bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–12–07
57 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
  2. The role of FIS1 and its post-translational modifications in diseases and health damage caused by environmental pollution.
  3. FoxM1 promotes TFAM expression and regulates Mitochondrial Dynamics in Glioblastoma cells.
  4. Integrated multi-omics and machine learning elucidate the pathogenic role of mitophagy in osteoarthritis and identify novel therapeutic strategies.
  5. USP30 Knockdown Drives Mitophagy and Suppresses Pyroptosis in Heart Failure by Activating the PINK1/Parkin Pathway.
  6. Comparative effects of antimalarial drugs on oxidative phosphorylation, mitochondrial dynamics and mitophagy in Plasmodium berghei-infected mice.
  7. A Reversible Mitochondrial ROS Probe for Monitoring Mitophagy Dynamics: Development and Application of MitoFlare.
  8. The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies.
  9. Tumor peripheral stiffness modulates lenvatinib resistance in HCC preclinical models by regulating FIS1-dependent mitophagy.
  10. Receptor-mediated mitophagy: a new target of neurodegenerative diseases.
  11. Mitophagy and oxidative stress in chronic kidney disease (Review).
  12. Mdivi-1 alleviates aseptic craniofacial osteolysis via inhibition of PINK1/Parkin-dependent mitophagy.
  13. Cycloastragenol Regulates Mitochondrial Homeostasis-Mediated Renal Tubular Injury to Ameliorate Diabetic Kidney Disease by Directly Targeting ERK to Modulate TFEB.
  14. Impaired lipolysis and mitochondrial dysfunction in the epididymal tissues of high-fat diet-fed mice.
  15. Neuroprotective Effects of Yizhi Decoction via Inhibition of PINK1/Parkin-Mediated Mitophagy in the Prefrontal Cortex of Rats with Attention Deficit Hyperactivity Disorder.
  16. Oxidative stress as a nexus: Integrating mitophagy and ferroptosis in endometrial carcinogenesis (Review).
  17. P110 Inhibits DRP1/FIS1-Mediated Mitochondrial Fission to Alleviate Uric Acid-Induced Apoptosis in HK-2 Cells.
  18. Beauveria bassiana through miRNA-mediated mitophagy affects Lymantria dispar cellular immunity.
  19. UBC9 mediates mitophagy to attenuate oxidative stress by regulating SUMOylation of PINK1 in the Parkinson's disease progression.
  20. Correction to "Mitochondrial Dynamics as a Pathobiological Mediator of Clonal Myeloid Disorders".
  21. Calreticulin attenuates intervertebral disc degeneration by suppressing NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy.
  22. Identification of Mitochondrial Unfolded Protein Response-Related Genes and Diagnostic Biomarkers in Atherosclerosis by Integrative Multidimensional Analysis and Experimental Validation.
  23. Involvement of the PINK1/PARKIN pathway in enhancing mitochondrial function and mitophagy in reserpine-induced fibromyalgia mice through strength exercise and coenzyme Q10.
  24. Comparative analysis of adipose tissue mitophagy and inflammatory markers in obesity and health.
  25. Integrated multi-omics reveals GABARAP-mediated mitophagy and pyruvate metabolism as key drivers of osteosarcoma progression.
  26. Integrated multi-omics of mitophagy-related molecular subtype characterization and biomarker identification in sepsis.
  27. XLOC_010588 Promotes Mitophagy Via BAG2-Mediated PINK1 Stabilization in HPH.
  28. Molecular hydrogen-mediated SIRT1 activation alleviates sepsis-associated encephalopathy by promoting mitophagy.
  29. The Vitamin D Receptor Ortholog Hr96 Modulates Neuronal and Mitochondrial Dynamics in a Drosophila Model of Alzheimer's Disease.
  30. Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
  31. Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
  32. Genetic factors and comorbid pathologies interact to drive regional mitophagy alterations in Lewy body dementia.
  33. The Rieske iron-sulfur protein is a primary target of molecular hydrogen.
  34. Assessment of Mitochondrial Fission/Fusion Dynamics in Kidney Proximal Tubular Cells.
  35. Forsythiaside A ameliorates acetaminophen-induced liver injury by suppressing ferroptosis through activating USP11/SIRT3-mediated mitophagy.
  36. SYK regulates Schwann cell metabolic reprogramming to promote axonal regeneration in immune-mediated neuropathy.
  37. Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review).
  38. γ-Elemene Impairs Mitochondrial Biogenesis in Breast Cancer Cells by Upregulating GCN5-Mediated PGC-1α Acetylation.
  39. Inhibition of glycolysis and stimulation of mitochondrial biogenesis lead to increased ROS levels and cell death in HNF-1ß positive clear cell carcinoma.
  40. Alpinetin Targets Mitophagy Pathways to Mitigate Parkinson's Disease Progression.
  41. Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Diabetic Neuropathic Pain via TRPV1-[Ca2+]i-AMPK Signaling-Mediated Mitochondrial Restoration in Schwann Cells.
  42. Butyrate-Modified Hyaluronic Acid Ameliorates MPTP-Induced Parkinson's Disease via Modulating PINK1/Parkin-Involved Mitophagy and Intestinal Flora.
  43. Mitochondrial dynamics and function in neural differentiation: a systematic review.
  44. Electroacupuncture promotes functional recovery and activates energy metabolism in a rat model of sciatic nerve injury.
  45. Mitochondrial immunometabolism in sepsis: orchestrating macrophage polarization and dysfunction.
  46. Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.
  47. DL-3-n-Butylphthalide Protects Mitochondria Against Ischemia/Hypoxia Damage via Suppressing GCN5L1-Mediated Drp1 Acetylation in Neurons and Mouse Brains.
  48. β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition.
  49. Control of mitochondrial dynamics by the metabolic regulator dPGC1 limits Yorkie-induced oncogenic growth in Drosophila.
  50. Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
  51. Procyanidin Capsules Combat ALF by Restoring Mitochondrial Homeostasis and Inhibiting Necroptosis via the PGAM5/DRP1/PINK1 Pathway.
  52. Cu-Fe3O4 Nanozyme Reverses Age-Impaired Alveolar Healing via Reactive Oxygen-Nitrogen Species Scavenging and Mitophagy Reactivation.
  53. Biocompatible hydrogel eradicates pregnancy-associated genital warts.
  54. Coenzyme Q10 Ameliorates Fibromyalgia-like Symptoms and Cognitive Deficits by Enhancing Hippocampal PGC-1α/FNDC5/BDNF Pathway in Reserpine-Treated Rats.
  55. Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.
  56. Fontan Circulation Beyond Preload: Metabolic Pathways and Mitochondrial Stress.
  57. Xiangsha Liujunzi Decoction restores mitochondrial function and ameliorates chronic ulcerative colitis by regulating the PI3K/AKT/Nrf2 and AMPK/SIRT1/PGC-1α signaling pathways.
  1. Mol Cell Biochem. 2025 Dec 01.
    Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
    Chuanlong Zhang, Xiaoxia Zheng, Lijuan Xiang, Zhanguo Su.
      The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue, and muscle weakness are often attributed to impaired mitochondrial dynamics, involving key mechanisms such as mitophagy, fusion, and fission. Exercise has been shown to positively influence mitochondrial health by regulating mitochondrial biogenesis, dynamics, and turnover. This review examines the exercise-induced modulation of mitochondrial processes in aging muscle and delineates its prospects as an intervention for managing mitochondrial diseases. We highlight the molecular mechanisms by which exercise orchestrates mitochondrial dynamics, augments organelle function, and triggers mitophagy-all of which are crucial for the preservation of muscle cell homeostasis. Furthermore, we explore how pivotal molecular pathways such as AMPK, PGC-1α, and SIRT1 regulate mitochondrial adaptations to exercise. This review also underscores the therapeutic promise of exercise in attenuating mitochondrial disease progression via enhanced mitochondrial quality control and improved muscle function. By integrating findings from mitochondrial science, gerontology, and exercise physiology, this review positions exercise as a crucial regulator of mitochondrial dynamics and a viable non-pharmacological strategy for maintaining muscle integrity in the contexts of aging and mitochondrial disease.
    Keywords:  Aging muscle; Exercise; Mitochondrial diseases; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s11010-025-05441-6
  2. Cell Biol Toxicol. 2025 Dec 06.
    The role of FIS1 and its post-translational modifications in diseases and health damage caused by environmental pollution.
    Lingyu Qin, Pinya Liu, Shuhua Xi.
      Mitochondrial fission protein 1 (FIS1) is present in the cytoplasm and can be transported to the outer mitochondrial membrane. It can interact with DRP1 (Dynamin-Related Protein 1) to mediate mitochondrial fission and fusion, and most of the studies on FIS1 have centered on FIS1-DRP1 mitochondrial fission. However, more and more studies are now showing that FIS1 is not only involved in mitochondrial fission, but also plays a role in mitophagy, peroxisomal dynamics, and lysosomes. Post-translational modification (PTM) of proteins enables proteins to perform distinct functions and exhibit diverse properties, thereby creating multiple possibilities for many proteins. The post-translational modification of FIS1 protein is associated with the occurrence of many diseases. Environmental pollution has become a serious public health problem that affects people's health. The role of FIS1 in human health caused by environmental pollutants is worth in-depth study and exploration.
    Keywords:  Environmental pollutants; FIS1; Mitochondrial autophagy; Mitochondrial fission; Post-translational modification of proteins
    DOI:  https://doi.org/10.1007/s10565-025-10129-0
  3. J Cancer. 2025 ;16(15): 4378-4389
    FoxM1 promotes TFAM expression and regulates Mitochondrial Dynamics in Glioblastoma cells.
    Nida Fatima Moazzam, Muhammad Asad Iqbal, Xiu Han, Zhangzuo Li, Aihua Gong.
      To investigate the contribution of individual arginines, we employed site-directed mutagenesis to generate arginine-to-alanine (R→A) substitution mutations in the N-terminal domain of Forkhead box M1 (FoxM1). The R15A mutation impaired FoxM1 transcriptional activity, hindered FoxM1 nuclear translocation and failed to promote the migratory and invasive behavior of glioma cells than other single arginine mutations. Furthermore, we demonstrated that FoxM1 expression was associated with Mitochondrial transcription factor A (TFAM) expression. Overexpressing FoxM1 increased TFAM protein levels, which was reversed by FoxM1 knockdown in glioblastoma multiforme (GBM) cells. The siRNA-mediated reduction of TFAM expression was rescued by FoxM1 overexpression. Also, FoxM1 overexpression promoted TFAM promoter luciferase activity. Importantly, the R15A mutation failed to promote TFAM expression. Additionally, FoxM1 increased the expression of mitochondrial fusion markers, Optic atrophy protein 1 (OPA1) and Mitofusin 1 (MFN1) and led to interconnected mitochondria, while FoxM1 knockdown reversed this effect. Moreover, FoxM1 promoted mitochondrial fission markers, Dynamin-related protein 1 (DRP1), Mitochondrial fission factor (MFF) and Mitochondrial fission protein 1 (FIS1). Notably, the R15A mutation resulted in loss of FoxM1 regulation of fusion and fission-related protein expression. Taken together, our findings reveal that that the N-terminal arginine 15 is a key site for the transcriptional activation and function of FoxM1 in GBM cells, suggesting its potential as a therapeutic target in GBM.
    Keywords:  FoxM1; N-terminal arginine residues, GBM; TFAM; mitochondrial fusion/fission
    DOI:  https://doi.org/10.7150/jca.111013
  4. Int Immunopharmacol. 2025 Dec 01. pii: S1567-5769(25)01904-6. [Epub ahead of print]168(Pt 2): 115916
    Integrated multi-omics and machine learning elucidate the pathogenic role of mitophagy in osteoarthritis and identify novel therapeutic strategies.
    Qiu Dong, Hao Huang, Ying Feng, Longteng Chao, Zelin Wu, Zhengang Zha, Ruobin Li, Junyuan Chen.
       INTRODUCTION: Osteoarthritis (OA), the most prevalent degenerative joint disease, is characterized by chronic synovial inflammation, cartilage degradation, and disrupted cellular homeostasis. Impaired mitophagy has been implicated in OA pathogenesis, yet effective therapeutic strategies remain limited. This study aims to elucidate the role of mitophagy in OA and to identify cordycepin as a novel therapeutic agent that activates mitophagy, highlighting its potential clinical significance.
    METHOD: Mitophagy alterations in clinical OA samples were assessed using immunohistochemistry and validated with public bulk transcriptomic data. Differences in mitophagy pathways were characterized, followed by machine learning to identify pivotal genes for a diagnostic nomogram. Single-cell gene set analysis and computational drug repositioning identified potential mitophagy-modulating therapeutics. In vitro, qPCR and Western blot measured inflammation and mitophagy markers, while autophagic flux dynamics were analyzed using JC-1 staining and tandem fluorescent LC3 (mRFP-GFP) transduction. In vivo efficacy and safety were evaluated in OA animal models.
    RESULTS: We found significantly reduced mitophagy scores in OA synovium through integrated multi-omics approach. Machine learning identified seven pivotal mitophagy regulators: ULK1, ATG12, MAP1LC3B, UBB, UBC, TOMM40, and CSNK2B. Computational drug repositioning nominated cordycepin as a candidate therapeutic. In vitro, cordycepin demonstrated potent anti-inflammatory effects, attenuated cellular oxidative stress, inhibited mitochondrial outer membrane depolarization, and activated mitophagic flux. In vivo, cordycepin promoted LC3-TOMM20 co-localization, confirming mitophagy activation. This resulted in significant amelioration of synovitis and attenuation of cartilage degradation.
    CONCLUSION: Our findings establish mitophagy impairment as a critical factor in OA pathogenesis and present cordycepin as a promising therapeutic option that targets mitochondrial quality control. This study lays the groundwork for future precision therapies aimed at degenerative joint disorders.
    Keywords:  Cordycepin; Mitochondrial metabolism; Mitophagy; Multi-omics bioinformatics analysis; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115916
  5. Int Heart J. 2025 ;66(6): 1002-1014
    USP30 Knockdown Drives Mitophagy and Suppresses Pyroptosis in Heart Failure by Activating the PINK1/Parkin Pathway.
    Yanna Yang, Congfei Zhu, Xiaobin Zhou, Xinwei Zhang.
