. Avasimibe treatment and ACAT1 small interfering RNA (siRNA) microinjection were performed to investigate the effect of impaired cholesterol-cholesteryl ester metabolism on oocyte quality. Single-oocyte RNA sequencing was conducted to explore the mechanism. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, reactive oxygen species (ROS), and mitochondrial autophagosomes were detected to evaluate mitochondrial function and mitophagy.
    RESULTS: There is a profound increase in the conversion of cholesterol to cholesteryl ester in oocytes during maturation, which depends on ACAT1. Conversely, disturbing the homeostasis of cholesterol-cholesteryl ester metabolism by manipulating ACAT1 impairs oocyte quality, primarily manifested as decreased polar body extrusion (PBE), increased meiotic defects, and abnormal early embryonic development. Mechanistically, the impaired conversion of cholesterol to cholesteryl ester reduces oocyte mitophagy, leading to mitochondrial dysfunction, including reduced MMP and ATP production, and excessive accumulation of ROS. Notably, we also reveal that this metabolic homeostasis is impaired in aged oocytes, accompanied by decreased ACAT1 levels. Moreover, cholesteryl ester supplementation via cholesterol conjugated to methyl-β-cyclodextrin (CCM) can effectively ameliorate aged oocyte quality by enhancing mitophagy.
    CONCLUSIONS: This study reveals the mechanism by which cholesterol-cholesteryl ester metabolism regulates oocyte quality and thus participates in the process of oocyte aging by influencing mitophagy and mitochondrial function.
    Keywords:  ACAT1; Cholesterol–cholesteryl ester metabolism; Mitochondrial function; Mitophagy; Oocyte aging; Oocyte maturation
    DOI:  https://doi.org/10.1186/s11658-025-00811-w
  48. J Neuroinflammation. 2025 Nov 24. 22(1): 276
    Upregulated astrocytic HDAC7 induces depression-like disorders via deacetylating PINK1 and inhibiting mitophagy.
    Rui-Zhu Yue, Xing Guo, Cheng-Jia Li, Li-Juan Wu, Yu-Tong Liu, Juan Hu, Bing-Kang Yan, Hai-Tong Lin, Ying-Ling Tang, Wei-Ming Yan, Shifeng Xiao, Yue Hao, Jinwang Ye.
      
    Keywords:  Astrocyte; Depression; HDAC7; Mitophagy; PINK1
    DOI:  https://doi.org/10.1186/s12974-025-03603-3
  49. Mater Today Bio. 2025 Dec;35 102483
    ATG7-driven mitophagy in BMSC@CS hydrogel reprograms metabolism to boost bone regeneration.
    Qiumei Lan, Mengtian Fan, Fengmei Zhang, Qian Gong, Jiayan Zhong, Miao Yi, Qiqi Zeng, Jianqiang Chen, Yiming Pan, Nana Geng, Biao Kuang, Yu Du, Chuanrong Zhao, Deping Zeng, Chunliang Zhao, Zhen Li, Guixue Wang, Fengjin Guo.
      Bone regeneration remains a formidable challenging due to impaired energy metabolism and the limited osteogenic potential of transplanted stem cells. Mitochondrial homeostasis orchestrates osteogenesis, with mitophagy maintaining the metabolic rhythm essential for bone formation. However, the role of autophagy related gene 7(ATG7), a pivotal regulator of mitochondrial function, in bone regeneration remains elusive. In this study, we developed a ATG7-overexpressing bone marrow mesenchymal stem cells (ATG7-BMSCs) encapsulated within a thermoresponsive chitosan (CS) hydrogel, creating a biocompatible, living platform capable of adapting to physiological conditions. The hydrogel exhibited excellent injectability, physiological gelation at 37 °C, and prolonged biocompatibility, providing a favorable microenvironment for stem cell survival and proliferation. The system was evaluated through in vitro assays for mitochondrial function and osteogenic differentiation, as well as in vivo using rat cranial and femoral defect models. Mechanistically, ATG7 activation enhanced mitophagy, preserved mitochondrial integrity, reduced reactive oxygen species (ROS) accumulation, and reactivated oxidative phosphorylation via the PI3K-AKT signaling pathway, thereby reprogramming osteogenic metabolism and promoting differentiation. Conversely, ATG7 deficiency led to mitochondrial dysfunction, glycolytic dependence, and impaired bone formation. In vivo, the ATG7-BMSC@CS hydrogel markedly accelerated new bone formation and mineral density recovery while maintaining excellent injectability, biocompatibility, and systemic safety. Collectively, this study identifies ATG7-driven mitophagy as a critical regulator of osteogenic metabolism and bone formation, and establishes a smart, living hydrogel platform that seamlessly integrates metabolic reprogramming with stem cell delivery. This strategy provides a conceptual blueprint for next-generation, metabolism-oriented bone repair at the intersection of cell biology, biomaterials, and precision medicine.
    Keywords:  ATG7-BMSC@CS; Bone formation; Metabolic reprogramming; Mitophagy; Osteogenesis
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102483
  50. Mol Nutr Food Res. 2025 Nov 29. e70343
    Pumpkin Polysaccharide Ameliorates Type 2 Diabetes in Mice via Inhibition of p38 MAPK, Activation of PINK1-PRKN Mitophagy, and Gut Microbiota Modulation.
    Haizhao Song, Fangmin Chen, Tong Sun, Fang Wang, Luanfeng Wang, Ling Xiong, Xinchun Shen.
      Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose and lipid metabolism and gut microbiota dysbiosis. This study investigated the therapeutic potential and mechanisms of pumpkin polysaccharide fraction 3 (PPS3), a pumpkin polysaccharide, in a T2DM mouse model. Results demonstrated that PPS3 administration significantly increased body weight, reduced fasting blood glucose, attenuated hyperphagia and polydipsia, and enhanced glucose tolerance and insulin sensitivity. Hepatic analyses showed that PPS3 promoted glycogen synthesis and upregulated key glycolytic enzymes, hexokinase, and pyruvate kinase, contributing to restored glucose homeostasis. Mechanistically, PPS3 inhibited p38 mitogen-activated protein kinase (p38 MAPK) signaling and activated PTEN-induced kinase 1 (PINK1)-Parkin (PRKN)-mediated mitophagy, enhancing mitochondrial quality control. Gut microbiota analysis showed that PPS3 reduced the Firmicutes/Bacteroidota ratio and pathogenic genera while enriching beneficial bacteria including Akkermansia and short-chain fatty acid (SCFA) producers. Fecal metabolomics revealed partial restoration of metabolic disturbances, notably increased levels of propionyl-l-carnitine, indole-3-lactic acid, and β-lapachone. PPS3 exerted multifaceted metabolic benefits via inhibition of p38 MAPK, activation of PINK1-PRKN mitophagy, and gut microbiota modulation, positioning it as a promising candidate for T2DM intervention.
    Keywords:  Type 2 diabetes mellitus; gut microbiota; metabolites; mitophagy; p38 MAPK; pumpkin polysaccharide
    DOI:  https://doi.org/10.1002/mnfr.70343
  51. Research (Wash D C). 2025 ;8 1013
    FGF2 Attenuated Inflammation-Mediated Cardiac Damage: A Novel Mechanistic Insight into the AMPK-FUNDC1-Mitophagy.
    Pingjun Zhu, Xi Wang, Xinjie Han, Yan Wang, Yongkai Ding, Min Zhu, Xin Zhang, Qian Xu, Yukun Li, Zhongxuan Li, Zhi Lu, Qi Zhang, Yan Yin, Guogang Xu, Yingzhen Du.
