bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–12–14
eighty papers selected by
Gavin McStay, Liverpool John Moores University
  1. Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.
  2. Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.
  3. Association of thymoquinone-induced changes in PINK1, DRP1, TFEB, and cytochrome c expression with mitochondrial dynamics and apoptosis in HepG2 and HDF cells.
  4. Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.
  5. Mitochondrial Dynamics in Neurodegenerative Diseases: Research Hotspots and Trends from 2005 to 2025.
  6. Commentary: Hyperoside alleviates myocardial ischemia-reperfusion injury in heart transplantation by promoting mitochondrial fusion via activating the Stat3-Tom70-Opa1 pathway.
  7. Reprogramming mitochondrial homeostasis in renal ischemia-reperfusion injury.
  8. The role of Drp1-Pink1-Parkin mediated mitophagy in cisplatin-induced damage to primary cochlear SV pericytes.
  9. Exercise regulates mitophagy to alleviate parkinsonian neurodegeneration.
  10. Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
  11. Targeting endothelial mitochondrial dynamics in glaucoma: A novel therapeutic opportunity.
  12. Isorhamnetin attenuates lipopolysaccharide-induced myocardial inflammatory injury by inhibiting PPARγ and preserving mitochondrial homeostasis.
  13. Exosomal delivery of GrpE-like 1 from synovial mesenchymal stem cells activates PINK1-mediated mitophagy for cartilage repair in osteoarthritis.
  14. Therapeutic Modulation of Mitophagy by Cafestol in Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis.
  15. ZC3H13-mediated m6a methylation mitigates endothelial injury in venous thrombosis by inhibiting elevated mitochondrial fission.
  16. Mitochondria-specific targeting of noncanonical EGR1 ntmRNA-coordinated mitophagy receptor BNIP3 homodimerization disrupts mitochondrial metabolism and suppresses hepatocellular carcinoma growth in vitro and in vivo.
  17. Involvement of mitochondrial unfolded protein response and activating transcription factor 4 in the mitochondrial damage pathway of BEAS-2B cells induced by cigarette smoke extracts.
  18. Targeting mitochondria to protect the heart: a matter of balance?
  19. Identification of an uncharacterized gene as a mitochondrial methionine tRNA-synthetase in Caenorhabditis elegans.
  20. Protective Effect of SESN2 on Glutamate Neurotoxicity via Keap1-Nrf2 Pathway-Mediated Mitophagy.
  21. ESRRA-ATG5-Mediated mitophagy enhances arginine metabolism to alleviate diabetic kidney disease.
  22. Mitophagy in Botulinum Toxin Type A-Induced Muscle Atrophy.
  23. Antiretroviral Drugs Impact Autophagy Differently in Primary Human Astrocytes.
  24. The toxic effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming are associated with impaired mitochondrial dynamics balance.
  25. SIRT6-Mediated Regulation of TFAM: A Central Mechanism Connecting Nuclear and Mitochondrial Transcriptional Processes and Mitophagy.
  26. Autophagy and Mitophagy in Diabetic Retinopathy: The Effects and Mechanism of Action on the Neurovascular Unit.
  27. Liproxstatin-1 Protects SH-SY5Y Cells by Inhibiting H2O2-Induced Excessive Mitophagy and Apoptosis.
  28. Fisetin carbon dots alleviate periodontitis by enhancing mitophagy through regulation of sirtuin 3 SUMOylation.
  29. Cinnamaldehyde suppresses ovarian cancer progression by activating ROS-mediated apoptosis and mitophagy.
  30. Alleviating the Toxic Effects of Nitrite: Histidine Mitigates Hepatopancreas Damage by Suppressing Ferroptosis and Enhancing Mitochondrial Quality Control.
  31. Impairment of mitochondrial quality control exacerbates diabetes-related atrial fibrillation by cGAS-STING signaling pathway and cardiomyocyte-macrophage crosstalk.
  32. Dysregulated mitochondrial dynamics in cancer: Unlocking new strategies to combat drug resistance.
  33. Swietenine attenuates renal tubular injury by activating mitophagy in diabetic nephropathy.
  34. Overexpression of PRDX2 alleviates chronic thromboembolic pulmonary hypertension by modulating inflammation and mitophagy.