      This study probed into the mechanism of USP30 in mitophagy and pyroptosis during heart failure (HF).A cell model was constructed with oxygen-glucose deprivation (OGD), and an HF rat model was generated by permanently ligating the left anterior descending branch of the left coronary artery. Loss-of-function experiments were carried out with the use of si-USP30 and si-PINK1. Cell viability was assessed using MTT, and cell death was measured by LDH release. Mitophagy was analyzed using immunofluorescence double staining, mitochondrial membrane potential (MMP) changes were detected by JC-1, and ROS levels were measured using specific kits. WB was performed to detect autophagy markers LC3II/I and p62, pyroptosis-related proteins NLRP3, active-caspase-1, GSDMD-N, and PINK1/Parkin protein expression. The inflammatory cytokines IL-18 and IL-1β were measured by ELISA. Histological changes and fibrosis in heart tissue were observed by H&E and Masson staining.USP30 was expressed abundantly in OGD-induced H9C2 cells and HF rats. USP30 knockdown enhanced viability, mitophagy, MMP, and LC3II/I but reduced death, NLRP3, p62, active-caspase-1, and GSDMD-N protein expression, and ROS, IL-1β, and IL-18 levels in OGD-treated H9C2 cells. PINK1 knockdown or mitophagy inhibition abolished the effects of USP30 knockdown on mitophagy and pyroptosis in OGD-treated H9C2 cells. Additionally, USP30 knockdown improved cardiac function and mitophagy while repressing pyroptosis in HF rats.In summary, USP30 controls mitophagy and pyroptosis in HF by mediating the PINK1/Parkin pathway.
    Keywords:  Autophagy; Inflammatory response; Myocardial damage; Oxygen-glucose deprivation
    DOI:  https://doi.org/10.1536/ihj.24-738
  6. Toxicol Rep. 2025 Dec;15 102156
    Comparative effects of antimalarial drugs on oxidative phosphorylation, mitochondrial dynamics and mitophagy in Plasmodium berghei-infected mice.
    John Oludele Olanlokun, Oluseye Osovehe Yahaya, Cecilia Opeyemi Babarinde, Oluwakemi Marvellous Oloke, Paul Steenkamp, Gerhard Prinsloo.
      Mitochondria occupy prominent position in cell metabolism. Information on changes in host mitochondrial capacity in electron transport system, dynamics and mitophagy in mice infected with resistant Plasmodium berghei and thereafter treated with some orthodox drugs, is critical to the survival and the organelles' metabolism. In this study, the effects of some antimalarial drugs were investigated on mitochondrial permeability transition (mPT) pore opening, FoF1 ATPase and lipid peroxidation, oxidative phosphorylation and mitochondrial dynamics in mice infected with chloroquine resistant (ANKA) strain of Plasmodium berghei. Thirty-five Swiss-mice (18 ± 3 g) were infected intraperitoneally with chloroquine resistant (ANKA) strain of Plasmodium berghei and treated orally and once daily with (10 mg/kg) dose of Amodiaquine artesunate (AA), Artemether-Lemefantrine (AL), Sulfadoxine- pyrimethamine (SP) and Artesunate (ART), On day 6, animals were sacrificed and livers were removed. Liver mitochondria were isolated and mitochondrial permeability transition (mPT) pore opening, F0F1 ATPase (mATPase) and lipid peroxidation (mLPO) were determined spectrophotometrically. Gene expressions on liver mitochondrial complexes I, II, III, IV and V, DNM1L, DRP1, OPA 1 Mitofusin 1 and 2, PINK 1, FUNDC1, PGC-1α and prohibitins 1 and 2 were determined using gel electrophoresis. AA, AL and SP did not significantly open the mPT pore while ART caused its opening (7 fold) and enhance mitochondrial FoF1 ATPase (P < 0.01), SP and AA induced peroxidation of mitochondrial membrane phospholipids (P < 0.01) when compared to the infected control. SP and AA significantly silenced the expressions of mitochondrial complexes. The effects of these drugs on mitochondrial fission and fusion vary significantly: AA down-regulated the expressions of DRP1, OPA 1 while AA, AL and ART decreased the expression of Mitofusin 2 as observed in the infected control. Significant down-regulation in the expressions of PINK 1 by SP, FUNDC1 by AA and AL, DNM1L by ART, PGC-1α by AA, AL, and ART, and prohibitins 1 and 2 by AA and AL similar to the infected control were observed. This study showed that host mitochondria respond differently to antimalarial drugs.
    Keywords:  Electron transport; Fission; Fusion; Mitochondrial dynamics; Permeability transition Plasmodium berghei
    DOI:  https://doi.org/10.1016/j.toxrep.2025.102156
  7. bioRxiv. 2025 Nov 18. pii: 2025.11.18.689025. [Epub ahead of print]
    A Reversible Mitochondrial ROS Probe for Monitoring Mitophagy Dynamics: Development and Application of MitoFlare.
    Shanshan Hou, Xin Yan, Xiaoxu Li, Jingyue Ju, Zhiying Shan, Lanrong Bi.
      Mitochondrial dysfunction and defective mitophagy are defining features of numerous neurodegenerative and metabolic disorders, yet existing tools provide limited ability to quantify mitophagy dynamics in real time within living, post-mitotic cells. Here we present MitoFlare, a mitochondria-targeted, reversible mtROS-responsive fluorogenic probe that enables continuous, non-genetic visualization of mitochondrial oxidative activation and turnover. MitoFlare incorporates dual TEMPO nitroxide quenchers into a long-wavelength rhodamine scaffold, producing >95% basal quenching and rapid, fully reversible fluorescence activation in response to mitochondrial superoxide, hydroxyl radicals, lipid-derived peroxyl species, and peroxynitrite. When combined with LysoTracker Green, MitoFlare forms a dual-probe imaging platform that resolves the entire mitophagy cascade with high spatial and temporal fidelity in intact PC12 neuronal cells. Using this platform, we established a quantitative framework comprising three mechanistically distinct metrics: (i) a proximity index that reports early mitochondrial engagement with lysosomes, (ii) Manders' M1 coefficient that captures mid-stage mitochondria-lysosome fusion and mitophagosome formation, and (iii) a quenching/swelling index that resolves terminal lysosomal degradation. Nutrient deprivation induced a complete, temporally ordered mitophagy program, including mtROS priming, Parkin-OPTN-associated fusion, and efficient acidification-dependent cargo degradation. In contrast, inhibition of v-ATPase with bafilomycin A1 arrested mitophagy at the fusion stage, resulting in persistent redox-active mitochondrial cargo that failed to undergo lysosomal digestion. Importantly, MitoFlare's reversible redox chemistry uniquely revealed accumulation of undegraded, oxidatively active mitochondrial remnants within non-acidified vesicles-pathological intermediates that are undetectable using irreversible ROS dyes or genetically encoded reporters. These findings demonstrate that mitophagy proceeds through discrete, redox-regulated and lysosome-dependent phases that can be quantitatively mapped in real time. By enabling synchronized measurement of oxidative activation, organelle trafficking, fusion, and degradation, the MitoFlare-LysoTracker system establishes a new benchmark for dynamic mitophagy analysis in physiologically relevant models. This platform provides a powerful foundation for mechanistic interrogation of mitochondrial quality control and for accelerating the discovery of therapeutic strategies aimed at restoring mitophagic fidelity in neurodegenerative, cardiovascular, and metabolic diseases.
    DOI:  https://doi.org/10.1101/2025.11.18.689025
  8. Front Endocrinol (Lausanne). 2025 ;16 1645711
    The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies.
    Huiyi Zhao, Ying Wang, Han Han, Yue Jiang, Xiang Ji, Yuehui Zhang.
      Mitophagy is a catabolic mechanism that selectively degrades damaged mitochondria and precisely modulates mitochondrial content, thereby maintaining intracellular homeostasis under stress conditions. To date, most reviews on mitophagy have predominantly focused on neurodegenerative diseases, cardiovascular disorders, cancer, metabolic syndromes, and inflammation- or immune-related diseases. In recent years, accumulating evidence has highlighted the critical involvement of mitophagy in various physiological and pathological processes associated with female reproduction. This review systematically synthesizes existing evidence to elucidate the regulatory roles of mitophagy during the occurrence and development of follicles, oocyte fertilization, and embryo implantation, as well as its essential contributions to the pathogenesis of endometriosis, polycystic ovary syndrome, primary ovarian insufficiency, and ovarian aging. Furthermore, we outline current therapeutic strategies targeting mitophagy while emphasizing the potential value of traditional Chinese medicine. Our aim is to provide novel insights into the regulatory network and specific targets of mitophagy in female reproduction, facilitate clinical translation, and offer innovative approaches for managing female reproductive health.
    Keywords:  female reproductive; female reproductive dysfunction; mitochondrial function; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3389/fendo.2025.1645711
  9. JHEP Rep. 2025 Dec;7(12): 101588
    Tumor peripheral stiffness modulates lenvatinib resistance in HCC preclinical models by regulating FIS1-dependent mitophagy.
    Kunjin Wu, Jing Li, Yunong Fu, Kaibo Yang, Ting Lin, Yaohui Wang, Ming Wang, Yunxiang Long, Fengping Zhang, Bo Cheng, Yuan Li, Cong Wang, Feng Xu, Chang Liu, Kai Qu.
       Background & Aims: Hepatocellular carcinoma (HCC) displays heterogeneous responses to lenvatinib, with tumor microenvironment (TME) stiffness emerging as a key resistance modulator. This study investigates how tumor peripheral stiffness governs lenvatinib efficacy via mitochondrial fission/mitophagy and evaluates matrix-targeting combination therapies.
    Methods: Clinical HCC tissues underwent stiffness measurement (atomic force microscopy [AFM]/rheometry) and survival correlation analyses. In vitro, cells grown on soft vs. stiff hydrogels (5 vs. 15 kPa) were assessed for their lenvatinib response, mitophagy, and mitochondrial fission 1 (FIS1)-trimethylation of histone H3 lysine 27 (H3K27me3) regulation. Subcutaneous xenografts received collagenase-lenvatinib combination therapy.
    Results: Elevated tumor peripheral stiffness, quantified by AFM and rotational rheometry, was significantly associated with HCC recurrence. Patients with stiff peripheries exhibited reduced recurrence-free survival (p <0.05), correlating with upregulated mitophagy markers (Parkin and FIS1) and diminished H3K27me3 in high-stiffness human HCC tissues (p <0.0001). In vitro, HCC cells on stiff matrices (15 kPa) showed attenuated lenvatinib-induced apoptosis (TUNEL: p = 0.0003 vs. soft 5 kPa) and preserved mitochondrial membrane potential (JC-1: p = 0.0004), concomitant with fragmented mitochondria driven by FIS1 upregulation via H3K27me3 depletion at its promoter (chromatin immunoprecipitation: p <0.0001). FIS1 knockdown reversed mitochondrial fragmentation (p <0.001) and resensitized cells to lenvatinib. Stiffness amplified cytoprotective mitophagy under lenvatinib stress, evidenced by enhanced LC3/TOM20 colocalization (p = 0.0008) and mitochondrial Parkin accumulation. In vivo, collagenase-mediated matrix softening synergized with lenvatinib, suppressing tumor growth (volume: p <0.001; weight: p <0.001) while reducing FIS1/Parkin expression and augmenting apoptosis.
    Conclusions: Tumor peripheral stiffness drives lenvatinib resistance in HCC via H3K27me3-mediated FIS1 upregulation, triggering mitochondrial fission and cytoprotective mitophagy to evade drug-induced apoptosis. Targeting matrix stiffness (via collagenase-mediated softening) synergizes with lenvatinib to overcome microenvironment-driven resistance, providing a novel mechanoadjuvant strategy for HCC therapy.
    Impact and implications: This study shows that tumor peripheral matrix stiffness reduces lenvatinib sensitivity in HCC by enhancing FIS1-dependent mitophagy, explaining therapeutic response heterogeneity. These findings are clinically relevant, highlighting tumor stiffness as a potential biomarker for lenvatinib resistance and mitophagy as a targetable pathway. Clinically, stiffness assessments (e.g. imaging/biopsy) could be used to stratify patients for personalized treatment. Combining lenvatinib with matrix-softening agents or mitophagy inhibitors could improve efficacy. However, translational potential requires validation in larger cohorts and development of non-invasive stiffness measurement methods, given challenges associated with the clinical application of current invasive techniques or collagenase-based preclinical models.
    Keywords:  Hepatocellular carcinoma; Lenvatinib sensitivity; Mechanical microenvironment; Mechanomedicine; Mitochondrial fission; Mitophagy
    DOI:  https://doi.org/10.1016/j.jhepr.2025.101588
  10. Front Neurol. 2025 ;16 1665315
    Receptor-mediated mitophagy: a new target of neurodegenerative diseases.
    Junlan Yang, Fuquan Yang, Guiyan Chen, Ming Liu, Shiqing Yuan, Tian-E Zhang.
      Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.
    Keywords:  PINK1/Parkin-independent mitophagy; autophagy receptors; mitochondria; mitochondrial dysfunction; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fneur.2025.1665315
  11. Mol Med Rep. 2026 Feb;pii: 61. [Epub ahead of print]33(2):
    Mitophagy and oxidative stress in chronic kidney disease (Review).
    Quwu Mushuo, Yihuai Tian, Jianchun Li, Yanqin Qiu, Hui Fan, Qiongdan Hu, Qiong Zhang.
      Chronic kidney disease (CKD) progression is driven by a harmful interplay between impaired mitophagy and sustained oxidative stress. Under normal conditions, mitophagy serves as a protective mechanism by removing damaged mitochondria and limiting the production of reactive oxygen species. However, in CKD, a self‑reinforcing cycle of mitochondrial dysfunction, defective mitophagy oxidative stress, and inflammation occurs, which promotes fibrosis. The present review examines the molecular mechanisms governing mitophagy, with a specific focus on the regulatory roles of core signaling pathways, namely the PTEN‑induced kinase l/Parkin, BCL2 interacting protein 3/Nip3‑like protein X and FUN14 domain‑containing protein l pathways, and how their disruption contributes to CKD. The mechanistic crosstalk between mitophagy and oxidative stress is highlighted as a central pathogenic axis in CKD progression. In addition, emerging therapeutic strategies that aim to restore mitophagy and enhance antioxidant capacity are discussed, suggesting new strategies for targeted CKD treatment.
    Keywords:  mitophagy; oxidative stress; reactive oxygen species; signaling pathways; therapeutic strategies
    DOI:  https://doi.org/10.3892/mmr.2025.13771
  12. Bone. 2025 Nov 29. pii: S8756-3282(25)00350-3. [Epub ahead of print]204 117738
    Mdivi-1 alleviates aseptic craniofacial osteolysis via inhibition of PINK1/Parkin-dependent mitophagy.
    Xiaoyue Sun, Binqian Liu, Zetong Li, Songqin Zhou, Zijun Wang, Jingjing Yu, Qing Nie, Lingxin Zhu.