      Septic cardiomyopathy, a severe complication of sepsis, is characterized by high morbidity and mortality rates, and its effective management remains an important challenge. Although fibroblast growth factor 2 (FGF2) has been shown to exert cardioprotective effects, its role in septic cardiomyopathy has not been extensively investigated. To address this knowledge gap, FGF2 knockout (FGF2-/-) mice were injected with lipopolysaccharide (LPS) to establish septic cardiomyopathy in vivo, and the resulting cardiac injury was evaluated after 72 h. The results demonstrated that LPS inhibited FGF2 expression in cardiomyocytes, and genetic ablation of FGF2 exacerbated myocardial inflammation, oxidative stress, apoptosis, and cardiac dysfunction. Notably, treatment with recombinant FGF2 (rFGF2) effectively reversed these detrimental effects. Proteomic analysis revealed that FGF2 significantly modulated mitophagy, and further verification assays confirmed that FGF2 prevented LPS-induced mitochondrial injury and followed apoptosis by activating FUNDC1-mediated mitophagy. Molecular studies demonstrated that rFGF2 triggered the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, leading to the activation of FUNDC1-mediated mitophagy, which in turn mitigated myocardial mitochondrial injury and apoptosis. These findings suggest that FGF2 exerts its cardioprotective effects in septic cardiomyopathy by activating the AMPK-FUNDC1-mediated mitophagy pathway, thereby providing a potential therapeutic strategy for mitigating sepsis-induced cardiac damage.
    DOI:  https://doi.org/10.34133/research.1013
  52. Biomolecules. 2025 Nov 11. pii: 1585. [Epub ahead of print]15(11):
    A Small-Molecule Mitofusin 1 Agonist Enhances Islet Survival Under Hypoxic Conditions In Vitro and Improves Transplantation Outcomes.
    Yue Wang, Bofeng Yang, Pengkun Song, Zexiang Ji, Di Zhang, Wenxuan Chen, Lei Du, Lei Liu.
      Background: Hypoxia-induced oxidative stress compromises the survival and function of transplanted islets, contributing to high rates of islet transplantation failure. Methods: This study investigated the small-molecule mitochondrial fusion agonist S89, which specifically activates mitofusin 1 (MFN1). We assessed its protective effects against hypoxia-induced oxidative stress and apoptosis in pancreatic β-cells. Results: In mouse insulinoma cells (Min6), S89 enhanced cell viability by promoting mitochondrial fusion to inhibit mitochondrial reactive oxygen species (mtROS) overaccumulation (S89 reduced mtROS by approximately 30%) and attenuated mitochondrial lipid peroxidation; furthermore, it suppressed hypoxia-induced apoptosis via downregulation of the BAX/BCL-2 ratio, thus protecting the cells from hypoxia-induced oxidative damage. Notably, S89 significantly potentiated glucose-stimulated insulin secretion (GSIS) in both the Min6 β-cell line and primary mouse islets. Critically, S89 pretreatment enhanced hypoxia resistance in islets and significantly increased graft survival upon transplantation into streptozotocin (STZ)-induced type 1 diabetic (T1D) mice, maintaining prolonged blood glucose homeostasis. Conclusions: These findings demonstrate that S89 protects β-cells from hypoxic injury, indicating its efficacy as a therapeutic approach for improving islet transplantation outcomes.
    Keywords:  hypoxia; islet; mitochondrial fusion; oxidative stress
    DOI:  https://doi.org/10.3390/biom15111585
  53. Zool Res. 2025 Nov 18. pii: 2095-8137(2025)06-1488-13. [Epub ahead of print]46(6): 1488-1500
    Regulation of UBC12 expression and protein neddylation by PINK1 suggests a primate-specific function.
    Wei Huang, Ting Xu, Gong-Ke Zhou, Yu-Xuan Li, Chuang-Zhen Lin, Xiu-Sheng Chen, Tong Zhang, Liang Jiang, Yan-Ting Liu, Xin Xiong, Xue-Ying Liang, Xiang-Yu Guo, Shi-Hua Li, Xiao-Jiang Li, Wei-Li Yang.
      Mutations in PTEN-induced putative kinase 1 ( PINK1) are implicated in early-onset Parkinson's disease (PD). Despite various in vitro studies indicating the importance of PINK1 in mitophagy, its physiological function in the brain remains poorly defined due to undetectable protein levels in rodents and cultured cells under basal conditions. Here, PINK1 was found to be selectively expressed in the primate brain, enabling exploration of its endogenous role in vivo. Proteomic profiling via mass spectrometry identified the ubiquitin-conjugating enzyme E2M (UBC12) as a PINK1-interacting partner, with strong colocalization in the monkey brain. Knockdown of PINK1 in monkeys resulted in marked reductions in UBC12 protein abundance and global neddylation, effects not observed in brain tissues from PINK1 knockout mice or pigs. These findings reveal a primate-specific PINK1-UBC12 axis and uncover a previously unrecognized role for PINK1 in protein neddylation, distinct from its established mitophagy function.
    Keywords:  Monkey model; Neddylation; PINK1; Parkinson’s disease; UBC12
    DOI:  https://doi.org/10.24272/j.issn.2095-8137.2025.106
  54. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Nov 20. pii: 1673-4254(2025)11-2437-07. [Epub ahead of print]45(11): 2437-2443
    [Qingre Lidan Jiedu Recipe improves high copper load-induced cognitive dysfunction in rats by regulating mitophagy].
    Yulan Wang, Xiang Fang, Zeming Chen, Bingkun Ruan, Xinli Han, Yujie Tang, Luyao Zhu.
       OBJECTIVES: To explore the mechanisms of Qingre Lidan Jiedu Recipe (QLJR) for improving cognitive dysfunction in rats with high copper load.
    METHODS: Seventy-five male SD rats were randomized into normal control group, model group, QLJR group, penicillamine (PCA) group, and QLJR+ PCA group. Except for those in the control group, all the rats were fed a high-copper diet for 12 weeks. The effects of the treatments on cognitive function of the rats were assessed using the Barnes maze and passive avoidance tests. Hippocampal expressions of NIX, FUNDC1 and LC3 of the rats were detected using Western blotting and immunofluorescence staining, and changes in mitochondrial morphology were observed with transmission electron microscopy.
    RESULTS: Behavioral tests showed prolonged target hole latency, shortened latency to enter the dark chamber, and increased error counts of the rats in the model group, which were significantly improved in QLJR+PCA group; the error counts were significantly lower in QLJR+PCA group than in either QLJR or PCA group. Among all the groups, the hippocampal expressions of NIX and FUNDC1 were the lowest and LC3 I/II expression the highest in the model group; NIX and FUNDC1 expressions were significantly higher and LC3 I expression was lower in QLJR+PCA group than in QLJR group and PCA group. Immunofluorescence staining revealed weakened NIX and FUNDC1 expressions and enhanced LC3 expression in the hippocampus of the rats in the model group as compared with those in the normal control and QLJR+PCA groups, but their expressions did not differ significantly between QLJR and PCA groups. The rats in the model group showed obvious structural disarray of the mitochondria, which were improved in all the treatment groups.
    CONCLUSIONS: QLJR improves cognitive dysfunction in rats with high copper load possibly by regulating mitophagy.
    Keywords:  FUNDC1; NIX; Qingre Lidan Jiedu Recipe; Wilson's disease; cognitive impairment
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.11.16
  55. BMC Biol. 2025 Nov 26.
    New insights into mitochondrial segregation from the Doubly Uniparental Inheritance system in bivalves.
    M Iannello, G Piccinini, F Salatiello, G Forni, F Nicolini, U Valdrè, M Martini, J Martelossi, F Ghiselli, E D'Aniello, L Milani.
       BACKGROUND: While nuclear genome segregation is well characterized, mechanisms underlying mitochondrial partitioning remain partially obscure, even though its failure can cause developmental arrest or harmful mutations. This knowledge gap invokes the need for new, more suitable model systems to study such mechanisms. Doubly Uniparental Inheritance (DUI) of mitochondria in bivalves is a useful system for such studies. In DUI, sperm mitochondria in male embryos are actively transported across cell divisions to precursors of the germline, and this male-specific pattern depends on maternal factors stored in eggs. The presence of distinct mitochondrial segregation patterns in male and female embryos offers a unique opportunity to investigate the molecular bases of this process.
    RESULTS: Here, we leveraged this system by (1) performing RNA-Seq on eggs producing male-biased versus female-biased progenies in the Mediterranean mussel Mytilus galloprovincialis to identify factors involved in differential mitochondrial segregation; and (2) inferring signatures of convergent evolutionary rate across DUI bivalve genomes to separate segregation-specific factors from those involved in sex determination. We show that differentially transcribed genes across eggs that give rise to either male- or female-biased progeny are predominantly associated with mitochondrial dynamics, cytoskeletal organization, and vesicular trafficking. We also identified multiple long noncoding RNAs-many derived from transposable elements-that might have roles in the regulation of other maternally supplied factors that shepherd paternal mitochondria.
    CONCLUSIONS: By overlaying clues from expression and sequence evolution, we delineate a conserved protein-protein interaction network of factors that mediate mitochondrial segregation. This study reveals general principles of organelle selection in animals and unveils the contribution of new factors.
    Keywords:   Mytilus galloprovincialis ; CDK1 gene; Doubly Uniparental Inheritance (DUI); Mitochondrial fission; RALA gene
    DOI:  https://doi.org/10.1186/s12915-025-02459-6
  56. Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01392-9. [Epub ahead of print]
    Activation of RXRα mitigates maternal separation-induced hippocampal neurodevelopmental impairment in mice by inhibiting oxidative stress and restoring mitochondrial homeostasis.
    Shijie Zhang, Daowei Tang, Yuanyuan Liu, Ziye Zang, Senyue Yang, Haidong Wei, Lu Xing, Jianhong Li.
      Adverse events in early life can alter the developmental trajectory of glial cells and neurons in the brain, increasing an individual's risk of developing neuropsychiatric disorders later in life. Retinoid X receptor alpha (RXRα), a member of the nuclear receptor superfamily, has been shown to exert protective effects on the central nervous system when activated. However, whether RXRα plays a role in maternal separation (MS) and the underlying mechanisms remain unclear. In this study, we used MS in BALB/c mice to simulate early-life stress, aiming to investigate the impact of MS on hippocampal neuronal development in mice during early life, as well as the neuroprotective role of RXRα and its mechanisms. The results showed that MS induced hippocampal neuronal damage and inhibited RXRα expression in offspring mice. In contrast, RXRα activation significantly ameliorated hippocampal neuronal damage in MS mice and exerted neuroprotective effects by suppressing oxidative stress, repairing mitochondrial dysfunction, reducing neuronal apoptosis, and promoting mitophagy. Further analysis revealed that bexarotene (an RXR agonist) exerted neuroprotective effects by upregulating the expression levels of RXRα and peroxisome proliferator-activated receptor gamma (PPARγ). In HT22 cells with hydrogen peroxide (H2O2)-induced damage, knockdown of PPARγ expression via small interfering RNA (siRNA) significantly attenuated the neuroprotective effect of RXRα activation against neuronal damage. In conclusion, MS impairs the development of hippocampal neurons in offspring mice, which may alter the developmental trajectory of the nervous system and increase the risk of neuropsychiatric disorders in adulthood. Activation of RXRα can effectively alleviate oxidative stress and neuronal damage in the hippocampus by improving mitochondrial dysfunction. Therefore, targeting RXRα holds promise as a potential strategy for treating the consequences of early-life trauma.
    Keywords:  Maternal separation; Mitochondrial dysfunction; Neuronal damage; Oxidative stress; Retinoid X receptor alpha (RXRα)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.047
  57. Sci Rep. 2025 Nov 25.
    Low dose ionising radiation elicits MPTP comparable alterations in locomotor Function, oxidative balance and mitochondrial homeostasis in zebrafish embryos.
    Ezgi Cahide, Aydas Bayramov, Merih Beler, Derya Cansiz, Ismail Unal, Gizem Egilmezer, Selma Yaltkaya, Atakan Karagoz, Hüseyin Gündüz, Ebru Emekli-Alturfan, Sebnem Ercalik Yalcinkaya.
      Prenatal exposure to environmental factors including low-dose ionising radiation and neurotoxins may disrupt the oxidant-antioxidant balance. Our aim was to assess the effects of exposure to low-dose ionising radiation (LDIR) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is a neurotoxin used to model Parkinson's disease (PD), on developing zebrafish embryos, focusing on the oxidant-antioxidant system and markers of mitochondrial damage associated with PD. Zebrafish embryos were divided into four groups: control, LDIR, MPTP, and LDIR combined with MPTP (LDIR + MPTP). A dental x-ray unit (60 kVp, 7 mA) was used for the exposures. The 0.08 s LDIR exposure was measured as 0.065 mGy using optically stimulated dosimeters. At the end of 72 h after fertilization, locomotor activities, acetylcholine esterase (AChE) activity, oxidative stress and antioxidant status were assessed. Expressions of genes associated with in PD as markers of mitochondrial damage (pink1, parkin, dj1 and lrrk2) were determined by RT-PCR. Developmental toxicity was observed in all exposure groups as evidenced by pericardial edema, yolk sac edema and spinal curvature. LDIR exposure in zebrafish embryos affected oxidative and mitochondrial stress markers, as well as locomotor activity and AChE as a marker of cognitive function at levels comparable to the MPTP exposure. Our study is the first to determine the effects of LDIR from a dental x-ray unit on the response to MPTP, and we aim to further elucidate the mechanism of these changes observed particularly in the LDIR + MPTP group.
    Keywords:  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Antioxidant; Locomotor activity; Low-dose ionising radiation; Oxidative stress
    DOI:  https://doi.org/10.1038/s41598-025-29382-8
  58. Stem Cell Res Ther. 2025 Nov 26. 16(1): 663
    Extracellular vesicles from Yiguanjian-primed bone-marrow mesenchymal stem cells ameliorate chronic liver fibrosis via miR-7045-5p.
    Zhejun Liu, Xiaodan Jiang, Hongjie You, Zuoqing Tang, Yun Ma, Niancong Che, Chongyang Ma, Wenlan Liu.
       BACKGROUND: Liver fibrosis is a crucial pathological stage in the progression of chronic liver diseases. Yiguanjian (YGJ), a Chinese herbal formula, exhibits anti-inflammatory, anti-fibrotic, and hepatoprotective effects. Extracellular vesicles from bone-marrow mesenchymal stem cells (BMSC-EVs) have shown potential in treating various disorders, including liver fibrosis. This study investigated the regulatory effects of EVs from YGJ-preconditioned BMSCs (YGJ-EVs) on TGF-β1-stimulated hepatic stellate cells (HSCs) and their therapeutic potential in a mouse model of liver fibrosis, with a focus on identifying the causative microRNA cargo.
    METHODS: YGJ-EVs and control EVs were isolated from BMSC culture supernatants and characterized via western blotting, transmission electron microscopy, and nanoparticle tracking analysis. Their cellular uptake in vitro and in vivo was evaluated using DIR labeling. To identify candidate miRNAs mediating YGJ-EV bioactivity, miRNA microarray analysis was conducted. To assess the effect of YGJ-EVs on liver fibrosis, TGF-β1-activated HSC cells were treated with YGJ-EVs or control-EVs for 24 h, and then the expression of proteins related to fibrotic activation (COL1-A1 and α-SMA), lysosomal biogenesis (LAMP1, TPP1, CTSD, and CTSB) mitophagy (p62, LC3, PINK1, and Parkin), and the Akt/AMPK/TFEB pathway was assessed. To determine whether miR-7045-5p is the causative factor, HSC cells transfected with miR-7045-5p were similarly analyzed.
    RESULTS: miRNA microarray analysis revealed miR-7045-5p upregulation in YGJ-EVs versus control EVs. In CCl4-treated mice, YGJ-EV-derived miR-7045-5p ameliorated the liver fibrosis, improved the hepatic function, and suppressed the HSC activation by inhibiting the Akt/AMPK/TFEB pathway. In vitro, miR-7045-5p overexpression attenuated TGF-β1-induced HSC activation.