      Aseptic craniofacial osteolysis around the implant-bone interface, induced by wear particles, leads to the loosening and failure of dental implants, temporomandibular joint prostheses and internal fixation during maxillofacial reconstruction. Osteoclasts, as terminally differentiated multinucleated giant cells and the exclusive bone resorptive cells, play an important role in this pathological process. The PINK1/Parkin pathway is involved in mitochondrial quality control; however, its effects on osteoclast-mediated physiological bone homeostasis and the therapeutic potential on craniofacial osteolysis remains unexplored. We generated the mutant mice in which Parkin was conditionally deleted in myeloid lineage cells (LysM-Cre/Park2flox/flox; Park2ΔM/ΔM). Unexpectedly, the Park2ΔM/ΔM mice displayed no overall skeletal phenotype. In tandem, upon osteoclastogenic induction, Park2ΔM/ΔM macrophages undergone RANKL-induced osteoclastogenesis normally with compensated increased PINK1 expression. Notably, Mdivi-1 remarkably simultaneously inhibited the PINK1 and Parkin expression, leading to significant attenuated osteoclastogenesis in a concentration-dependent manner. The aseptic titanium particle-induced calvaria erosion model was constructed to simulate craniofacial osteolysis. Importantly, Mdivi-1 effectively alleviated the bone resorption and trabecular structure destruction induced by titanium particles, and blocked the osteoclast accumulation in the lesions. Taken together, Mdivi-1 alleviated titanium particle-induced aseptic craniofacial osteolysis via inhibition of PINK1/Parkin-dependent mitophagy. In summary, while myeloid lineage conditionally deletion of Park2 does not interfere with osteoclast differentiation and physiological bone homeostasis in mice probably due to the compensation by PINK1 expression, Mdivi-1 as the inhibitor of PINK1/Parkin-dependent mitophagy may provide a novel therapeutic strategy towards aseptic craniofacial osteolysis.
    Keywords:  Aseptic osteolysis; Mdivi-1; Osteoclast; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.bone.2025.117738
  13. Phytother Res. 2025 Dec 04.
    Cycloastragenol Regulates Mitochondrial Homeostasis-Mediated Renal Tubular Injury to Ameliorate Diabetic Kidney Disease by Directly Targeting ERK to Modulate TFEB.
    Gai Gao, Zhiwen Liu, Hui Wang, Pan Wang, Shuyan Liu, Ruidi Liu, Yanrao Wu, Zhenzhen Wang, Jiangyan Xu, Zhenqiang Zhang, Xiaowei Zhang, Zhishen Xie.
       BACKGROUND AND AIM: Restoring mitochondrial homeostasis to inhibit apoptosis in renal tubular epithelial cells (RTECs) has emerged as a promising therapeutic strategy for diabetic kidney disease (DKD). This study focuses on the therapeutic effect and mechanism of the triterpenoid compound cycloastragenol (CAG) from Astragali Radix in the treatment of DKD.
    EXPERIMENTAL PROCEDURE: The DKD model was established in C57BL/6Jdb/db mice and AGEs-induced HK-2 cells. Various biological techniques such as WB and RT-PCR revealed that CAG enhanced mitophagy via TFEB, reducing apoptosis in RTECs. Mechanistic studies combining CETSA, molecular docking, and molecular dynamics simulations confirmed the CAG-ERK interaction.
    KEY RESULTS: CAG improved renal function and reduced renal tubular injury in db/db mice. CAG effectively reduced the accumulation of mitoROS, enhanced mitochondrial membrane potential, promoted mitophagy and mitochondrial biogenesis, and restored mitochondrial homeostasis. Mechanistically, CAG enhanced mitophagy in db/db mice and AGEs-induced HK-2 cells by stimulating the autophagic flux via regulating TFEB. Moreover, CAG inhibited AGEs-induced HK-2 apoptosis, which was reversed by autophagy inhibitor chloroquine (CQ) and siRNA-TFEB. Importantly, after mutating the valine (VAL) at position 39 of the ERK to alanine (ALA), the binding effect between CAG and ERK was significantly reduced, revealing that CAG directly bound ERK at 39VAL, inhibiting its phosphorylation, thus preventing the phosphorylation of the S142 site of TFEB and enabling TFEB to translocate into the nucleus.
    CONCLUSIONS AND IMPLICATIONS: CAG ameliorated renal tubule damage in DKD by regulating mitochondrial quality though targeting ERK to regulate TFEB. This research advances drug development and proposes lifestyle interventions (e.g., dietary supplements).
    Keywords:  ERK/TFEB; apoptosis; cycloastragenol; diabetic kidney disease; mitophagy
    DOI:  https://doi.org/10.1002/ptr.70136
  14. Mol Biol Rep. 2025 Dec 05. 53(1): 162
    Impaired lipolysis and mitochondrial dysfunction in the epididymal tissues of high-fat diet-fed mice.
    Chongkang Wu, Zimeng Xu, Chao Liu, Zhengmei Lv.
       BACKGROUND: A high-fat diet (HFD) is associated with low fertility in male mice, characterized by reduced sex hormone levels and impaired sperm quality. The epididymis is crucial for sperm maturation, yet its vulnerability to metabolic disturbances remains poorly understood. METHODS AND RESULTS: Twelve C57BL/6J mice were randomly assigned to either a HFD (60% kcal from fat; Research Diets, D12492) or a standard diet group. The dietary intervention started at 5 weeks of age and was maintained for 10 weeks. Epididymal tissues from both groups were studied using immunofluorescence and Western blotting. Compared to the control group, HFD-fed mice exhibited significant increases in body weight, epididymal fat pad weight, serum lipids, along with decreased serum testosterone. Epididymal tissues from the HFD group showed marked lipid droplet accumulation and elevated oxidative stress. Consistently, the activity and expression of key lipolytic enzymes-hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL)-were significantly downregulated. Furthermore, HFD feeding disrupted mitochondrial dynamics, as indicated by reduced levels of fusion proteins (MFN1/MFN2) and altered expression of fission markers (p-DRP1(Ser616) and FIS1). Moreover, autophagy-particularly mitophagy and lipophagy-was impaired, evidenced by a significant reduction in autophagosomes and dysregulation of autophagy-related proteins.
    CONCLUSIONS: This study provides a mechanistic explanation for diet-induced male infertility, demonstrating that HFD impairs epididymal function and creates an adverse microenvironment for sperm maturation by disrupting lipid metabolism, mitochondrial function, and autophagy processes.
    Keywords:  Epididymis; High-fat diet (HFD); Lipid metabolism; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1007/s11033-025-11332-2
  15. J Ethnopharmacol. 2025 Dec 02. pii: S0378-8741(25)01680-0. [Epub ahead of print] 120988
    Neuroprotective Effects of Yizhi Decoction via Inhibition of PINK1/Parkin-Mediated Mitophagy in the Prefrontal Cortex of Rats with Attention Deficit Hyperactivity Disorder.
    Jue Hu, Ying Wang, Jing-Ying Ma, Bo-Han Wang, Jia-Ye Xu, Yu-Lu Pan, Xiao-Bo Xuan, Jian Chen.
       ETHNOPHARMACOLOGICAL RELEVANCE: Yizhi Decoction (YZD) is used in clinical medicine for the treatment of pediatric attention deficit hyperactivity disorder (ADHD).
    AIM OF THE STUDY: This study aimed to determine the neuroprotective actions of YZD in the modulation of the PTEN-induced kinase 1 (PINK1) / Parkin mitophagy pathway.
    MATERIALS AND METHODS: Thirty male spontaneously hypertensive rats (SHRs) were randomly allocated into five groups: an untreated group, a methylphenidate group (2 mg/kg), and three YZD treatment groups receiving low (7.5 g/kg), medium (15 g/kg), or high (30 g/kg) doses of YZD. An additional six male Wistar-Kyoto (WKY) rats constituted the control group. Prefrontal cortex neuronal morphology and quantity, apoptotic cells, mitochondrial functional integrity, and cell ultrastructural details were evaluated. Protein expression profiles related to PINK1/Parkin-driven mitophagy were analyzed by western blotting. Oxidative stress parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), oxidized glutathione (GSSG), and the GSH/GSSG ratio, were determined using commercial assay kits.
    RESULTS: YZD administration resulted in a dose-dependent suppression of hyperactive and impulsive behaviors in SHRs. It mitigated neuronal injury and restored mitochondrial integrity and functional capacity in the prefrontal cortex. Additionally, YZD enhanced SOD activity, GSH content, and the GSH/GSSG ratio, while reducing MDA and GSSG levels, indicating attenuated oxidative stress and apoptosis. Notably, these protective effects correlated with decreased expression of PINK1, Parkin, LC3-II/I, and Beclin-1, alongside increased p62 expression in the prefrontal cortex.
    CONCLUSION: YZD alleviates neuronal oxidative stress and damage in ADHD rat models by limiting excessive PINK1/Parkin-mediated mitophagy.
    Keywords:  ADHD; Parkin mitophagy pathway; YZD; oxidative stress
    DOI:  https://doi.org/10.1016/j.jep.2025.120988
  16. Oncol Lett. 2026 Jan;31(1): 40
    Oxidative stress as a nexus: Integrating mitophagy and ferroptosis in endometrial carcinogenesis (Review).
    Qixia Yu, Liangxin Ren, Feng Ren, Fengling Li.
      Endometrial cancer (EC), a malignancy of the uterine lining with rising global incidence that is linked to obesity and metabolic syndrome, is molecularly stratified into four The Cancer Genome Atlas subtypes (DNA polymerase ε ultramutated, microsatellite instability-high, copy-number low and copy-number high), each requiring tailored therapeutic strategies. Despite advancements, drug resistance remains a critical challenge, prompting exploration of regulated cell death pathways such as ferroptosis, an iron-driven process marked by lipid peroxidation and glutathione peroxidase 4 (GPX4) inactivation. Mitochondrial dysfunction, a hallmark of EC, exacerbates oxidative stress by disrupting fission/fusion dynamics (via dynamin-related protein 1/mitofusin 1/2 imbalance) and impairing mitophagy (through PTEN-induced kinase 1/Parkin or FUN14 domain-containing protein 1 pathway defects), thereby promoting iron overload and ferroptotic vulnerability. Reactive oxygen species (ROS), generated via mitochondrial electron transport chains and NADPH oxidases, exhibit dual roles: Moderate levels drive tumorigenesis through DNA damage and immune evasion, while excessive ROS levels induce ferroptosis by depleting antioxidants (such as glutathione) and amplifying lipid peroxidation. The present review systematically integrates evidence on mitophagy and ferroptosis in EC pathogenesis; it highlights oxidative stress as a central nexus linking mitochondrial surveillance failure (such as cristae collapse and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like-mediated mitophagy in TP53-mutant tumors) to iron-dependent membrane damage (via acyl-CoA synthetase long-chain family member 4 and ferroptosis suppressor protein 1-coenzyme Q10 dysregulation). Emerging therapeutic strategies targeting redox-sensitive nodes, including GPX4 degraders, mitophagy inducers (urolithin A) and chronotherapy, have the potential to overcome resistance. By elucidating the crosstalk between mitochondrial quality control and ferroptotic signaling, the present review provides a mechanistic framework for precision oncology in EC, emphasizing subtype-specific vulnerabilities and spatiotemporal redox profiling.
    Keywords:  ROS; TCGA molecular subtypes; drug resistance; endometrial cancer; ferroptosis; lipid peroxidation; mitochondrial dynamics; mitophagy; oxidative stress; precision therapy
    DOI:  https://doi.org/10.3892/ol.2025.15393
  17. Front Biosci (Landmark Ed). 2025 Nov 26. 30(11): 46700
    P110 Inhibits DRP1/FIS1-Mediated Mitochondrial Fission to Alleviate Uric Acid-Induced Apoptosis in HK-2 Cells.
    Yuli Shen, Geng Huang, Yu Liu, Fulin Pan, Canling Long, Jia Liu, Zhigang Ma.
       BACKGROUND: Hyperuricemic nephropathy is associated with mitochondrial dysfunction. Dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission, is activated under stress and translocates to the mitochondria, where it interacts with adapter proteins such as mitochondrial fission 1 protein (FIS1), thereby promoting excessive mitochondrial fission and apoptosis. Recent research has shown that inhibiting the DRP1/FIS1 interaction can reduce cellular injury in various disease models; however, its role in hyperuricemic nephropathy is unclear.
    METHODS: An in vitro model of hyperuricemic nephropathy was established by treating human renal tubular epithelial cells with uric acid (UA). Reverse transcription quantitative PCR and western blotting, and enzyme-linked immunosorbent assays were used to quantify the mRNA and protein levels of the target molecules. A specific peptide inhibitor, P110, was used to disrupt the binding between DRP1 and FIS1. Co-immunoprecipitation (Co-IP) was performed to confirm the interactions between DRP1 and FIS1. Cell viability was assessed using propidium iodide staining and the Cell Counting Kit-8 assay.
    RESULTS: UA significantly upregulated DRP1 expression, activated DRP1, and promoted mitochondrial translocation. P110 inhibited DRP1/FIS1 binding, preventing DRP1 UA-induced mitochondrial translocation. Excessive mitochondrial fission, reactive oxygen species generation, release of inflammatory factors, and apoptosis were significantly alleviated. In addition, inhibition of DRP1 mitochondrial translocation decreased the expression of apoptosis-related markers and apoptosis.
    CONCLUSIONS: The overactivation of DRP1 is crucial for UA-induced renal tubular epithelial cell injury. P110 exerts a cytoprotective effect by inhibiting the DRP1/FIS1 interaction and modulating the mitochondrial apoptotic pathway. This study proposes a possible target for therapeutic intervention in the treatment of hyperuricemic nephropathy.
    Keywords:  apoptosis; dynamin-related protein 1; mitochondrial dysfunction; renal tubular epithelial cells; uric acid
    DOI:  https://doi.org/10.31083/FBL46700
  18. Pestic Biochem Physiol. 2026 Jan;pii: S0048-3575(25)00447-X. [Epub ahead of print]216(Pt 1): 106734
    Beauveria bassiana through miRNA-mediated mitophagy affects Lymantria dispar cellular immunity.
    Yue Zhang, Zhe Xu, Ye Liu, JianYang Bai, Lu Li, TianTian Wang, JingXin Cao, JingYu Cao, Jian Diao, Wei Ma, Ling Ma.
      The entomopathogenic fungus Beauveria bassiana is widely used for biocontrol of destructive forest pests. However, the molecular mechanisms by which fungal infection disrupts host cellular homeostasis remain poorly understood. Here, we demonstrate that B. bassiana infection triggers mitophagy in Lymantria dispar hemocytes through reactive oxygen species (ROS) accumulation and miRNA-mediated regulation. Using transmission electron microscopy and gene expression profiling, we observed extensive mitochondrial damage and elevated expression of mitophagy-related genes (e.g., ATG13, BECN1) and lysosomal pathway components post-infection. Small RNA sequencing identified 93 differentially expressed miRNAs, with downregulated miRNAs (e.g., bmo-miR-2795, PC-3p-46410_42) targeting the PINK1-Parkin ubiquitination pathway. Functional enrichment analysis further linked these miRNAs to mitophagy activation. Our findings reveal a previously unrecognized strategy by which B. bassiana subverts host immunity via miRNA-regulated mitophagy, offering insights for optimizing fungal biocontrol agents.
    Keywords:  Entomopathogenic fungi; Insect immunity; MicroRNA; Mitophagy; PINK1-parkin pathway
    DOI:  https://doi.org/10.1016/j.pestbp.2025.106734
  19. Cell Biol Toxicol. 2025 Dec 06.
    UBC9 mediates mitophagy to attenuate oxidative stress by regulating SUMOylation of PINK1 in the Parkinson's disease progression.
    Jian Liu, Ge Jia, Yu Zhou, Junmei Zhang, Yanjin Wang, Yuxiang Cai.
       BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons. UBC9 is related to the formation of several cancers. Nevertheless, the function of UBC9 in PD and the potential mechanisms are vague.
    METHODS: MPP⁺-induced SH-SY5Y cells and MPTP-treated C57BL/6 mice were applied to induce PD models. Cell viability, proliferation and apoptosis were measured using CCK-8, EdU and Annexin V/PI staining, respectively. JC-1 staining and fluorescent probes DCFH-DA were employed to measure mitochondrial membrane potential and ROS production. The SOD, GSH and MDA content were determined by the commercially kits. SUMOylation of PINK1 were predicted by SUMOplot and verified by co-IP/Western blot. Mitophagy-related proteins, SUMO enzymes, and TH were analyzed by qRT-PCR/Western blot. LC3 expression was detected via immunofluorescence staining. Transmission electron microscopy was performed to detect autophagy. MPTP-induced brain injury was evaluated using Nissl staining, IHC and TUNEL assay. Motor function was observed via open field test and pole test.
    RESULTS: PINK1 and UBC9 were low-expressed in MPP+-induced SH-SY5Y cells. UBC9 mediated PINK1 SUMOylation. UBC9 overexpression promoted cell viability and reduced cells apoptosis in MPP+-stimulated SH-SY5Y cells, which was reversed after PINK1 silence or CsA treatment. Moreover, UBC9 overexpression counteracted MPP+-induced mitophagy, and oxidative stress. However, these findings were reversed by CsA or PINK1 silencing. PINK1 bound SUMO1 at the K522, K363 and K193 sites, further regulating cells viability and apoptosis. In MPTP-treated mice, UBC9 overexpression alleviated mitochondrial dysfunction and motor deficits via PINK1 SUMOylation.
    CONCLUSION: UBC9 mediated mitophagy to attenuate MPP+/MPTP-induced neurotoxicity and oxidative stress by regulating PINK1 SUMOylation, suggesting that UBC9 may play a preventive role in PD progression.
    Keywords:  Mitophagy; Oxidative stress; PINK1; Parkinson’s disease; UBC9
    DOI:  https://doi.org/10.1007/s10565-025-10126-3
  20. Cancer Sci. 2025 Dec 06.
    Correction to "Mitochondrial Dynamics as a Pathobiological Mediator of Clonal Myeloid Disorders".
      
    DOI:  https://doi.org/10.1111/cas.70295
  21. Int Immunopharmacol. 2025 Dec 04. pii: S1567-5769(25)01980-0. [Epub ahead of print]169 115992
    Calreticulin attenuates intervertebral disc degeneration by suppressing NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy.
    Ziyi Song, Yucheng Gao, Jiangkai Yu, Yang Zhang, Wenbin Xuan, Yijun Rong, Youheng Zhang, Zengxin Gao.
      This study investigates the role of calreticulin (CRT) in intervertebral disc degeneration (IVDD) and elucidates its underlying mechanisms. CRT expression was markedly reduced in degenerated disc tissues, implicating its involvement in IVDD pathogenesis. Both in vitro and in vivo experiments were conducted to assess the effects of CRT on nucleus pulposus cell (NPC) pyroptosis, apoptosis, and mitochondrial function. Functional analyses demonstrated that CRT overexpression alleviated disc degeneration, inhibited pyroptotic cell death, and preserved mitochondrial integrity. Mechanistically, CRT promoted the clearance of damaged mitochondria through PINK1/Parkin-mediated mitophagy, restoring mitochondrial homeostasis and suppressing ROS accumulation and NLRP3 inflammasome activation. In vivo studies using an IVDD animal model further validated these protective effects, showing reduced disc degeneration and maintenance of extracellular matrix integrity. Recent studies have demonstrated the protective effect of CRT in IVDD. This study builds on these findings and investigates a novel mechanism through which CRT mediates its protective effects in IVDD. Specifically, our study identifies the involvement of PINK1/Parkin-mediated mitophagy in CRT's ability to preserve mitochondrial function and mitigate inflammation in NPCs, offering new insights into the molecular pathways underlying CRT's protective role in IVDD.
    Keywords:  Calreticulin; IVDD; Mitochondrial dysfunction; Mitophagy; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115992
  22. J Inflamm Res. 2025 ;18 16637-16665
    Identification of Mitochondrial Unfolded Protein Response-Related Genes and Diagnostic Biomarkers in Atherosclerosis by Integrative Multidimensional Analysis and Experimental Validation.
    Shuguang Wu, Yanhong Liu, Yu Li, Junyu Lai, Qiang Wan, Jianguang Wu, Yirong Ma.
       Background: Atherosclerosis (AS) is a common cardiovascular disease worldwide. The mitochondrial unfolded protein response (UPRmt) is a defense mechanism that enhances protein folding and degradation to maintain mitochondrial function and cellular homeostasis under stress. Research suggests a strong link between mitochondrial dysfunction and AS, particularly related to oxidative stress and inflammation. However, the exact relationship between UPRmt and AS is unclear. Identifying biomarkers associated with UPRmt is crucial for improving AS diagnosis and treatment.
    Methods: Microarray datasets related to AS were retrieved from the Gene Expression Omnibus (GEO) database. After integrating these datasets and eliminating batch effects, we obtained 101 AS and 67 control samples. Based on the expression levels of UPRmt-related genes (MRGs), the samples were classified into two subtypes and subjected to differential analysis, weighted correlation network analysis, and immune infiltration analysis. A predictive model was built using 12 machine learning algorithms to identify hub genes associated with UPRmt. Additionally, single-cell RNA-seq data and the CellChat algorithm were used to explore intercellular communication mechanisms mediated by these hub genes in AS. Mendelian randomization analysis was performed to identify biomarkers linked to AS. Molecular simulation techniques assessed the therapeutic potential of Iloprost. Finally, the expression and distribution of core genes were analyzed by RT-qPCR, Western blot, and immunofluorescence.
    Results: We identified seven hub genes at the intersection of UPRmt dysregulation and atherosclerosis. These genes showed consistent differential expression across cohorts and formed coherent mitochondria-stress modules. Their expression correlated with multiple immune-cell infiltration scores, including macrophage and T-cell signatures, and with inflammatory mediators. A classifier based on the seven-gene panel distinguished atherosclerotic from non-atherosclerotic samples across external datasets and remained robust after accounting for clinical covariates. Experimental assays confirmed altered expression of selected genes and their modulation under mitochondrial stress. Molecular simulation suggested that Iloprost can bind to the APOC1 protein's active pocket.
    Conclusion: ARHGAP25, CYTH4, ITGB7, APOC1, WDFY4, MARCO and PLCB2 are pivotal genes intimately linked to AS and the UPRmt. They potentially play crucial roles in mitochondrial dysfunction and immune regulation. As such, these genes may be promising biomarkers and therapeutic targets for AS.
    Keywords:  atherosclerosis; immune infiltration; machine learning; mitochondrial unfolded protein response; molecular dynamics; single-cell sequencing analysis
    DOI:  https://doi.org/10.2147/JIR.S562903
  23. Eur J Appl Physiol. 2025 Dec 02.
    Involvement of the PINK1/PARKIN pathway in enhancing mitochondrial function and mitophagy in reserpine-induced fibromyalgia mice through strength exercise and coenzyme Q10.
    Hoda M Moghazy, A A Seham, Motamed Mahmoud, Sahar M Gebril, Dina M Monir.
       PURPOSE: To assess the impact of reserpine-induced fibromyalgia and evaluate the potential effects of resistance exercise or CoQ10 administration on muscle strength, structure, and expression of mitochondrial markers in adult mice. Central to this investigation is an exploration of the molecular mechanisms underlying mitophagy via the PINK1/Parkin pathway.
    METHODS: This study sought to elucidate the Impact of 4 weeks of either climbing exercise or coenzyme Q10 (CoQ10) supplementation (10 mg/kg, administered once daily) on skeletal muscle and mitochondrial functions within a reserpine-induced fibromyalgia (FM) mouse model. Evaluation encompassed the assessment of key mitochondrial markers, including PTEN-induced kinase 1 (PINK1), PARKIN, Mitofusion2, cytochrome c oxidase, citrate synthase, and fibronectin type III domain-containing protein 5 (FNDC5), alongside morphological examinations of the gastrocnemius muscle.
    RESULTS: Climbing exercise significantly improved fibromyalgia (FM)-like symptoms and enhanced the expression of mitochondrial marker genes in the gastrocnemius muscle. Histological and ultra-structural studies showed nearly normal muscle fiber structure, banding patterns, mitochondria shape and size, and a notable reduction in collagen fibrosis compared to FM. CoQ10 supplementation also improved mitochondrial gene expression but did not significantly affect FNDC gene expression. Ultrastructural analysis revealed mostly normal muscle fibers with regular banding, though some areas showed disturbances with multiple sub-sarcolemmal and interfibrillar mitochondria.
    CONCLUSION: This study underscores the efficacy of both resistance exercise and CoQ10 supplementation as viable strategies for improving FM-related symptoms and enhancing mitochondrial function in mice.
    Keywords:  Climbing exercise; Coenzyme Q10; Fibromyalgia; Mitochondria; Mitophagy; PARKIN; PINK1
    DOI:  https://doi.org/10.1007/s00421-025-05990-0
  24. Adipocyte. 2025 Dec;14(1): 2596407
    Comparative analysis of adipose tissue mitophagy and inflammatory markers in obesity and health.
    Shaghayegh Mohammadzadeh, Mitra Nourbakhsh, Parichehreh Yaghmaei, Atefeh Kashanizadeh.
      Obesity is associated with chronic inflammation and disruptions in cellular homeostasis, including impaired autophagy in adipose tissue. This study aimed to investigate the key mitophagy markers in the adipose tissue of individuals with obesity, compared to healthy controls. A total of 60 participants were enrolled, comprising 30 individuals with obesity and 30 healthy controls. Adipose tissue and peripheral blood samples were collected from all participants. Biochemical analyses included measurement of tumor necrosis factor-alpha (TNF-α), leptin, succinate dehydrogenase (SDH), and oxidative stress markers. Gene expression levels of mitophagy-related genes, PARK2, PINK1, and BNIP3L were assessed using quantitative real-time PCR. Additionally, immunohistochemistry was performed to evaluate BNIP3L protein levels in adipose tissue. Compared to the control group, individuals with obesity showed significantly elevated levels of TNF-α and SDH, along with evidence of oxidative stress. Moreover, the expression of PARK2, PINK1, and BNIP3L was significantly upregulated in the obesity group, suggesting increased mitophagy activity in adipose tissue. These findings indicate heightened inflammation and upregulation of mitophagy pathways in the adipose tissue of individuals with obesity. The upregulation of mitophagy-related genes seems to indicate a possible activation of mitophagy-associated pathways in the altered metabolic and inflammatory environment of obesity.
    Keywords:  Obesity; adipose tissue; autophagy; inflammation
    DOI:  https://doi.org/10.1080/21623945.2025.2596407
  25. Front Immunol. 2025 ;16 1680554
    Integrated multi-omics reveals GABARAP-mediated mitophagy and pyruvate metabolism as key drivers of osteosarcoma progression.
    Xiuxin Han, Yiqin Li, Yongheng Liu, Feng Wang, Tingfang Li, Qingchen Zhang, Guowen Wang, Jinyan Feng.
       Background: Osteosarcoma is a highly aggressive bone malignancy characterized by frequent metastasis and therapy resistance. Although mitophagy and pyruvate metabolism are increasingly recognized as critical metabolic regulators, their interaction in osteosarcoma remains poorly understood. The autophagy-related protein GABARAP, central to mitochondrial quality control, has not been systematically evaluated in osteosarcoma.
    Methods: Single-cell RNA sequencing (scRNA-seq) datasets (GSE162454, GSE237070) were analyzed to delineate cellular heterogeneity and malignant states, with prognostic clusters identified by Scissor and inferCNV. Tumor microenvironment (TME) composition and intercellular signaling were profiled using CellChat. Pathway enrichment and multi-omics integration across TARGET, GSE21257, and GSE32981 highlighted mitophagy-pyruvate coupling, which were further validated by spatial transcriptomics and in vitro functional assays.
    Results: We mapped the osteosarcoma ecosystem and identified two malignant subpopulations, Ost_1 and Cho_2 (Mal_Ost/Cho), exhibiting high genomic instability, stemness, and poor prognosis. The osteosarcoma TME displayed profound immune remodeling, characterized by infiltration of T/NK cells alongside enrichment of immunosuppressive Tregs and M2-polarized macrophages. Enhanced MIF-mediated signaling between Mal_Ost/Cho and T/NK compartments suggested a key mechanism of immune evasion. Both malignant subtypes demonstrated coordinated activation of mitophagy and pyruvate metabolism, sustaining metabolic adaptation and tumor progression. Multi-omics integration pinpointed GABARAP as a central hub regulating this mitophagy-metabolism axis, spatially enriched within metabolic hotspots and immunosuppressive niches. Functionally, GABARAP depletion disrupted mitophagy flux, mitochondrial integrity, and energy production, thereby impairing osteosarcoma cell proliferation and migration.
    Conclusion: These findings reveal that GABARAP links mitophagy-driven metabolic adaptation with immune evasion, representing a key regulator and potential therapeutic target in osteosarcoma.
    Keywords:  GABARAP; Osteosarcoma; Single-cell RNA-sequencing; mitophagy; pyruvate metabolism
    DOI:  https://doi.org/10.3389/fimmu.2025.1680554
  26. Sci Rep. 2025 Dec 01.
    Integrated multi-omics of mitophagy-related molecular subtype characterization and biomarker identification in sepsis.
    Chao Wan, Yajing Wang.