    CONCLUSION: YGJ increases miR-7045-5p abundance in BMSC-EVs. YGJ-EVs alleviate liver fibrosis by delivering the anti-fibrotic miRNA miR-7045-5p, which inhibits the Akt/AMPK/TFEB pathway, thereby promoting lysosomal biogenesis and mitophagy in HSCs.
    Keywords:  Bone marrow mesenchymal stem cells; Extracellular vesicles; Liver fibrosis; Lysosomal biogenesis; Mitophagy; miR-7045-5p
    DOI:  https://doi.org/10.1186/s13287-025-04780-x
  59. Mol Neurobiol. 2025 Nov 29. 63(1): 219
    Oxymatrine Alleviates Cerebral Ischemia/Reperfusion Injury By Targeting HDAC1 to Regulate Mitochondria-Related Autophagy and Oxidative Stress.
    Chang-Sheng Ma, Bo Han, Yu-Xi Liu, Chang-Ku Shi, Dong-Lun Li, Jin-Fen Guo, Min Bai, Shu-Chen Meng, Li-Ying Zhang, Meng-Yuan Duan, Mao-Tao He.
      Oxymatrine (OMT), a major alkaloid extracted from Sophora flavescens, has been widely recognized for its anti-inflammatory and anti-cancer properties. However, its precise neuroprotective mechanisms in cerebral ischemia/reperfusion (I/R) injury remain to be fully elucidated. In this study, we combined in vivo and in vitro models to investigate the therapeutic effects of OMT on cerebral I/R injury and glutamate-induced neuronal toxicity during the reperfusion process. In vivo, a mouse middle cerebral artery occlusion (MCAO) model was established to recapitulate I/R injury, whereas glutamate-exposed HT22 hippocampal neurons were utilized as an in vitro model to mimic excitotoxic damage. Bioinformatics analysis, integrated with molecular docking, identified histone deacetylase 1 (HDAC1) as a potential direct target of OMT. Subsequent experimental validation demonstrated that OMT attenuates I/R-induced brain damage by modulating HDAC1-mediated pathways involved in autophagy and oxidative stress regulation. OMT treatment significantly reduced infarct volume and improved neurological function in mice. At the cellular level, OMT suppressed mitochondrial apoptosis and reactive oxygen species (ROS) accumulation, restored mitochondrial membrane integrity, and rebalanced mitochondrial dynamics by downregulating fission-related proteins (Fis1) and upregulating fusion markers (Mfn2). Additionally, OMT inhibited excessive autophagy through modulation of the PINK1/Parkin signaling pathway, as evidenced by decreased expression of LC3-II/I ratio, PINK1, Parkin, and NBR1, along with restored levels of P62.These findings suggest that OMT exerts its neuroprotective effects in cerebral I/R injury by targeting HDAC1, thereby alleviating oxidative stress and excessive autophagy. This study provides new mechanistic insights and supports OMT as a promising therapeutic candidate for ischemic stroke treatment.
    Keywords:  Cerebral ischemia/reperfusion (I/R) injury; Excessive autophagy; HDAC1; Oxidative stress; Oxymatrine
    DOI:  https://doi.org/10.1007/s12035-025-05423-1
  60. Cell Death Differ. 2025 Nov 25.
    Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.
    Ismael Sánchez-Vera, Ana M Cosialls, Nekane Maritorena-Hualde, Max-Hinderk Schuler, Rodolfo Lavilla, Gabriel Pons, Lucas T Jae, Daniel Iglesias-Serret, Joan Gil.
      Prohibitins (PHBs) are predominantly located at the inner mitochondrial membrane, displaying significant roles in tumor progression, invasion, and apoptotic resistance, often overexpressed in primary tumors. Importantly, we developed a synthetic molecule, fluorizoline, that induces apoptosis by selectively targeting PHBs in various cancer cell lines and primary samples from different hematological neoplasms. Fluorizoline induces apoptosis by activating the pro-apoptotic branch of the integrated stress response (ISR) pathway in HeLa and HAP1 cells, specifically via the ATF4-CHOP-NOXA axis. We identified compensatory mechanisms for four ISR-related kinases, with HRI emerging as the primary kinase responsible for the activation of the ISR and apoptosis induction, implicating mitochondrial stress in ISR activation. Here, we investigate the mitochondrial stress response signaling pathway responsible for activating HRI after targeting PHBs either by fluorizoline treatment or by PHBs downregulation in HeLa and HAP1 cancer cell lines. In this study, we describe how PHBs regulate the localization of the mitochondrial stress sensor DELE1, leading to ISR activation and apoptosis induction in HeLa and HAP1 cells. Our findings demonstrate that DELE1 promotes ISR activation upon fluorizoline treatment and PHBs downregulation. Although fluorizoline treatment activates the cleavage of long DELE1 (L-DELE1) to its cleaved form (S-DELE1), OMA1 was found to be dispensable for activating the ISR upon fluorizoline treatment. Furthermore, our findings indicate a potential impairment of the mitochondrial protein import machinery upon targeting PHBs, as the import of other mitochondrial proteins beyond DELE1 is also disrupted. These findings reveal a previously unknown physiological role of PHBs in preserving the mitochondrial protein import pre-sequence pathway, possibly due to the interaction between PHBs and DNAJC19. This novel insight underscores the potential of targeting PHBs, such as with fluorizoline, to overwhelm mitochondrial stress in cancer.
    DOI:  https://doi.org/10.1038/s41418-025-01618-0
  61. Adv Sci (Weinh). 2025 Nov 23. e19527
    A Sirtuin-1-Targeted Gene-Activating Tetrahedral DNA Attenuates Bladder Fibrosis by Restoring Mitophagy in Fibroblasts via the SIRT1-FOXO3-BNIP3 Axis.
    Wei Wang, Ran Yan, Lede Lin, Lei Xiang, Xiaozhi Xia, Liao Peng, Xiaoshuai Gao, Jiawei Chen, Yang Xiong, Liang Zhou, Yunfeng Lin.
      Bladder fibrosis represents a widespread global health challenge associated with substantial socioeconomic burden. To date, no effective therapeutic interventions are available to halt or reverse its progression. Small activating RNA (saRNA)-based therapy has recently garnered increasing interest due to its high target specificity and potent efficacy. Nevertheless, the clinical translation of saRNA is hampered by inherent limitations including structural instability, nuclease sensitivity, and inefficient cellular internalization. In this study, single-cell and bulk transcriptomic analyses are integrated, which reveal that SIRT1 is the only sirtuin family member significantly downregulated in both fibrotic bladder tissues and activated fibroblasts. To address this, a tetrahedral DNA functionalized with saRNA targeting SIRT1 activation is engineered, termed TSA. TSA exhibits exceptional biocompatibility and markedly attenuates bladder dysfunction and fibrotic remodeling in a bladder outlet obstruction model. Mechanistically, TSA administration robustly restores SIRT1 expression, facilitating FOXO3A deacetylation and alleviating its transcriptional repression of BNIP3. This cascade leads to the activation of PINK1-PARKIN-mediated mitophagy, suppresses mitochondrial reactive oxygen species accumulation, and ultimately leads to the inhibition of fibroblast activation and collagen deposition. These compelling findings underscore the therapeutic potential of TSA as a promising strategy for the treatment of bladder fibrosis, with broad implications for clinical application.
    Keywords:  bladder fibrosis; fibroblast; sirtuin‐1; small‐activating RNA; tetrahedral framework nucleic acid
    DOI:  https://doi.org/10.1002/advs.202519527
  62. ChemMedChem. 2025 Nov 22. e202500449
    Photodynamic Anticancer Efficacy of meso-tris-p-Carboxyphenylporphyrin-Fullerene Dyads: Apoptosis Induction and Mitochondrial Deregulation in Glioblastoma Therapy.
    Debdulal Sharma, Madhumanti Halder, Prem Das, Oishee Chakrabarti, Devashish Sengupta.