      As a life-threatening condition driven by dysregulated host responses to infection, sepsis suffers from high mortality and heterogeneity. Mitophagy is the selective removal of damaged mitochondria, which is implicated in mitigating sepsis-related damage. The systematic identification and validation of key mitophagy-associated genes (MAG) for sepsis diagnosis, stratification, and immune modulation are lacking. Bulk transcriptomic datasets were integrated for differential expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and machine learning. We analyzed single-cell RNA-seq data to map MAG expression, performed immune infiltration analyses by ESTIMATE, single-sample Gene Set Enrichment Analysis (ssGSEA) and conducted consensus clustering based on MAG for molecular subtyping. As a screened MAG, the role of NUP93 was functionally validated in mitophagy using lipopolysaccharide (LPS)-stimulated RAW264.7 cells with adenoviral overexpression. Integration of machine learning identified four MAG biomarkers (RPL18, PRPF8, NUP93, CUL1) with high diagnostic power (individual AUCs 0.957-0.975, nomogram AUC = 0.990). Consensus clustering based on these MAG stratified sepsis patients into distinct molecular subtypes with differing MAG expression, immune landscapes, and underlying immune-related pathways. NUP93 overexpression in vitro rescued LPS-induced mitophagy impairment by restoring mitochondrial PINK1 and LC3B levels. This study identifies RPL18, PRPF8, NUP93, and CUL1 as robust diagnostic MAG biomarkers for sepsis, demonstrates their utility in defining molecular subtypes with divergent immune microenvironments, and provides functional evidence that NUP93 promotes mitophagy during sepsis, offering novel tools for precision diagnosis and insights for targeted therapeutic strategies.
    Keywords:  Immunity; Mitophagy; NUP93; Sepsis; Single-cell sequencing
    DOI:  https://doi.org/10.1038/s41598-025-30153-8
  27. Hypertension. 2025 Dec 03.
    XLOC_010588 Promotes Mitophagy Via BAG2-Mediated PINK1 Stabilization in HPH.
    Pulin Li, Binbin Zhang, Jiling Wang, Wenhao Li, Wenlong Wu, Can Wang, Rui Han, Daxiong Zeng, Ran Wang.
       BACKGROUND: Pulmonary hypertension (PH) is a severe disorder, with hypoxic PH (HPH) representing a major subtype characterized by elevated pulmonary artery pressure due to chronic hypoxia. Long noncoding RNAs are implicated in various cellular processes, but their role in mitophagy regulation within pulmonary artery smooth muscle cells remains unclear. This study aims to investigate the role of long noncoding RNA XLOC_010588 (XLOC_010588) in modulating mitophagy and HPH pathogenesis.
    METHODS: We examined the interaction between XLOC_010588 and BAG2 (BCL2-associated athanogene 2), a regulator of PINK1 stability, using molecular and cellular assays. The role of XLOC_010588 in BAG2-mediated PINK1 stabilization and mitophagy activation was assessed in hypoxic pulmonary artery smooth muscle cells. Additionally, the transcriptional regulation of XLOC_010588 by SP1 (specificity protein 1) was investigated. Clinical samples from patients with HPH were analyzed for SP1/BAG2/PINK1 expression, and in vivo experiments were conducted in HPH rats with BAG2 knockdown to evaluate its therapeutic potential.
    RESULTS: XLOC_010588 was found to bind to BAG2, thereby inhibiting PINK1 ubiquitination and promoting its stabilization on damaged mitochondria. This activation of the PINK1/Parkin pathway increased mitophagy and pulmonary artery smooth muscle cell proliferation. SP1 was identified as a positive regulator of XLOC_010588 expression. Clinically, BAG2 levels were significantly elevated in patients with HPH. In vivo, BAG2 knockdown alleviated HPH in rats, confirming its role in disease progression.
    CONCLUSIONS: Our study reveals a novel mechanism in which XLOC_010588 promotes mitophagy via BAG2-dependent suppression of PINK1 ubiquitination, contributing to pulmonary artery smooth muscle cell proliferation and HPH development. These findings highlight the potential of targeting the XLOC_010588/BAG2/PINK1 axis for HPH treatment.
    Keywords:  cell proliferation; hypoxia; mitochondria; mitophagy; pulmonary artery
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.25742
  28. Eur J Med Res. 2025 Dec 05.
    Molecular hydrogen-mediated SIRT1 activation alleviates sepsis-associated encephalopathy by promoting mitophagy.
    Jianfeng Liu, Shuqi Meng, Zhiwei Wang, Yan Fan, Shuaijie Pei, Jiatian Cui, Jie Liu, Yu Song, Xiaofan Huang, Xuguang Li, Yan Cui, Keliang Xie.
       BACKGROUND: Sepsis-associated encephalopathy (SAE) constitutes a major determinant of sepsis-related mortality across acute and survivorship phases. While molecular hydrogen (H₂) exhibits neuroprotective capacities in SAE, its precise mechanistic underpinnings remain unresolved. This study investigates the protection of SAE by H2 through regulating SIRT1-mediated mitophagy.
    METHODS: SAE was modeled in mice via cecal ligation and puncture (CLP). The cognitive abilities of mice were evaluated via behavioral tests (Morris water maze), observation of the pathological morphology of brain tissues (HE staining), and observation of neuronal cell structure (Nissl staining). Proteomics was employed to explore the specific mechanism by which hydrogen regulates mitophagy. Western blotting, immunofluorescence, and electron microscopy were used to quantify the dynamic changes of sirtuin 1 (SIRT1) and mitophagy during SAE. In addition, an SIRT1 inhibitor (EX527) was utilized to observe its effects on hydrogen treatment and mitophagy.
    RESULTS: Inhalation of 2% hydrogen significantly enhanced the 7-day survival rate of septic mice (from 50 to 75%, P < 0.01) and improved cognitive performance in the Morris water maze, as evidenced by increased platform crossings (P < 0.05) and reduced escape latency. Hydrogen treatment upregulated SIRT1 expression and promoted PINK1/Parkin-mediated mitophagy, leading to reduced phosphorylation of STING, decreased levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and suppressed neuronal apoptosis in the hippocampal CA1 region. These protective effects were reversed by the SIRT1 inhibitor EX527.
    CONCLUSIONS: This study demonstrates that inhalation of 2% H2 exerts significant protective effects against SAE, in which SIRT1 plays a pivotal role by modulating PINK1-dependent mitophagy, thereby ameliorating neuroinflammation and neuronal apoptosis. By rescuing mitophagy deficits, SIRT1 targeting merits clinical exploration for SAE.
    TRIAL REGISTRATION: Not applicable.
    Keywords:  Cognitive dysfunction; EX527; Hydrogen; Mitophagy; SAE; SIRT1
    DOI:  https://doi.org/10.1186/s40001-025-03600-5
  29. Mol Neurobiol. 2025 Dec 03. 63(1): 238
    The Vitamin D Receptor Ortholog Hr96 Modulates Neuronal and Mitochondrial Dynamics in a Drosophila Model of Alzheimer's Disease.
    Guilherme Gischkow Rucatti, Francisco Muñoz-Carvajal, Nicole Sanhueza, Sebastian Oyarce-Pezoa, Yesid Cuesta-Astroz, Leandro Murgas, Melissa Caru-Ruiz, Alberto J M Martin, Melissa Calegaro-Nassif, Carol D SanMartín, Mario Sanhueza.
      Alzheimer's disease (AD) is the most common cause of dementia, characterized by amyloid-β (Aβ42) accumulation, with a progressive breakdown of synapsis connection, neuronal death, and cognitive loss. Mitochondrial impairment emerges early in AD, preceding cognitive symptoms and contributing to disease progression. Vitamin D (VD) is a neurosteroid that acts as a transcription factor through its nuclear receptor, the vitamin D receptor (VDR), playing a central role in metabolic control. The Drosophila VDR ortholog, hormone receptor 96 (Hr96), is known to regulate xenobiotic protection and energy metabolism, but its neuronal functions and impact on AD pathomechanisms are poorly understood. Here, we investigate Hr96's role in neuronal and mitochondrial homeostasis, hypothesizing that its signaling modulates mitochondrial dynamics and mitigates neurodegeneration in AD. We identified Hr96-regulated genes involved in lipid metabolism, oxidative stress, and mitochondrial dynamics. Modulation of Hr96 expression in fly neurons revealed that knockdown had minimal early effects but led to reduced lifespan and motor decline, while overexpression induced metabolic imbalances, circadian disruptions, and premature mortality. Mitochondrial analyses showed that Hr96 overexpression affected functionality, increased fragmentation, and upregulated fission markers, such as Drp1, suggesting a role in mitochondrial dynamics. Then, when we studied an AD fly model, Hr96 loss exacerbated Aβ42-induced neurotoxicity, reducing lifespan and motor performance. Conversely, Hr96 overexpression extended lifespan under Aβ42 toxicity but did not affect neuromuscular junction bouton number and size. Furthermore, when mitochondrial parameters were analyzed, overexpression of this gene suppresses Aβ42-linked mitochondrial phenotypes to levels closer to wild type. These findings unveil Hr96 as a potential modulator of mitochondrial and neuronal homeostasis, and that in the context of a time-dependent insult such as Aβ42 accumulation, its overexpression is protective. Further studies are needed to elucidate its role in mitochondrial regulation and transcriptional networks, paving the way for therapeutic strategies targeting mitochondrial dysfunction in neurodegeneration.
    Keywords:  Alzheimer’s disease; Drosophila; Hr96; Vitamin D
    DOI:  https://doi.org/10.1007/s12035-025-05502-3
  30. Nat Commun. 2025 Dec 05.
    Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
    Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.
      The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-66901-7
  31. Nat Commun. 2025 Dec 01.
    Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
    J Botella, E Perri, N J Caruana, S López-Calcerrada, M Brischigliaro, N A Jamnick, V Oorschot, N J Saner, J Díaz-Lara, D F Taylor, A Garnham, E Fernández-Vizarra, C Ugalde, G Ramm, D A Stroud, M Lazarou, D J Bishop.
      Exercise is a key lifestyle intervention for mitochondrial health, yet the molecular mechanisms by which different exercise prescriptions regulate mitochondrial remodeling remain unclear. We conducted an open-label counterbalanced randomized controlled trial (ACTRN12617001105336) and observed that sprint-interval exercise (SIE; n = 14), compared to moderate-intensity continuous exercise (MICE; n = 14), induces a mitochondrial stress signature and unfolded protein response (UPRmt). SIE triggers morphological and structural mitochondrial alterations along with activation of the integrated stress response (ISR) and mitochondrial quality control (MQC) pathways. Following eight weeks of training, moderate-intensity continuous training (MICT) increases mitochondrial content, complex I activity, and displays an enrichment of tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) proteins, while sprint-interval training (SIT) improves respiratory function and upregulates pathways involved in 1-carbon metabolism and protein quality control. We identify COX7A2L accumulating in III2 + IV1 supercomplexes only after SIT. These findings elucidate how exercise intensity shapes mitochondrial remodeling, informing tailored exercise prescriptions.
    DOI:  https://doi.org/10.1038/s41467-025-66625-8
  32. Acta Neuropathol. 2025 Dec 01. 150(1): 59
    Genetic factors and comorbid pathologies interact to drive regional mitophagy alterations in Lewy body dementia.
    Xu Hou, Tyrique Richardson, Michael G Heckman, Fabienne C Fiesel, Launia J White, Shunsuke Koga, Owen A Ross, Dennis W Dickson, Wolfdieter Springer.
      The kinase-ligase pair PINK1-PRKN initiates mitophagy by recognizing and selectively tagging worn-out and dysfunctional mitochondria with phosphorylated ubiquitin (pS65-Ub) to facilitate their elimination via autophagy. In human autopsy brains, the number of pS65-Ub positive cells increases with age but is also associated with Lewy body (LB), neurofibrillary tangles (NFT), and senile plaque (SP) burden. Through a recent genome-wide association study, we identified two genetic modifiers of pS65-Ub levels, APOE4 and ZMIZ1 rs6480922. While LB, NFT, and SP pathologies often coexist in Lewy body dementia (LBD), it is unclear how genetic factors and comorbid neuropathologies interact to impact mitophagy in vulnerable brain regions. We therefore measured levels of the age and disease marker pS65-Ub in the hippocampus and amygdala of 371 LBD cases. Significant and independent associations with pS65-Ub levels were observed for each of the three pathologies LB, NFT, and SP in both regions, and the presence of APOE4 significantly strengthened the association between NFT and pS65-Ub in the hippocampus. While no interaction between LB and SP pathologies was observed regarding association with pS65-Ub, a significant interaction between LB and NFT pathologies on pS65-Ub accumulation was found in the amygdala, which was primarily observed in carriers of the minor allele of ZMIZ1 rs6480922. In summary, our study revealed complex interactions between LB pathology, NFT pathology, and genetic mitophagy modifiers in LBD brains, highlighting potential convergent molecular mechanisms underlying α-synuclein- and tau-associated mitophagy alterations.
    Keywords:  APOE4; Mitochondria; Mitophagy; PARK2; PINK1; Parkin; Tau; Ubiquitin; ZMIZ1; α-Synuclein
    DOI:  https://doi.org/10.1007/s00401-025-02964-6
  33. Redox Biol. 2025 Nov 27. pii: S2213-2317(25)00465-3. [Epub ahead of print]88 103952
    The Rieske iron-sulfur protein is a primary target of molecular hydrogen.
    Shuto Negishi, Mikako Ito, Tomoya Hasegawa, Hikaru Otake, Bisei Ohkawara, Akio Masuda, Hiroyuki Mino, Tyler W LeBaron, Kinji Ohno.
      The mechanisms underlying the biomedical effects of molecular hydrogen (H2) remain poorly understood and are often attributed to its selective reduction of hydroxyl radicals, based on the long-held notion that H2 is biologically inert. We demonstrate that H2 is biologically active, specifically targeting the Rieske iron-sulfur protein (RISP). We first observed that H2 induces the mitochondrial unfolded protein response (UPRmt) in cultured cells exposed to H2 and in mouse liver after H2 water administration. H2 suppressed electron transport chain complex III activity in mouse liver homogenates to 78.5 % within 2 min. Given the evolutionary link with hydrogenases, we examined RISP as a potential target of H2. We found that H2 promotes RISP degradation within 1 h in cultured cells by activating mitochondrial Lon peptidase 1 (LONP1). Loss of RISP and subsequent UPRmt induction may explain the pleiotropic and paradoxical effects of H2. These findings identify RISP as a primary target of H2, demonstrating that H2 is biologically active as a signaling molecule.
    Keywords:  Hydrogenase; Mitochondrial unfolded protein response; Molecular hydrogen; Rieske iron-sulfur protein
    DOI:  https://doi.org/10.1016/j.redox.2025.103952
  34. J Vis Exp. 2025 Nov 14.
    Assessment of Mitochondrial Fission/Fusion Dynamics in Kidney Proximal Tubular Cells.
    Vikky Awasthi, Sulaiman Qamar Sharief, Meriem Bkhache, Aasthika Das, Rihab Bouchareb.
      Mitochondria are best recognized for their role in ATP synthesis and serve as key regulators of cellular metabolism. Mitochondrial dynamics comprehend the intracellular and intercellular movement of mitochondria, as well as the processes of fission/fusion. These events are fundamental to maintaining mitochondrial function by maintaining cellular homeostasis, morphology, bioenergetics, quality control, and stress responses. On the other hand, dysregulation of mitochondrial dynamics impacts cellular morphology and function. Precise measurement of mitochondria fission/fusion events can be indicative of cellular health. Current methodologies to measure mitochondria dynamics employ advanced imaging like super-resolution microscopy, fluorescence techniques (Fluorescence Recovery After Photobleaching (FRAP)) for connectivity, and optogenetic tools for spatiotemporal control. Quantitative analysis utilizes computational tools to measure parameters like length, number, and branching, which indicate fission/fusion balance. However, these methods require skills and sophisticated instruments. In this article, we describe the use of confocal microscopy combined with free-to-use tools in ImageJ (Fiji) to study fission/fusion events using the photo-switching property of the dendra2 protein, tagged to mitochondrial cytochrome c.
    DOI:  https://doi.org/10.3791/69268
  35. J Ethnopharmacol. 2025 Dec 01. pii: S0378-8741(25)01679-4. [Epub ahead of print] 120987
    Forsythiaside A ameliorates acetaminophen-induced liver injury by suppressing ferroptosis through activating USP11/SIRT3-mediated mitophagy.
    Mengling Zhou, Lihong Gong, Yujie Yu, Jianlan Zhang, Chaoyang Zhang, Cheng Peng, Yunxia Li.
       ETHNOPHARMACOLOGICAL RELEVANCE: Acetaminophen (APAP), a widely used antipyretic and analgesic, frequently causes liver injury upon overdose. The fruit of Forsythia suspensa (Thunb.) Vahl, known as Forsythiae Fructus, is a traditional Chinese medicine used to clear heat and toxic, remove lumps, and reduce swelling. Forsythiaside A (FTA), an important active ingredient in Forsythiae Fructus, has significant antioxidant, anti-inflammatory and hepatoprotective effects. However, its protective mechanisms against acetaminophen-induced liver injury (AILI) remain unclear.
    AIM OF THE STUDY: This study aimed to investigate the protective role and underlying molecular mechanisms of FTA in AILI.
    METHODS: The AILI model was established to evaluate the hepatoprotective effects of FTA. H&E staining was used to observe histopathology, while serum transaminase activities and hepatic biochemical parameters were assessed using commercial assay kits. To understand the mechanisms, in vivo studies included immunohistochemistry, immunofluorescence, western blot, and real-time quantitative polymerase chain reaction (RT-qPCR). In vitro analyses further evaluated the efficacy and mechanistic actions through MTT, western blot, RT-qPCR, immunofluorescence, co-immunoprecipitation, molecular docking, and cell transfection assays.
    RESULTS: FTA alleviated liver histopathological damage and reduced serum transaminases. FTA decreased malondialdehyde (MDA) and Fe2+ levels, restored glutathione (GSH), and up-regulated key ferroptosis suppressors at both protein and mRNA levels. Moreover, FTA promoted the colocalization of the autophagy marker microtubule-associated protein light chain 3B (LC3B) with mitochondria, while increasing the expression of ubiquitin-specific peptidase 11 (USP11) and sirtuin 3 (SIRT3). Importantly, USP11 silence by siRNA reversed FTA-mediated mitigation of mitophagy and ferroptosis.
    CONCLUSION: FTA ameliorates AILI by suppressing ferroptosis through activating USP11/SIRT3-mediated mitophagy, revealing a novel mechanistic pathway.
    Keywords:  Acetaminophen-induced liver injury; Ferroptosis; Forsythiaside A; Mitophagy; USP11/SIRT3 axis
    DOI:  https://doi.org/10.1016/j.jep.2025.120987
  36. J Neuroinflammation. 2025 Dec 06.
    SYK regulates Schwann cell metabolic reprogramming to promote axonal regeneration in immune-mediated neuropathy.
    Nannan Zhang, Chen Liu, Fangyu Chen, Qian Zheng, Yuzhong Wang, Fangzhen Shan.
      Immune-mediated peripheral neuropathies like acute motor axonal neuropathy (AMAN) drive axonal degeneration through unresolved neuroinflammation, where Schwann cell (SC) metabolic reprogramming fails to support regeneration. While Spleen Tyrosine Kinase (SYK) is recognized for orchestrating immune responses and central glial function, its role in SC immunometabolism remains unknown. We identify SYK as a master regulator bridging neuroinflammation and SC metabolic adaptation in AMAN. SYK was compensatorily upregulated in SCs at sciatic nerve lesions following anti-GD1a IgG-mediated autoimmune injury, suggesting its activation is part of the protective response. Experimental SYK deficiency triggered catastrophic metabolic collapse, impairing glycolysis and oxidative phosphorylation via dysregulated PI3K/AKT/mTOR and HIF-1α/c-Myc signaling. This suppressed glucose uptake, glycolytic enzymes, mitochondrial biogenesis, and electron transport chains, exacerbating mitochondrial damage. Crucially, loss of this SYK response disrupted AMPK/STAT3-dependent mitophagy, causing ROS accumulation and mitochondria-dependent apoptosis, linking metabolic failure to glial degeneration. SYK deficiency further impaired neuro-glial metabolic coupling, reducing lactate production and MCT1-mediated transfer to axons, which compromised axonal bioenergetics. In vivo, targeted SYK knockdown in AMAN mice to block this endogenous upregulation amplified neuroinflammation, impaired nerve bioenergetics, exacerbated muscle atrophy, and worsened neurofunctional deficits. Mechanistically, SYK integrates immune-triggered metabolic reprogramming with mitochondrial quality control to fuel regeneration. These findings establish SYK as a pivotal upstream coordinator of SC metabolism and neuro-immunomodulation that enables metabolic support for axonal regeneration. Targeting SYK to enhance its activity represents a promising metabolic therapy for immune-mediated neuropathy.
    Keywords:  Energy metabolism; Mitophagy; Peripheral nerve regeneration; Schwann cell; Spleen tyrosine kinase
    DOI:  https://doi.org/10.1186/s12974-025-03624-y
  37. Int J Mol Med. 2026 Feb;pii: 34. [Epub ahead of print]57(2):
    Mitochondria-associated endoplasmic reticulum membranes: Emerging regulators of cardiac microvascular ischemia/reperfusion injury (Review).
    Yan Wang, Baowei Feng, Yanting Wu, Zongle Sun, Hao Yuan, Wei Chen, Chang Zhao, Zhi Liu.
      Ischemic heart disease remains the leading cause of global disease burden among cardiovascular disorders. In addition to cardiomyocyte injury, ischemia-reperfusion (I/R)-induced microvascular damage plays a crucial role in determining tissue dysfunction and overall prognosis. Mitochondria-associated endoplasmic reticulum membranes (MAMs), specialized contact sites between the ER and mitochondria, are now recognized as key regulators of cardiovascular pathophysiology. The present review summarized current knowledge of the structure of MAMs and their effects on endothelial cells under hypoxia/reoxygenation conditions. Particular attention was given to their role in regulating mitochondrial quality control processes, including fission, fusion, oxidative stress, mitophagy and Ca2+ homeostasis, within the context of cardiac microvascular I/R injury. Targeting MAMs may represent a promising strategy for microvascular protection in ischemic heart disease.
    Keywords:  Ca2+ homeostasis; mROS; microvascular I/R injury; mitochondria-associated membranes; mitochondrial dynamics
    DOI:  https://doi.org/10.3892/ijmm.2025.5705
  38. Biomol Ther (Seoul). 2025 Dec 02.
    γ-Elemene Impairs Mitochondrial Biogenesis in Breast Cancer Cells by Upregulating GCN5-Mediated PGC-1α Acetylation.
    Ling Tang, Mingyan Wang, Jia Liu, Qiong Yu, Chen Chen, Lihua Jia, Jiyi Xia.
      Mitochondrial biogenesis represents a promising therapeutic target in triple-negative breast cancer (TNBC) due to its essential role in cancer cell metabolism and survival. The natural compound γ-Elemene exhibits potent anti-tumor activity, but its effects on mitochondrial regulation in TNBC remain unclear. In this study, we demonstrate that γ-Elemene induces dose-dependent cytotoxicity in MDA-MB-468 and HCC1806 TNBC cells while significantly impairing mitochondrial function, as shown by reduced membrane potential, oxidative phosphorylation capacity, and ATP production. γ-Elemene treatment markedly suppressed mitochondrial biogenesis, decreasing mitochondrial DNA content and downregulating key mitochondrial genes and proteins. These effects were associated with reduced expression of the master regulators NRF1 and TFAM, but independent of PGC-1α expression levels. Mechanistically, γ-Elemene upregulated the acetyltransferase GCN5, leading to enhanced PGC-1α acetylation. This upregulation occurs primarily through increased GCN5 transcription. Genetic ablation of GCN5 completely reversed γ-Elemene-induced PGC- 1α acetylation and restored mitochondrial biogenesis and cell viability, establishing a critical role for GCN5 in mediating these effects. Our findings reveal a novel mechanism whereby γ-Elemene disrupts mitochondrial function in TNBC through GCN5-mediated PGC-1α acetylation, providing new insights into its anti-cancer properties and potential therapeutic applications against TNBC.
    Keywords:  GCN5; Mitochondrial biogenesis; PGC-1α; Triple-negative breast cancer; γ-Elemene
    DOI:  https://doi.org/10.4062/biomolther.2025.119
  39. Cell Death Dis. 2025 Dec 01. 16(1): 879
    Inhibition of glycolysis and stimulation of mitochondrial biogenesis lead to increased ROS levels and cell death in HNF-1ß positive clear cell carcinoma.
    Naoki Kawahara, Hiroki Kuniyasu, Shiori Mori, Shingo Kishi, Sumire Sugimoto, Tomoka Maehana, Shoichiro Yamanaka, Ryuji Kawaguchi, Fuminori Kimura.
      Ovarian clear cell carcinoma is characterized by HNF-1ß overexpression and is known to be resistant to chemotherapy. An inhibitor screening that specifically targets HNF-1ß led us to identify Actinonin as a candidate for cancer treatment. Actinonin, which is known to inhibit aminopeptidase M, has also been recognized for its antibacterial properties. We confirmed that GSK-3ß interference/inhibition, as a component of the HNF-1ß pathway, combined with Actinonin, has a highly potent antitumor effect compared to monotherapy. The same effect was observed in renal clear cell carcinoma lines expressing HNF-1ß. Actinonin promoted mitochondrial production by suppressing aerobic respiration, which decreased AMPK levels and increased ROS production. However, it also elevated GADD45α expression and induced mitophagy. GSK-3ß inhibition suppressed glycolysis and shifted energy production to OXPHOS, leading to increased ROS production. Furthermore, this combination produced excess ROS beyond metabolic capacity, which accumulated in lipid bilayers, leading to a further increase in CHOP gene expression and suppression of mitochondrial turnover. The GSK-3ß inhibitor and Actinonin combination demonstrated a powerful tumor-suppressive effect in vivo without severe side effects. Combining GSK-3ß inhibition with Actinonin can effectively eliminate cancer cells with HNF-1ß overexpression by inhibiting glycolysis and promoting mitochondrial turnover, highlighting new options for cancer therapy.
    DOI:  https://doi.org/10.1038/s41419-025-08243-2
  40. CNS Neurosci Ther. 2025 Dec;31(12): e70676
    Alpinetin Targets Mitophagy Pathways to Mitigate Parkinson's Disease Progression.
    Zilu Shen, Xuesong Shan, Shenglan Zhang, Dan Huang, Haijun Hu, Yonglin Liang, Hong Zhu, Lieliang Zhang, Yayu Chen.
       AIMS: Parkinson's disease (PD) is a complex neurodegenerative disorder lacking disease-modifying therapies. This study aimed to systematically investigate the therapeutic potential and underlying mechanisms of Alpinetin in PD.
    METHODS: An integrated approach combining network pharmacology and molecular docking was employed to predict the core targets and pathways of Alpinetin in PD. These computational predictions were subsequently validated through in vivo animal experiments.
    RESULTS: Network pharmacology analysis predicted that Alpinetin exerts its effects by modulating mitophagy and dopaminergic synaptic pathways. Molecular docking revealed strong binding affinities between Alpinetin and key targets, including HIF1A, SQSTM1, and SRC. Guided by these findings, animal experiments confirmed the neuroprotective effects of Alpinetin, aligning with the predicted mechanisms.
    CONCLUSION: Our findings demonstrate that Alpinetin has significant therapeutic potential for PD, likely mediated through the regulation of mitophagy and dopaminergic synapses. This study elucidates the molecular targets and mechanisms of Alpinetin, providing a solid foundation for its further investigation as an anti-PD agent.
    Keywords:  Alpinetin; mitophagy; network pharmacology; parkinson's disease
    DOI:  https://doi.org/10.1002/cns.70676
  41. Stem Cells Int. 2025 ;2025 5533136
    Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Diabetic Neuropathic Pain via TRPV1-[Ca2+]i-AMPK Signaling-Mediated Mitochondrial Restoration in Schwann Cells.
    Yi-Kun Zhou, Jun-Dong He, Xiao-Chun Yang, Li-Fen Yang, Pei-Yu Jiang, Zhi Liang, Yang Ou.
       Background: The therapeutic potential of human umbilical cord mesenchymal stem cells (HUCMSCs) for diabetic peripheral neuropathy (DPN) and the underlying mechanisms involving transient receptor potential vanilloid 1 (TRPV1) signaling remain incompletely defined.
    Objective: This study aimed to elucidate the role of the TRPV1-[Ca2+]i-AMPK signaling axis in mediating the beneficial effects of HUCMSCs on neuropathic pain and Schwann cell (SC) dysfunction in DPN.
    Methods: A murine model of DPN was established. Mechanical allodynia and thermal hyperalgesia were assessed using Von Frey filaments and the KW-LB hot plate test, respectively. Primary mouse SCs were isolated and cultured under high glucose (HG) conditions. Intracellular calcium ([Ca2+]i) levels were quantified by flow cytometry. Protein expression (TRPV1, p-TRPV1, AMPK, p-AMPK, cleaved-caspase-3, Bax, Bcl-2, Drp1, PGC-1α, TFAM, Mfn2) was analyzed via Western blotting. Apoptosis and cell proliferation were evaluated using TUNEL staining and the CCK-8 assay, respectively. Specific inhibitors (AMG9810 for TRPV1 and compound C for AMPK) were employed to probe pathway involvement.
    Results: HUCMSC administration significantly alleviated mechanical allodynia and thermal hyperalgesia in diabetic mice. In vitro, HUCMSC coculture counteracted HG-induced effects in SCs by: (1) increasing the p-TRPV1/TRPV1 ratio and [Ca2+]i influx (effects blocked by AMG9810); (2) reducing apoptosis (decreased cleaved-caspase-3/Bax, increased Bcl-2); (3) enhancing the p-AMPK/AMPK ratio (attenuated by both AMG9810 and compound C); and (4) promoting mitochondrial homeostasis, increasing PGC-1α, TFAM, and Mfn2 expression, mitochondrial membrane potential and ATP levels, and decreasing Drp1 expression. These mitochondrial improvements were reversed by compound C.