      This work explores the toxicity profile and anticancer mechanisms of reported anti-HIV carboxyphenyl porphyrin-fullerene dyads, PB3C60 and PB3C70, together with their precursor porphyrin PB3OH, within noncationic porphyrin-based donor-π-acceptor (D-π-A) assemblies. This study evaluates the patented compounds meso-tris-p-carboxyphenyl porphyrin-fullerene (P-F) dyads, PB3C60 and PB3C70, and precursor PB3OH within noncationic donor-π-acceptor (D-π-A) assemblies as amphiphilic photosensitizers (PSs) for glioblastoma photodynamic therapy (PDT). Emphasis is placed on light-induced apoptosis, mitochondrial disruption in glioma-derived cells, along with the already reported anti-HIV properties, indicating potential for dual-action therapy in immunocompromised individuals. Given the critical need for therapies effective in immunocompromised patients, further investigation into noncationic P-F dyads could yield dual-action agents. P-F dyads were administered to tumour-derived as well as nontransformed cells and subjected to PDT. PB3C60 exhibited the highest selective phototoxicity in gliomblastoma cells under PDT, inducing apoptosis with moderate ROS and mitochondrial fragmentation. PB3OH caused nonspecific cytotoxicity via excessive ROS, while PB3C70 triggered apoptosis even without light. PB3C60 showed strong potential as a targeted photosensitizer for glioblastoma, with light-dependent selectivity for cancer cells. Unlike PB3OH and PB3C70, its apoptotic effect was both specific and light activated, highlighting PB3C60's promise as a nanohybrid therapeutic for glioblastoma.
    Keywords:  U87‐mG glioblastoma cells; anti‐cancer pDT; apoptosis; mitochondrial dynamics; porphyrin‐fullerene dyads
    DOI:  https://doi.org/10.1002/cmdc.202500449
  63. Sci Rep. 2025 Nov 25. 15(1): 41980
    Ailanthone restrains hepatocellular carcinoma progression by inducing ferroptosis and disrupting mitochondrial homeostasis.
    Kewen Ye, Zhenghao Zhang, Shanmei Lv, Jintao Wu, Jiaoping Zhao.
      Ailanthone (AIL), a natural compound derived from the Ailanthus species, demonstrates substantial clinical efficacy in managing diverse diseases, notably cancer. Despite this, the precise mechanisms underlying AIL's regulation of hepatocellular carcinoma (HCC) progression remain unclear. Our investigation revealed that AIL effectively suppresses HCC cell proliferation in vitro and in vivo, and inhibits metastasis-related phenotypes in vitro. Mechanistically, we discovered that AIL directly interacted with HSP90, thereby enhancing the ubiquitination of GPX4 proteins. This interaction led to a reduction in GPX4 expression levels and subsequently induced ferroptosis in HCC cells. Furthermore, the combination of AIL with GPX4 inhibitors exhibited a strong synergistic anti-proliferative effect on HCC cells. Collectively, these findings underscore the critical role of the HSP90/GPX4/ferroptosis axis in AIL-mediated inhibition of HCC progression.
    Keywords:  Ailanthone; Ferroptosis; GPX4; HSP90; Hepatocellular carcinoma
    DOI:  https://doi.org/10.1038/s41598-025-26038-5
  64. Antioxidants (Basel). 2025 Oct 25. pii: 1279. [Epub ahead of print]14(11):
    Nrf2 Activated by PD-MSCs Attenuates Oxidative Stress in a Hydrogen Peroxide-Injured Retinal Pigment Epithelial Cell Line.
    Se Jin Hong, Dae-Hyun Lee, Jeong Woo Choi, Hankyu Lee, Youngje Sung, Gi Jin Kim.
      Age-related macular degeneration (AMD) is a retinal degenerative disease caused by oxidative stress. Thus, we aimed to reduce oxidative stress through the use of placenta-derived mesenchymal stem cells (PD-MSCs). To induce oxidative stress in ARPE-19 cells, we treated them with 200 µM hydrogen peroxide (H2O2) for 2 h and then cocultured them with PD-MSCs. The dissociation of the KEAP1/Nrf2 complex, along with the expression of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), increased in the coculture group compared with the H2O2 treatment group (* p < 0.05). The expression levels of antioxidant genes increased in the cocultured group compared with those in the H2O2 treatment group (* p < 0.05), whereas the ROS levels decreased in the cocultured group (* p < 0.05). Additionally, both the expression of mitochondrial dynamics markers and the mitochondrial membrane potential increased when the cells were cocultured with PD-MSCs (* p < 0.05). PD-MSC cocultivation decreased the expression levels of lipoproteins (* p < 0.05). Finally, we confirmed that PD-MSCs promoted the expression of RPE-specific genes in H2O2-injured ARPE-19 cells (* p < 0.05). These findings suggest a new aspect of stem cell treatment for AMD induced by oxidative stress.
    Keywords:  ARPE-19; KEAP1; Nrf2; age-related macular degeneration; mitochondrial dynamics; oxidative stress; placenta-derived mesenchymal stem cells
    DOI:  https://doi.org/10.3390/antiox14111279
  65. Biomolecules. 2025 Nov 09. pii: 1572. [Epub ahead of print]15(11):
    Mitochondrial Dysfunction in Cardiomyopathy and Heart Failure: From Energetic Collapse to Therapeutic Opportunity.
    Nikola Pavlović, Petar Todorović, Mirko Maglica, Marko Kumrić, Katarina Vukojević, Zenon Pogorelić, Joško Božić.
      The heart's relentless contractile activity depends critically on mitochondrial function to meet its extraordinary bioenergetic demands. Mitochondria, through oxidative phosphorylation, not only supply ATP but also regulate metabolism, calcium homeostasis, and apoptotic signaling, ensuring cardiomyocyte viability and cardiac function. Mitochondrial dysfunction is a hallmark of cardiomyopathies and heart failure, characterized by impaired oxidative phosphorylation, excessive production of reactive oxygen species (ROS), dysregulated calcium handling, and disturbances in mitochondrial dynamics and mitophagy. These defects culminate in energetic insufficiency, cellular injury, and cardiomyocyte death, driving heart disease progression. Diverse cardiomyopathy phenotypes exhibit distinct mitochondrial pathologies, from acute ischemia-induced mitochondrial collapse to chronic remodeling seen in dilated, hypertrophic, restrictive, and primary mitochondrial cardiomyopathies. Mitochondria also orchestrate cell death and inflammatory pathways that worsen cardiac dysfunction. Therapeutic strategies targeting mitochondrial dysfunction, including antioxidants, modulators of mitochondrial biogenesis, metabolic therapies, and innovative approaches such as mitochondrial transplantation, show promise but face challenges in clinical translation. Advances in biomarker discovery and personalized medicine approaches hold promise for optimizing mitochondrial-targeted therapies. Unlike previous reviews that examined these pathways or interventions individually, this work summarizes insights into mechanisms with emerging therapeutic strategies, such as SGLT2 inhibition in HFpEF, NAD+ repletion, mitochondrial transplantation, and biomarker-driven precision medicine, into a unified synthesis. This framework underscores the novel contribution of linking basic mitochondrial biology to translational and clinical opportunities in cardiomyopathy and heart failure. This review synthesizes the current understanding of mitochondrial biology in cardiac health and disease, delineates the molecular mechanisms underpinning mitochondrial dysfunction in cardiomyopathy and heart failure, and explores emerging therapeutic avenues aimed at restoring mitochondrial integrity and improving clinical outcomes in cardiac patients.
    Keywords:  bioenergetics; cardiomyopathy; heart failure; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/biom15111572
  66. MedComm (2020). 2025 Dec;6(12): e70499
    mTORC1-USP30-LEF1 Cascade Regulates Cancer Stemness and Malignant Progression Through Mitonuclear Crosstalk.
    Xiaolin Li, Haowei Zhang, Jia Li, Cheng Luo, Zijian Yang, Jin Cai, Li Xia, Yapei Jiang, Ruonan Wang, Hongli Zeng, Yuetong Li, Haitao Yang, Tong Gao, Weidong Xie, Yaou Zhang, Naihan Xu.