    Conclusion: HUCMSCs ameliorate diabetic neuropathic pain primarily through activation of the TRPV1-[Ca2+]i-AMPK signaling pathway in SCs, which may provide a new molecular target for enhancing the clinical therapeutic effect of HUCMSCs on DPN.
    Keywords:  AMPK; TRPV1; diabetic peripheral neuropathy; human umbilical cord mesenchymal stem cells; intracellular calcium; mitochondrial dynamics
    DOI:  https://doi.org/10.1155/sci/5533136
  42. Biomacromolecules. 2025 Dec 01.
    Butyrate-Modified Hyaluronic Acid Ameliorates MPTP-Induced Parkinson's Disease via Modulating PINK1/Parkin-Involved Mitophagy and Intestinal Flora.
    Yu Sun, Li Cui, Wanqiu Peng, Rong Chen, Xueneng Guan, Jiangyun Liu.
      Parkinson's disease (PD) is difficult to treat clinically and lacks an effective treatment. The aim of this study was to synthesize and characterize butyrate-modified hyaluronic acid (HA-But), validate its therapeutic efficacy, and elucidate its mechanisms of action in PD. Behavioral tests, including the open field test, Y-maze, and elevated plus maze test, demonstrated that HA-But significantly alleviated motor dysfunction in PD mice. ELISA results indicated a marked reduction in pro-inflammatory cytokine levels following the HA-But treatment. In addition, immunohistochemistry, immunofluorescence, and Western blot analyses revealed that HA-But improved dopaminergic neuron survival and reduced α-synuclein aggregation. Furthermore, HA-But activated PINK1/Parkin-mediated mitophagy, modulated gut microbiota composition, and increased short-chain fatty acid (SCFA) levels, especially butyric acid. Combining HA-But with gastrodin further improved the PD symptoms in mice. These findings suggested the potential of HA-But as a novel approach for PD treatment.
    DOI:  https://doi.org/10.1021/acs.biomac.5c00967
  43. Eur J Med Res. 2025 Dec 03. 30(1): 1209
    Mitochondrial dynamics and function in neural differentiation: a systematic review.
    Arman Armat, Arash Pooladi, Seyedeh Asrin Seyedoshohadaei, Borhan Moradveisi, Maedeh Khanyabzadeh, Shaho Badri, Ramyar Rahimi Darehbagh.
       BACKGROUND: Mitochondrial function has emerged as a critical regulator of neural differentiation, yet a comprehensive understanding of its diverse roles and temporal dynamics remains elusive. This systematic review synthesizes current evidence regarding mitochondrial contributions to neural stem cell differentiation and their implications for neurodevelopmental disorders.
    METHODS: A systematic search was conducted across PubMed, Web of Science, and Scopus databases from inception to January 2025. Studies investigating mitochondrial properties during neural differentiation were included. Data extraction focused on temporal changes in mitochondrial function, molecular mechanisms, and pathological implications. Quality assessment was performed using modified SYRCLE criteria.
    RESULTS: Analysis of 50 studies revealed distinct temporal patterns of mitochondrial regulation during neural differentiation. Early stages (days 0-3) showed predominant mitochondrial fragmentation and elevated ROS levels, while intermediate stages (days 4-7) demonstrated a shift toward oxidative phosphorylation with increased fusion events. Late-stage differentiation (beyond day 7) exhibited mature mitochondrial networks and stable bioenergetic profiles. The key molecular mechanisms included calcium signaling, Wnt/β-catenin pathway activation, and dynamic regulation of fusion/fission proteins. Mitochondrial dysfunction was consistently associated with impaired neural differentiation across multiple neurodevelopmental disorders.
    CONCLUSIONS: Mitochondrial regulation of neural differentiation involves stage-specific changes in morphology, metabolism, and signaling functions. The identification of key molecular pathways provides promising therapeutic targets for neurodevelopmental disorders. Future research should focus on standardizing assessment methods, understanding tissue-specific regulation, and developing targeted interventions for clinical applications. These findings highlight the therapeutic potential of mitochondrial-targeted approaches in treating neurodevelopmental disorders and advancing regenerative medicine strategies.
    Keywords:  Mitochondria; Mitochondrial dynamics; Neural differentiation; Neural stem cells; Neurodevelopment; Systematic review
    DOI:  https://doi.org/10.1186/s40001-025-03478-3
  44. Acupunct Med. 2025 Dec 01. 9645284251399240
    Electroacupuncture promotes functional recovery and activates energy metabolism in a rat model of sciatic nerve injury.
    Jian-Lan Wang, Lin An, Xiao-Hong Du, Ming Lu, Wei Qu, Shuang Zhang, Yu-Xuan Wu.
       BACKGROUND: Electroacupuncture (EA) accelerates repair of peripheral nerve injury. The aim of this study was to explore how EA regulates energy metabolism by examining its effects on glucose transport and mitochondrial dynamic balance in a rat model of sciatic nerve injury.
    METHODS: In experiment 1, expression of glucose transporter (GLUT)4 was measured in n = 16 rats at 1, 3, 5 and 7 days following EA to identify the optimal glucose uptake time. In experiment 2, n = 32 rats were randomly divided into the following four groups: Normal, Injury, EA and ES (electrical stimulation). Three days after sciatic nerve injury modeling, micro-positron emission tomography/computed tomography (PET/CT) was performed to observe glucose uptake in the sciatic nerve and surrounding tissues. After 1 week, we measured nerve conduction velocity and expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), mitofusin (Mfn)1/2 and dynamin-related protein (Drp)1 in the sciatic nerve (by Western blotting) and observed pathological changes in the sciatic nerve and gastrocnemius.
    RESULTS: Protein expression levels of GLUT4, Mfn1/2 and Drp1 were significantly higher in the EA group, and histopathological changes were improved, compared with other groups. Glucose uptake by micro-PET/CT in the target area in the EA group was significantly higher than that in the other groups. Furthermore, nerve conduction velocity and NGF/BDNF expression was significantly higher in the EA group compared with the other three groups.
    CONCLUSION: EA accelerated the repair and regeneration of the injured sciatic nerve, activated glucose transport and improved mitochondrial dynamic balance, in a rat model.
    Keywords:  electroacupuncture; energy metabolism; glucose transport; mitochondrial dynamics; nerve repair
    DOI:  https://doi.org/10.1177/09645284251399240
  45. Eur J Med Res. 2025 Dec 02.
    Mitochondrial immunometabolism in sepsis: orchestrating macrophage polarization and dysfunction.
    Ke Yang, Qiang Zhao, Youhan Sun, Li Lin, Xiao Han.
      Sepsis is a life-threatening condition marked by dysregulated immune responses and organ dysfunction, with macrophages playing central roles in both hyperinflammation and immunosuppression. Recent advances highlight mitochondrial metabolism as a key regulator of macrophage polarization and function. Pro-inflammatory M1 macrophages rely on glycolysis and produce high levels of reactive oxygen species (ROS) and cytokines, while reparative M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Mitochondrial dysfunction-characterized by excessive mitochondrial ROS (mtROS), impaired mitophagy, and disrupted fission/fusion dynamics-exacerbates immune dysregulation and tissue injury. Organ-specific macrophage metabolic reprogramming further influences sepsis pathology, particularly in the kidney, lung, and heart. Therapeutic strategies targeting mitochondrial pathways-such as small-molecule modulators, stem cell-derived extracellular vesicles, and RNA-based gene therapies-have shown promise in restoring macrophage homeostasis and improving outcomes. This review underscores the importance of immunometabolic regulation in sepsis and advocates for mitochondria-targeted interventions as a novel precision approach to immune modulation.
    Keywords:  Immunometabolism; Macrophage polarization; Mitochondrial dysfunction; Mitophagy; Sepsis
    DOI:  https://doi.org/10.1186/s40001-025-03590-4
  46. Cell Metab. 2025 Dec 02. pii: S1550-4131(25)00489-9. [Epub ahead of print]37(12): 2298-2300
    Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.
    Sébastien Ibanez, Olivier Feron.
      Cancer cells experience multiple stresses within tumors, stemming from elevated metabolic activity, including nutrient shortage, waste buildup, hypoxia, and acidosis. According to Groessl et al.,1 acidosis is the dominant environmental factor offering metabolic flexibility to support tumor fitness and resilience to the other stresses by promoting mitochondria fusion and enhancing respiration capacity.
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.005
  47. CNS Neurosci Ther. 2025 Dec;31(12): e70682
    DL-3-n-Butylphthalide Protects Mitochondria Against Ischemia/Hypoxia Damage via Suppressing GCN5L1-Mediated Drp1 Acetylation in Neurons and Mouse Brains.
    Haitao Zhang, Ning Zhang, Xiaotong Yang, Jiejie Zhang, Xiaoli Ge, Lei Wang, Shan Wang, Ya Wen.
       BACKGROUND: Mitochondrial dysfunction is an initial event of the cascade reactions triggered by ischemic stroke, contributing to the pathogenesis of ischemic brain injury. DL-3-n-butylphthalide (NBP), a compound originally isolated from the seeds of Apium graveolens Linn, exerts neuroprotective effects by improving mitochondrial function in ischemic brain tissues; however, the exact molecular mechanisms underlying its action remain poorly understood.
    METHODS: The OGD-exposed neuronal cells and dMCAO mice were used to investigate the effects of ischemia/hypoxia on mitochondrial function and the protective action of NBP on mitochondrial damage. Co-immunoprecipitation and immunofluorescence staining were performed to identify the interaction between Drp1 and GCN5L1. Western blotting, immunofluorescence and immunohistochemical staining were conducted to detect the expression of GCN5L1, Drp1, ERK1/2, Bax, Bcl2, and caspase-3. The mitochondrial function was analyzed by measuring mitochondrial ROS, ATP production, mitochondrial membrane potential (MMP) and mPTP opening.
    RESULTS: We observed that mitochondrial dysfunction occurs in OGD-treated neuronal cells and brain tissues of dMCAO mice, as evidenced by the alteration in the mPTP, MMP, ATP content, and ROS levels, which are accompanied by a significant increase in mitochondrial fission and neuronal apoptosis, as shown by TUNEL staining and the changes in Bcl-2, Bax and caspase-3 expression. Importantly, NBP intervention significantly attenuates ischemia/hypoxia-induced mitochondrial dysfunction and cellular apoptosis in the neuron and mouse brains. Mechanistically, NBP not only reverses the upregulation of Drp1 and GCN5L1 expression by ischemia/hypoxia, but also inhibits the ischemia/hypoxia-induced phosphorylation of Drp1 by blocking the ERK1/2 signaling, which in turn suppresses the interaction between Drp1 and GCN5L1, thereby decreasing Drp1 acetylation by GCN5L1 and excessive mitochondrial fission.
    CONCLUSION: Our findings provide a novel insight into the molecular mechanism whereby NBP protects mitochondria against ischemia/hypoxia damage, offering a promising drug for mitochondria-targeting therapeutics for ischemic stroke.
    Keywords:  DL‐3‐n‐butylphthalide; Drp1; GCN5L1; ischemic stroke; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/cns.70682
  48. Mil Med Res. 2025 Dec 01. 12(1): 83
    β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition.
    Xiao-Xu Wang, Wei-Jie Zhong, Jie-Mei Li, Di Wang, Shuang-Qin Chen, Jin-Hua Miao, Wei-Wei Shen, Xiao-Long Li, Jie-Wu Huang, Shan Zhou, Cheng Wang, Jun Ai, Li-Li Zhou.
       BACKGROUND: Peritoneal fibrosis represents a major clinical challenge for end-stage renal disease (ESRD) patients when they are undergoing peritoneal dialysis (PD). Single-cell RNA sequencing identified that peritoneal mesothelial cells undergo a senescence fate transition in long-term PD patients. Whereas the existence of mesothelial cell senescence and the underlying mechanisms should be thoroughly explored.
    METHODS: To further investigate mesothelial cell senescence, we utilized a clinical cohort comprising dialysate effluents from PD patients and peritoneal biopsy specimens, peritoneal dialysis fluid (PDF)-induced mouse models, and cultured primary mesothelial cells. Single-cell RNA sequencing, transcriptome sequencing, immunofluorescence, Western blotting, and other analyses were administered. To validate the critical role of β-catenin in mesothelial cell senescence, β-catenin knockout mice were employed. Additionally, the senolytic drugs dasatinib plus quercetin were administered to PDF mice to assess the key role of mesothelial cell senescence in peritoneal fibrosis.
    RESULTS: Single-cell RNA sequencing demonstrated that mesothelial cells derived from long-term PD patients are major trend to senescence fate. Moreover, β-catenin signaling was significantly upregulated, as well as transforming growth factor-β (TGF-β) pathways. We observed that senescent mesothelial cells were highly increased in both dialysate effluent and peritoneal biopsies of long-term PD patients. In dialysate effluent, matrix metalloproteinase-7 (MMP-7), an indicator of downstream targets of β-catenin, was positively correlated with TGF-β1. Both biomarkers were also positively associated with PD duration. Mechanistically, we found that β-catenin promotes dynamin-related protein 1 (Drp1) expression, a key mediator of mitochondrial fission, thereby inducing mesothelial cell senescence. Then, TGF-β1 was secreted to activate the Smad signaling pathway in fibroblasts, leading to myofibroblast activation and subsequent peritoneal fibrosis. Notably, administration of senolytic drugs, dasatinib plus quercetin, significantly alleviated peritoneal fibrosis regardless of treatment timing.
    CONCLUSION: Targeting β-catenin signaling and mesothelial cell senescence may represent potential therapeutic interventions for preventing peritoneal fibrosis.
    Keywords:  Fibroblast; Mesothelial cell; Peritoneal dialysis (PD); Peritoneal fibrosis; Senescence; β-catenin
    DOI:  https://doi.org/10.1186/s40779-025-00669-1
  49. PLoS Biol. 2025 Dec 04. 23(12): e3003523
    Control of mitochondrial dynamics by the metabolic regulator dPGC1 limits Yorkie-induced oncogenic growth in Drosophila.
    Wei Qi Guinevere Sew, Maria Molano-Fernández, Zhiquan Li, Artim Lange, Nahia Pérez de Ciriza, Lene Juel Rasmussen, Hector Herranz.
      Mitochondrial function and dynamics are essential for maintaining cellular homeostasis and overall health. Disruptions in these processes can contribute to various diseases, including cancer. The Hippo signaling pathway, a key regulator of tissue growth, plays a central role in cancer through its main effector, the Yes-associated protein (YAP), known as Yorkie (Yki) in Drosophila. In this model organism, Yki upregulation drives benign tissue overgrowth in imaginal discs. Our research demonstrates that the conserved metabolic regulator dPGC1 restricts Yki-driven tissue hyperplasia and helps maintain epithelial integrity in vivo. Combined Yki upregulation and dPGC1 depletion results in tumors characterized by enlarged mitochondria and the upregulation of genes promoting mitochondrial fusion, a condition that is both necessary and sufficient for Yki-driven oncogenic growth. We further demonstrate that mitochondrial enlargement is associated with increased levels of the cell cycle regulator Cyclin E, which plays a critical role in tumor development. These findings identify dPGC1 as a context-dependent tumor suppressor that coordinates mitochondrial dynamics and cell cycle regulation in response to oncogene activation, with implications for understanding cancer development in humans.
    DOI:  https://doi.org/10.1371/journal.pbio.3003523
  50. bioRxiv. 2025 Nov 19. pii: 2025.11.19.688750. [Epub ahead of print]
    Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
    Young-Seung Lee, Hee Soo Kim, Phuc L Nguyen, Junhyeong Lee, Dong-Il Kim, Jeongmin Lee, Changjong Moon, Kyoung-Oh Cho, Byung-Eun Kim, Jiyun Ahn, Timothy F Osborne, Taner Duysak, Jeong-Sun Kim, Chang Hwa Jung, Tae-Il Jeon.
      Copper is an essential trace element required for mitochondrial respiration and cellular metabolism, yet its role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice leads to copper deficiency, resulting in exercise intolerance, metabolic dysfunction, and hallmarks of mitochondrial myopathy, including ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Copper deficiency disrupted electron transport chain proteome and induced mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator of mitochondrial copper distribution and morphology. Restoring copper levels via the copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings highlight MTCH2 as a key mediator of a critical link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.
    DOI:  https://doi.org/10.1101/2025.11.19.688750
  51. Adv Sci (Weinh). 2025 Dec 03. e08742
    Procyanidin Capsules Combat ALF by Restoring Mitochondrial Homeostasis and Inhibiting Necroptosis via the PGAM5/DRP1/PINK1 Pathway.
    Qing Shi, Minmin Wu, Jinwei Zhong, Chao Chen, Zhuang Huang, Jingxuan Peng, Dong Yang, Xingjie Zan, Zhengfei Wang.
      Acute liver failure (ALF) is a life-threatening, multifactorial condition characterized by rapid progression, extensive hepatocellular necrosis, and high mortality rates. Current therapeutic options, including artificial liver support systems (ALSS) and liver transplantation, are limited by high costs, donor shortages, and insufficient efficacy. Mitochondrial dysfunction and necrotic cell death play central roles in both acute and chronic liver injury; however, their contribution to ALF remains poorly understood. In this study, self-assembled procyanidin capsules (PC-Ca) are developed with sustained antioxidant and anti-inflammatory properties that selectively accumulate in the liver of an ALF model. These findings demonstrate that PC-Ca significantly improves survival rates and more effectively mitigates liver injury, inflammation, and necrosis in thioacetamide (TAA)-induced ALF in mice and rabbits than the standard clinical agent, N-acetylcysteine (NAC). This protective effect is mediated through enhanced oxidative stress defense via activation of the KEAP1-NRF2 axis and inhibition of necroptosis via the RIPK1/RIPK3/MLKL pathway. In addition, PC-Ca preserves mitochondrial morphology and function via the PGAM5/DRP1/PINK1 pathway, offering hepatoprotection. These findings suggest that PC-Ca represents a promising therapeutic strategy for ALF, with the modulation of mitochondrial homeostasis offering valuable insights for the development of next-generation pharmacological interventions.
    Keywords:  PGAM5/DRP1/PINK1; acute liver failure; mitochondrial homeostasis; necroptosis; procyanidin capsules
    DOI:  https://doi.org/10.1002/advs.202508742
  52. Langmuir. 2025 Dec 05.
    Cu-Fe3O4 Nanozyme Reverses Age-Impaired Alveolar Healing via Reactive Oxygen-Nitrogen Species Scavenging and Mitophagy Reactivation.
    Zheng Cheng, Jikang Cao, Haobo Lin, Yuchen Wang, Ran Qin, Yuhao Ruan, Xinyu Hu, Jingxuan Cang, Chang Sun, Dong Qiu, Yifeng Bian, Yifei Du, Yongchu Pan.
      Age-related decline in bone healing capacity poses significant challenges for tooth extraction recovery in the elderly. Elevated reactive oxygen-nitrogen species (RONS) and impaired mitophagy drive this pathology. We engineered bimetallic Cu-Fe3O4 nanoclusters with oxygen vacancies (OVs) via hydrothermal synthesis. The abundant oxygen vacancies and bimetallic synergy endow Cu-Fe3O4 with exceptional enzyme-mimicking activity, enabling efficient scavenging of excess RONS and activation of mitophagy in senescent cells in vitro, thereby reversing functional decline. Owing to its excellent biocompatibility and negligible in vivo toxicity, Cu-Fe3O4 accelerates tooth extraction wound healing in aged animal models.
    DOI:  https://doi.org/10.1021/acs.langmuir.5c04365
  53. Naunyn Schmiedebergs Arch Pharmacol. 2025 Dec 06.
    Biocompatible hydrogel eradicates pregnancy-associated genital warts.
    Zhaohui Yang, Zian Cai, Taiquan Lv, Yongquan Pan, Liangzhi Wu, Xiaoyong Zhao, Xiaoli Zhang.
      Current treatments for pregnancy-associated genital warts (PGW) often fail to balance safety and efficacy, especially during gestation. In this study, we introduce GelPV-5-ALA-Matrine, a smart, photoresponsive hydrogel designed for localized photodynamic therapy (PDT) targeting HPV-infected tissues. Co-delivery of 5-ALA and matrine facilitates mitochondrial autophagy through reactive oxygen species (ROS) elevation and MAPK8 activation. Using Mendelian randomization, we identified mitochondrial DNA copy number as a risk factor for sexually transmitted infections, supporting mitochondrial pathways as viable therapeutic targets. The hydrogel demonstrated strong in vitro efficacy in HPV-positive HeLa cells and significantly reduced wart burden and viral load in vivo under near-infrared (NIR) light. Molecular docking and functional validation highlighted MAPK8's key role in mediating ROS-induced mitochondrial clearance and apoptosis. Importantly, no systemic toxicity or adverse biochemical responses were observed. This innovative hydrogel system provides a blueprint for next-generation, patient-safe therapies for PGW and may be adaptable to other HPV-related pathologies in reproductive health.
    Keywords:  MAPK8 signaling; Mitochondrial autophagy; Photodynamic therapy; Photosensitive hydrogel; Pregnancy-associated warts
    DOI:  https://doi.org/10.1007/s00210-025-04552-7
  54. Mol Neurobiol. 2025 Dec 04. 63(1): 248
    Coenzyme Q10 Ameliorates Fibromyalgia-like Symptoms and Cognitive Deficits by Enhancing Hippocampal PGC-1α/FNDC5/BDNF Pathway in Reserpine-Treated Rats.
    Muaz Belviranlı, Nilsel Okudan, Tuğba Sezer.
      This study investigated the effects of coenzyme Q10 (CoQ10) administration on fibromyalgia (FM) symptoms and cognitive functions in a reserpine-induced FM model. It is also aimed to evaluate the role of the PGC-1α/FNDC5/BDNF pathway and oxidative stress in this process. Female Wistar rats were randomly assigned to control, FM, CoQ10, and FM + CoQ10 groups. The FM groups received daily subcutaneous reserpine (1 mg kg-1) for three consecutive days. The CoQ10 groups were administered 150 mg kg-1 of oral CoQ10 for 7 days. Behavioral and sensory assessments were conducted on days 0, 4, and 6. Mechanical allodynia was measured with the Von Frey test, while depressive-like behavior was assessed using the forced swim test. Locomotor activity and anxiety levels were evaluated via the elevated plus maze, and learning/memory performance were tested using the Morris water maze probe test. Reserpine exposure led to increased mechanical allodynia, decreased locomotor activity, elevated anxiety levels, increased depressive-like behavior, and impaired learning/memory (p < 0.05). These behavioral abnormalities were accompanied by decreased hippocampal levels of CoQ9 and CoQ10, increased oxidative stress, and reduced antioxidant defenses (p < 0.05). Additionally, hippocampal PGC-1α, FNDC5 and BDNF expression levels were reduced (p < 0.05). CoQ10 treatment resulted in significant improvements in these neuropathological parameters (p < 0.05). These results imply that CoQ10 can counteract the behavioral, biochemical, and molecular disturbances characteristic of FM. The mechanism is suggested to involve stimulating the PGC-1α/FNDC5/BDNF cascade, which in turn reduces behavioral deficits linked to pain, depression, and cognitive function.
    Keywords:  Coenzyme Q10; FNDC5; Fibromyalgia; Mitochondrial biogenesis; Reserpine
    DOI:  https://doi.org/10.1007/s12035-025-05585-y
  55. Front Cell Dev Biol. 2025 ;13 1701406
    Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.
    Jia-Xuan Huai, E-E Chang, Yi-Ran Zhu, Wen-Ling Ma, Tian-Su Lv, Jing Sun, Xi-Qiao Zhou.
      Diabetic encephalopathy (DE) is a serious neurological complication of diabetes and is expressed as progressive decline in cognitive function, emotional disorders, and changes in brain structure. This review brings together the relevant evidence and demonstrates that metabolic reprogramming, the adaptive reconfiguration of the core metabolic pathway in response to hyperglycemia, is a potential driver of accelerated brain aging in DE. The main pathological characteristics are: abnormal brain insulin signaling, resulting in a decrease in neuronal glucose intake and a decrease in mitochondrial oxidative phosphorylation, oxidative stress and neuroinflammation caused by high blood sugar, in which excess reactive oxygen species (ROS), impairs mitochondrial integrity and leads to activation of microglia cells. The impaired mitophagy and the macrophages remove defects and cause the accumulation and energy collapse of the dysfunctional organelles. In addition, it promotes excessive glycolytic flux, lipolysis disorder, lactic acid accumulation, and ceramide-dependent synaptic damage. We further examine shared metabolic mechanisms between DE and neurodegenerative diseases such as alzheimer's disease (AD) and treatment strategies for pathological metabolic reprogramming including GLP-1 receptor agonists, NAD+ boosters, and AMPK activators. This analysis laid the foundation for new intervention measures against the development of DE.
    Keywords:  GLP-1 receptor agonists; NAD⁺ boosters; brain insulin resistance; diabetic encephalopathy; glycolytic flux; metabolic reprogramming; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2025.1701406
  56. Can J Cardiol. 2025 Dec 02. pii: S0828-282X(25)01556-9. [Epub ahead of print]
    Fontan Circulation Beyond Preload: Metabolic Pathways and Mitochondrial Stress.
    Ashish H Shah.
      
    Keywords:  Fontan circulation; mitochondrial dysfunction; multi-omics
    DOI:  https://doi.org/10.1016/j.cjca.2025.11.046
  57. J Ethnopharmacol. 2025 Dec 02. pii: S0378-8741(25)01689-7. [Epub ahead of print] 120997
    Xiangsha Liujunzi Decoction restores mitochondrial function and ameliorates chronic ulcerative colitis by regulating the PI3K/AKT/Nrf2 and AMPK/SIRT1/PGC-1α signaling pathways.
    Qi Xu, Sirui Xiang, Qin Jian, Chuchu Wang, Rongrong Wang, Longcheng He, Junzhi Lin, Jiahui Yang, Ruli Li, Chuan Zheng.
       ETHNOPHARMACOLOGICAL RELEVANCE: Xiangsha Liujunzi Decoction (XS) is a classical formula traditionally employed to invigorate the spleen and treat digestive system disorders. Although XS has a therapeutic effect on chronic ulcerative colitis (UC) in clinical practice, the mechanism remains unclear.
    AIM OF THE STUDY: To investigate the therapeutic effects and underlying mechanisms of XS on dextran sodium sulfate (DSS)-induced chronic UC in mice and the LPS-induced RAW264.7 cell inflammation model.
    MATERIALS AND METHODS: The chemical components of XS were identified using UPLC-Q-Orbitrap HRMS. The chronic UC mouse model and LPS-induced RAW264.7 cell inflammation model were established and treated with XS. Body weight, disease activity index (DAI), colon length, colitis macroscopic damage index (CMDI), and histopathology changes in colonic tissues were assessed. The mRNA expression of inflammatory factors (IL-6, IL-1β, and TNF-α) in mice and cells was measured by qRT-PCR, while the expression of occludin and ZO-1 proteins and mRNAs in colonic tissue was detected by Western Blot (WB) and qRT-PCR. Transmission electron microscopy was used to observe the mitochondrial ultrastructure in colonic tissue. Cell viability was determined using the CCK-8 assay. Changes in reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured by flow cytometry. A PI3K inhibitor (LY294002) and an AMPK inhibitor (M2238) were employed to confirm the specificity of the cellular signaling pathways. Molecular docking was performed to validate the binding ability between the active compound and the targets.
    RESULTS: We identified 50 compounds in XS, mainly flavonoids and organic acids. In the chronic UC mouse model, XS alleviated weight loss, reduced DAI scores, increased colon length, and improved colonic mucosal and pathological changes; inhibited the mRNA expression of inflammatory factors (IL-6, IL-1β, TNF-α); and significantly increased the mRNA and protein expression of tight-junction proteins occludin and ZO-1 to reduce intestinal inflammation and protect the integrity of the colonic epithelial barrier. In vitro experiments showed that XS dose-dependently reduced the inflammatory response in LPS-induced RAW264.7 cells by inhibiting the expression of IL-6, IL-1β, and TNF-α, reducing ROS levels, restoring MMP, and improving mitochondrial function. Mechanistic studies showed that XS activated PI3K and AKT phosphorylation, upregulated Nrf2 and HO-1 expression, and reduced oxidative stress damage. XS promoted AMPK phosphorylation in the mitochondrial biogenesis pathway, increased the protein expression of SIRT1 and PGC-1α, and upregulated the expression of NRF1 and TFAM. The involvement of both pathways was confirmed in vivo and in vitro experiments, with inhibitor studies further validating the results in vitro experiments.
    CONCLUSIONS: XS mitigates chronic UC by decreasing ROS levels and inhibiting the macrophage inflammatory response by regulating the PI3K/AKT/Nrf2 and AMPK/SIRT1/PGC-1α signaling pathways.
    Keywords:  Chronic Ulcerative Colitis; Mitochondrial Biogenesis; Mitochondrial Function; Oxidative Stress; Xiangsha Liujunzi Decoction
    DOI:  https://doi.org/10.1016/j.jep.2025.120997
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