      USP30, a ubiquitin-specific protease, primarily characterized as a mitochondrial deubiquitinase regulating mitophagy, has not been previously reported to have nuclear functions. In this study, we demonstrate that USP30 is present in both mitochondrial and nuclear compartments. Nutrient deprivation triggers USP30 nuclear translocation via an N-terminal nuclear localization signal (NLS), mediated through suppression of mTORC1-dependent phosphorylation at serine 104, a modification constraining nuclear entry. Nuclear USP30 acts as a tumor suppressor by inhibiting cancer stemness and chemoresistance in triple-negative breast cancer (TNBC) cells. Mechanistically, USP30 directly interacts with and deubiquitinates the transcription factor TCF/LEF1 at K379 and K382 residues, disrupting recruitment of CBP/P300 co-activators to the β-catenin/LEF1 complex. This abolishes β-catenin/LEF1 transactivation and suppresses WNT signaling. Clinically, USP30 is downregulated in TNBC and cancer stem cells (CSCs), with notably reduced nuclear levels in cancer tissues. Overexpression of nuclear USP30 markedly reduces lung metastatic burden in TNBC mouse models. These findings uncover a novel role for nuclear USP30 in regulating cancer stemness and suggest that targeting the dynamic relocalization of USP30 from mitochondria to the nucleus could offer new therapeutic strategies for breast cancer metastasis.
    Keywords:  TCF/LEF1; USP30; WNT; chemoresistance; deubiquitination; stemness
    DOI:  https://doi.org/10.1002/mco2.70499
  67. Nat Commun. 2025 Nov 28. 16(1): 10761
    Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
    Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.
      Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.
    DOI:  https://doi.org/10.1038/s41467-025-65798-6
  68. Mol Neurobiol. 2025 Nov 29. 63(1): 218
    Neuroprotective Role of Piperine-Encapsulated Casein Micelles in Mitigating Intracellular Dyshomeostasis in Alzheimer's Disease Pathology.
    Jayapriya Mishra, Charan Singh, Jasvinder Singh Bhatti.
      Alzheimer's disease remains a complex neurodegenerative disorder characterized by multifactorial mechanisms that undermine the efficacy of monotherapeutic strategies. Multi-targeted therapies have emerged as promising strategies, particularly those addressing mitochondrial dysfunction, a key contributor to AD pathophysiology. This study explores the neuroprotective efficacy of piperine encapsulated casein micelles (PIP@CMs) against Aβ(1-42)-induced-neurotoxicity in differentiated SH-SY5Y cells, an established in vitro model of Alzheimer's pathology. The formulation was synthesized and characterized using techniques such as FTIR, DSC, PXRD, SEM, and TEM, confirming its physicochemical integrity and optimal surface morphology. Comprehensive physicochemical characterization confirmed the structural integrity and stability of PIP@CMs, which demonstrated a uniform particle size of 196.32 ± 5.70 nm, a negative zeta potential of -11.95 ± 6.08 mV, and a controlled release profile. Functional assays demonstrated that PIP@CMs exhibited superior antioxidant activity, mitigated oxidative stress, and restored mitochondrial homeostasis more effectively than free piperine. Key parameters, including intracellular ROS generation, calcium imbalance, mitochondrial superoxide levels, mitochondrial membrane potential, and expression profile of autophagy and mitophagy markers, were significantly improved in PIP@CMs-treated cells. Additionally, PIP@CMs provided dose-dependent protection against Aβ(1-42)-induced cytotoxicity and apoptosis. The findings suggest that PIP@CMs not only enhance the bioavailability of piperine but also amplify its neuroprotective effects through controlled drug release and targeted action on AD's pathological hallmarks. By combining piperine's neuroprotective properties with the enhanced delivery capabilities of casein micelles, this study provides a promising platform for developing effective AD treatments. However, the present study is limited by its exclusive reliance on in vitro cellular models without in vivo validation, which constrains direct clinical translation. Further investigations in relevant animal models are necessary to establish the pharmacokinetics, blood-brain barrier penetration, safety, and behavioral outcomes associated with PIP@CMs. Future research should also explore combinatorial approaches and extended nanocarrier applications to optimize therapeutic outcomes for neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Mitochondria homeostasis; Nano-micelles; Neurotoxicity; Oxidative stress; Piperine
    DOI:  https://doi.org/10.1007/s12035-025-05297-3
  69. Antioxidants (Basel). 2025 Nov 10. pii: 1348. [Epub ahead of print]14(11):
    Olivomycin A Targets Epithelial-Mesenchymal Transition, Apoptosis, and Mitochondrial Quality Control in Renal Cancer Cells.
    Ching-Yu Hsieh, Yih-Farng Liou, Yu-Tung Shih, Alexander S Tikhomirov, Andrey E Shchekotikhin, Pin Ju Chueh.
      Here, we show that the aureolic acid-class antibiotic, olivomycin A, exerts potent anticancer activity in renal cell carcinoma (RCC) by disrupting both cell survival and metastatic programs. In A-498 (wild-type p53) and 786-O (loss-of-function in p53 and PTEN) cells, olivomycin A markedly inhibited migratory capacity and reversed epithelial-mesenchymal transition (EMT), as shown by downregulation of nuclear Snail and the mesenchymal marker N-cadherin and restoration of the epithelial markers, E-cadherin and ZO-1. In parallel, olivomycin A induced apoptosis through distinct p53-dependent mechanisms: In A-498 cells, apoptosis was primarily mediated through the intrinsic pathway, characterized by the upregulation of Puma, Bak, and activation of caspase-9. In 786-O cells, caspase-8 activation and Bid truncation were observed alongside mitochondrial involvement, suggesting possible cross-talk apoptotic cascades. Notably, in p53-mutant 786-O cells, treatment with olivomycin A elicited severe genotoxic stress accompanied by robust DNA damage signaling, excessive reactive oxygen species (ROS) accumulation, and lysosomal activation, culminating in extensive mitochondrial removal. Such changes were weaker in p53-wild-type A-498 cells, suggesting that the altered p53 context sensitizes RCC cells to olivomycin A-mediated mitochondrial quality control mechanisms. Collectively, our findings delineate a multifaceted mechanism whereby olivomycin A coordinates EMT suppression, apoptotic induction, and mitochondrial clearance. Thus, olivomycin A has potential as a therapeutic candidate that can target both survival and metastatic pathways in heterogeneous genetic backgrounds.
    Keywords:  DNA damage; apoptosis; epithelial–mesenchymal transition (EMT); mitochondrial clearance; olivomycin A; renal cell carcinoma (RCC)
    DOI:  https://doi.org/10.3390/antiox14111348
  70. Mol Neurobiol. 2025 Nov 22. 63(1): 146
    Caenorhabditis Elegans Ortholog of TNF Alpha-Induced Protein 1 is Upregulated by TOL-1 and Exacerbates Amyloid-Beta-Associated Pathology.
    Yanmei Su, Donghua Zhang, Yixin Li, Huan Gu, Wenhu Li, Wenhui Zhou, Ninghui Zhao, Xiaowei Huang.
      Neuroinflammation has been recognized as a central pathological mechanism in Alzheimer's disease (AD), modulated by diverse molecular pathways. Among these, the tumor necrosis factor superfamily (TNFSF) pathway serves as a pivotal mediator of inflammatory responses in higher organisms, representing a potential therapeutic target for AD treatment. Notably, TNF alpha-induced protein 1 (TNFAIP1) is significantly upregulated following amyloid-beta1-42 (Aβ1-42) accumulation in the postmortem brains of patients with AD and in transgenic Caenorhabditis elegans models. However, the regulatory mechanism of its ortholog F22E5.6 in C. elegans and its role in Aβ neurotoxicity remain elusive due to the absence of the core TNFSF members in this model. Through systematic screening of TNFSF orthologs, the trf-1 gene that encodes the adapter protein, TNF receptor-associated factor (TRAF), has been identified as a critical regulator in Aβ1-42-induced F22E5.6 overexpression of C. elegans. In this genetic model, the only Toll-like receptor TOL-1 in C. elegans serves as a potential receptor to activate TRF-1 and to transmit this signal to the SRC-2/PMK-3 axis, thereby executing the effects on mitochondrial homeostasis disequilibrium. These findings reveal the regulatory mechanism on Aβ1-42-induced F22E5.6/TNFAIP1 overexpression and its involvement in AD model of C. elegans, providing a clue to resolve the paradox of TNFSF-mediated inflammation in organisms lacking the canonical TNFSF pathway.
    Keywords:   Caenorhabditis elegans ; Alzheimer’s disease; Mitochondrial homeostasis; Molecular mechanism of pathogenesis; TNFSF pathway; Toll-like receptor
    DOI:  https://doi.org/10.1007/s12035-025-05554-5
  71. Biomedicines. 2025 Oct 24. pii: 2603. [Epub ahead of print]13(11):
    Mitochondrial Dynamics in Aging Heart.
    Pankaj Patyal, Gohar Azhar, Ambika Verma, Shakshi Sharma, Jyotsna Shrivastava, Sayed Aliul Hasan Abdi, Xiaomin Zhang, Jeanne Y Wei.
      Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show morphological alterations including cristae disorganization, swelling, and fragmentation, along with reduced OXPHOS efficiency. These defects increase proton leak, lower ATP production, and elevate reactive oxygen species (ROS), causing oxidative damage. Concurrent disruptions in mitochondrial fusion and fission further impair turnover and quality control, exacerbating mitochondrial dysfunction and cardiac decline. Serum response factor (SRF) signaling, a crucial regulator of cytoskeletal and metabolic gene expression, plays a key role in modulating mitochondrial function during cardiac aging. Dysregulation of SRF impairs mitochondrial adaptability, contributing to dysfunction. Additionally, reduced levels of nicotinamide adenine dinucleotide (NAD+) hinder sirtuin-dependent deacetylation, further compromising mitochondrial efficiency and stress resilience. These cumulative defects activate regulated cell death pathways, leading to cardiomyocyte loss, fibrosis, and impaired diastolic function. Mitochondrial dysfunction therefore serves as both a driver and amplifier of cardiac aging, accelerating the transition toward heart failure. This narrative review aims to provide a comprehensive overview of mitochondrial remodeling in the aging myocardium, examining the mechanistic links between mitochondrial dysfunction and myocardial injury. We also discuss emerging therapeutic strategies targeting mitochondrial bioenergetics and quality control as promising approaches to preserve cardiac function and extend cardiovascular health span in the aging population.
    Keywords:  apoptosis; cardiac aging; interventions; mitochondria; mtDNA; sirtuins
    DOI:  https://doi.org/10.3390/biomedicines13112603
  72. Pathogens. 2025 Oct 28. pii: 1097. [Epub ahead of print]14(11):
    Mitochondrial Network Fragmentation Leads to Dysfunction of Macrophages During Echinococcus multilocularis Protoscoleces Infection.
    Zihan Yang, Yaogang Zhang, Tao Zhang, Jing Hou, Meiyuan Tian, Dengliang Huang, Yuan Jiang, Li Sun, Panlong Wei, Yanyan Ma.
      Alveolar echinococcosis (AE) is a fatal foodborne parasitic disease caused by the larvae of Echinococcus multilocularis. The disease primarily affects the liver. Previous studies have found that Kupffer cells have an immune protective effect, but in the late stages of AE, they are associated with parasite immune escape. The present study analyzed the effects of Echinococcus multilocularis protoscoleces (PSCs) infection on the mitochondrial morphology and function of macrophages, as well as their phagocytic function and apoptosis. Infection with PSCs has been shown to result in the fragmentation of the macrophage mitochondrial network, the impairment of mitochondrial membrane potential, the elevation of mitochondrial reactive oxygen species, and the reduction in mitochondrial DNA copy number. This cascade of events, consequent to the infection, has been demonstrated to promote the apoptosis of macrophages and impair their phagocytic function. Inhibiting mitochondrial fission during PSCs infection has been shown to mitigate mitochondrial dysfunction, suppress macrophage apoptosis, and enhance macrophage phagocytic function. This discovery provides insights into improving macrophage function during the progression of AE.
    Keywords:  Echinococcus multilocularis; macrophage phagocytosis; mitochondrial fragmentation; protoscoleces
    DOI:  https://doi.org/10.3390/pathogens14111097
  73. J Nutr Biochem. 2025 Nov 21. pii: S0955-2863(25)00349-3. [Epub ahead of print] 110187
    Coenzyme Q10 ameliorates obesity by promoting white adipose tissue browning and preserving mitochondrial dynamics in ovariectomized rats fed a high-fat diet.
    Tong Pan, Shu-Ying Chen, Ching-Wen Kung, Hsuan- Yu Chen, Pao-Yun Cheng, Hsin-Hsueh Shen, Ing-Luen Shyu, Yen-Mei Lee.
      Estrogen deficiency caused by menopause leads to obesity in women. In obesity, excessive visceral fat accumulation induces a chronic, low-grade inflammatory response, thereby increasing the risk of cardiovascular disease, insulin resistance, and type 2 diabetes mellitus. Browning of white adipose tissue (WAT) has emerged as a promising strategy to counteract obesity and related metabolic disorders. Coenzyme Q10 (CoQ10) has been reported to reduce oxidative stress, enhance mitochondria function and improve metabolic syndrome in obese and diabetic animals and patients. In this study, we evaluated whether long-term CoQ10 supplementation could induce WAT browning to ameliorate obesity in ovariectomized (OVX) rats fed a high-fat diet (HFD), and explored the underlying mechanisms. Supplementation with CoQ10 (20 and 40 mg/kg, once daily by gavage) for 12 weeks in OVX rats significantly reduced weight gain, excessive visceral fat accumulation, white adipocyte hypertrophy, plasma triglyceride levels, and glucose intolerance, while increasing energy expenditure compared to OVX rats treated with vehicle (p < 0.05). High dose CoQ10 (40 mg/kg) significantly lowered plasma insulin levels, reduced HIF-1α, MCP-1 and IL-6 protein expression, and increased phosphorylated AKT in retroperitoneal WAT (p < 0.05). In inguinal WAT (iWAT), CoQ10 enhanced the expression of browning-related proteins including UCP-1, CIDEA, PRDM16, PGC-1α, and phosphorylated AMPK, and elevated plasma irisin levels (p < 0.05). CoQ10 also regulated mitochondria dynamics of iWAT, as evidenced by increased MFN1, MFN2, and OPA1, and decreased FIS1 protein expression compared with the OVX group (p < 0.05). In 3T3-L1 adipocytes, CoQ10-induced expression of browning markers (UCP-1, TBX1 and PRDM16) was significantly suppressed by dorsomorphin, an AMPK inhibitor, and by AMPK knockdown (p < 0.05). In conclusion, long-term CoQ10 supplementation ameliorates weight gain, white adipocyte hypertrophy and inflammation in WAT, and metabolic disorders caused by combined estrogen deficiency and HFD, likely through its WAT browning effect. AMPK activation is suggested to contribute to the browning effect and enhance the expression of proteins involved in mitochondrial dynamics. Therefore, CoQ10 supplementation could be an effective intervention for preventing postmenopausal obesity.
    Keywords:  AMP-activated protein kinase; WAT browning; WAT inflammation; coenzyme Q10; estrogen deficiency; mitochondrial dynamics; ovariectomy; white adipocyte hypertrophy
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.110187
  74. Mol Biomed. 2025 Nov 25. 6(1): 119
    Obestatin treatment links mitochondrial homeostasis and skeletal muscle repair in Duchenne muscle dystrophy.
    Andrea C Lodeiro, Silvia Costas-Abalde, Tania Cid-Díaz, Lucía Debasa-Corral, Saúl Leal-López, Kamel Mamchaoui, Vincent Mouly, Xesús Casabiell, Rosalía Gallego, José Luis Relova, Yolanda Pazos, Icía Santos-Zas, Jesus P Camiña.
      Duchenne muscular dystrophy (DMD) is a genetic, progressive neuromuscular disease caused by mutations in the dystrophin protein which compromise the integrity of the sarcolemma. Current care of DMD involves both supportive and targeted disease modifying medications. Obestatin, a peptide derived from preproghrelin, is a potential candidate to enhance existing treatments for DMD. This study was conducted to analyse the molecular mechanism by which obestatin acts on myofiber metabolism and muscle restructuring in DMD. Through human and animal models of DMD, we identify the calcium-activated protein phosphatase 3 (PPP3) as key node in obestatin signalling for restoration of muscle homeostasis and activation of membrane repair. In particular, we describe how obestatin signalling recovers muscle function by coordinated activation of the transcription factor EB (TFEB) and the nuclear factor of activated T cell (NFATc1) in which PPP3 is a core component. TFEB dephosphorylation triggers its nuclear translocation and the activation of macroautophagic/autophagic and mitochondrial biogenesis. NFATc1 promotes the slow myofiber phenotype fibre marker utrophin. Overall, obestatin treatment ameliorates distinctive dystrophic features of DMD, including muscle contractile damage, elevated serum creatine kinase levels, and reduced muscle force. Hence, obestatin represents a promising therapeutic approach for treating DMD, not only as monotherapy but also as part of combinatorial treatment strategies aimed at overcoming the barriers that limit the efficacy of gene or cell therapy.
    Keywords:  Duchenne muscular dystrophy; Mitochondria; NFATc1; Obestatin; TFEB; Utrophin
    DOI:  https://doi.org/10.1186/s43556-025-00370-8
  75. Front Pharmacol. 2025 ;16 1710923
    Mitochondrial involvement in PC: improving therapeutic strategies.
    Jiaxin Zhang, Chang Lou.
      Prostate cancer (PC) is a complex disease propelled by various molecular mechanisms. The role of mitochondria in PC has recently emerged as a significant research focus. Mitochondria, often referred to as the cell's powerhouses, are not only essential for energy production but also crucial for key cellular processes like apoptosis, oxidative stress, and metabolic reprogramming. Changes in energy metabolism, marked by an increased dependency on oxidative phosphorylation (OXPHOS), have been noted in PC cells, offering a potential therapeutic target. Moreover, specific mitochondrial DNA (mtDNA) mutations have been linked with advanced tumors and adverse patient outcomes in PC. The mitochondrial reactive oxygen species (ROS), the disruption of mitochondrial dynamics and the fine balance between pro-apoptotic and anti-apoptotic signals mediated by Bcl-2 family proteins have also been implicated in PC. Comprehending the complex interaction between mitochondria and PC biology offers substantial potential for creating innovative targeted therapeutic strategies. This review emphasizes the role of mitochondria in the occurrence and malignant progression of PC, as well as the potential of targeted interventions on mitochondria in developing treatments, which may improve the prognosis of PC patients.
    Keywords:  apoptosis; membrane permeabilization; mitochondria DNA; mitochondrial dynamics; oxidative phosphorylation; prostate cancer; reactiveoxygen species
    DOI:  https://doi.org/10.3389/fphar.2025.1710923
  76. Anal Chem. 2025 Nov 24.
    Ultrasensitive Biocoded SERS Immunoassay for Tracing Molecular Gatekeeper Mfn2 Expression within Single Cells during Stem Cell Differentiation.
    Jiafeng Wang, Daijie Xie, Xiaozhang Qu, Tian Li, Xiuping Meng, Zhimin Zhang, Yongdong Jin, Guohua Qi.
      Mitochondrial fusion protein 2 (Mfn2) as a molecular gatekeeper in mitochondria plays a momentous role in regulating mitochondrial morphology and function to further influence cell behavior. However, ultrasensitive and in situ measurement of low-abundance Mfn2 at the single-cell level remains a challenge, especially during external stress. Herein, an ultrasensitive and "turn-on"-type immunoassay platform for analysis of Mfn2 expression at the single-cell level during the dental pulp stem cell (DPSC) differentiation process was exploited through surface-enhanced Raman spectroscopy (SERS) as a readout modality. In this system, the detection sensitivity of Mfn2 is markedly enhanced through the generation of gap-plasmon "hot spots" caused by the biocoded SERS nanoprobes consisting of AuNPs and AgNPs following the affinity binding of Mfn2. The developed SERS immunoassay exhibited a wide linear relationship for Mfn2, ranging from 0.5 ng/mL to 5 μg/mL. Notably, the biocoded plasmonic nanoprobes reacting with Mfn2 can self-assemble to form an SERS immunoassay biosensor within single cells, which enabled sensitive measurement of Mfn2 expressions during the DPSC differentiation process evoked by electric-impulse stimulation (EIS). Mechanistically, the Mfn2 expression within DPSCs showed palpable downregulation during the EIS-induced differentiation process. The work revealed at the single-cell level a previously unknown role of Mfn2 in DPSC differentiation during the EIS process. The developed SERS immunoassay sensing platform is promising for the early diagnosis of diseases associated with Mfn2.
    DOI:  https://doi.org/10.1021/acs.analchem.5c04642
  77. Tetrahedron Lett. 2026 Jan 15. pii: 155863. [Epub ahead of print]174
    Gram-scale synthesis of the thiazolidinedione-based mitoNEET ligand NL-1 using a Hantzsch ester reduction.
    James Mersch, Yehenew Agazie, Michael Menze, Mary Konkle, Jason D Huber, Werner J Geldenhuys.
      MitoNEET (CISD1), an [2Fe-2S] cluster protein located on the outer mitochondrial membrane and known for its role in cellular redox regulation and bioenergetics, has been identified as a novel ferroptosis-related drug target in neurodegeneration and cancer. The mitoNEET ligand NEET ligand-1 (NL-1) was developed as a pharmacological tool to elucidate the biochemistry of the novel protein in a variety of disease states, ranging from oncology to neurodegenerative disorders. Here, we present a scalable gram-level synthesis of the thiazolidinedione (TZD) containing NL-1 from the precursor CI-987 using the Hantzsch ester reduction as an alternative to conventional lithium borohydride or cobalt chloride-based methods. This optimized protocol enables the reliable production of NL-1 in quantities sufficient for preclinical disease modeling.
    Keywords:  ferroptosis; iron-sulfur cluster; mitochondria; mitophagy; reduction
    DOI:  https://doi.org/10.1016/j.tetlet.2025.155863
  78. Autophagy. 2025 Nov 28.
    Portioning organelles for autophagic clearance.
    Mikhail Rudinskiy, Maurizio Molinari.
      The lysosomal/vacuolar clearance of portions of organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus and the nucleus, organellophagy, is mediated by autophagy receptors anchored at the surface of their respective organelles. Organellophagy receptors are activated, induced or derepressed in response to stimuli such as nutrient or oxygen deprivation, accumulation of toxic or aged macromolecules, membrane depolarization, pathogen invasion, cell differentiation and many others. Their activation drives the portioning of the homing organelle, and the engagement of Atg8/LC3/GABARAP (LC3) proteins via LC3-interacting regions (LIRs) that results in autophagic clearance. In our latest work, we elaborate on the fact that all known mammalian and yeast organellophagy receptors expose their LIR embedded within intrinsically disordered regions (IDRs), i.e. cytoplasmic stretches of amino acids lacking a fixed three-dimensional structure. Our experiments reveal that the IDR modules of organellophagy receptors are interchangeable, required and sufficient to induce the fragmentation of the organelle that displays them at the limiting membrane, independent of LC3 engagement. LC3 engagement drives lysosomal delivery. Building on these findings, we propose harnessing practical and therapeutic potential of controlled organelle fragmentation and organellophagy through ORGAnelle TArgeting Chimeras (ORGATACs).
    Keywords:  Endoplasmic reticulum (Er)phagy; ORGAnelle TArgeted chimeras (ORGATACs); intrinsically disordered regions (IDRs); mitophagy; organellophagy receptors; targeted organelle degradation
    DOI:  https://doi.org/10.1080/15548627.2025.2597458
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