  35. MARCH5-mediated MIEF2 ubiquitination and degradation contribute to gigantol to against hepatic steatosis and mitochondrial fission in alcoholic liver disease.
  36. Corrigendum to "Kaempferol ameliorates BMSCs senescence in postmenopausal osteoporosis by targeting Sp1 to activate FUNDC1-mediated mitophagy" [Phytomedicine 148 (2025) 157456].
  37. Ion channels and atrial fibrillation: mitophagy as a key mediator.
  38. KDM6B induces demethylation of H3K27me3 in MFN1 to modulate aberrant mitophagy in sepsis-induced acute lung injury.
  39. Role of Acetaldehyde and Dysregulated Mitophagic Lysosomal Processing in Chronic-Binge Ethanol-Induced Liver Injury.
  40. PINK1/Parkin promotes liver regeneration via Sigma-1 ubiquitination to inhibit ER-Mitochondrial calcium transfer.
  41. Ubiquitin-specific protease 14 inhibition promotes mitophagy and attenuates neural apoptosis after spinal cord injury.
  42. Callunene, mitophagy, and flagellum removal in trypanosomatids.
  43. Piezo1-driven mechanotransduction regulates mitochondrial biogenesis by AMPK/SIRT1-mediated PGC-1α deacetylation to ameliorate bone loss in disuse osteoporosis.
  44. β-Cell Mitochondrial Dysfunction: Underlying Mechanisms and Potential Therapeutic Strategies.
  45. The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
  46. The role of mitophagy during hematopoiesis in an invertebrate, Pacifastacus leniusculus.
  47. Berberine Suppresses Pathogenic Fungus Aspergillus fumigatus Hyphal Growth via Mitochondrial Fragmentation-Induced ROS Elevation and Hog1-MAPK Activation.
  48. Modulatory Potential of Alpinetin on Inflammation, Oxidative Stress, Apoptosis, and Mitochondrial Dynamics in a Rat Middle Cerebral Artery Occlusion Model of Ischemic Stroke.
  49. Mitochondrial AAA+ protease activity uncovers differential sensitivity of Drosophila blood cell lineages to systemic cues.
  50. Astrocyte S1P1 regulates mitochondrial autophagy in inflammation and neuronal injury after epilepsy.
  51. Based on the PINK1/Parkin signaling pathway, the protective effect of salidroside on cerebral ischemia-reperfusion injury in male rats was investigated.
  52. Lobetyolin alleviates microglial inflammation by activating CK2α/Opa1-mediated mitochondrial fusion in ischemic stroke.
  53. Agomelatine alleviates hypoxia-induced pulmonary arterial hypertension by activating mitophagy via the SIRT1/FoxO1/ULK1 signaling pathway.
  54. Ferroptosis, autophagy, and mitochondrial dynamics: Front burners in cancer therapeutics.
  55. Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis.
  56. An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial import.
  57. RETRACTION: Melatonin Modulates Mitophagy, Innate Immunity and Circadian Clocks in a Model of Viral-Induced Fulminant Hepatic Failure.
  58. The transcription factor ANAC017 links mitochondrial retrograde signaling with the ubiquitin-proteasome system to control mitochondrial function in Arabidopsis.
  59. High matrix stiffness triggers the YAP-OPA1-TET1/3 loop to drive chemoresistance via enhanced nuclear-mitochondrial communication.
  60. Functional identification of two variants in unrelated Chinese patients with DNM1L-related mitochondrial disorders.
  61. Haematococcus pluvialis ameliorates renal fibrosis by restoring mitophagy via PINK1-Parkin-p62-LC3 signaling.
  62. Sini-Suanzaoren decoction regulates mitochondrial biogenesis mediated by MT-SIRT1 in the treatment of insomnia rats.
  63. Autophagy and mitophagy in dermatological disease: a comprehensive review from molecular pathways to therapeutic frontiers.
  64. S-Nitrosylation of Pyruvate Kinase Isoform 2 Drives Cardiac Fibrosis by Promoting Mitochondrial Fission.
  65. The role and mechanism of asiaticoside in regulating smooth muscle cell mitochondrial Drp1 during neointimal hyperplasia and atherosclerosis.
  66. A Bibliometric Analysis of Research Progress on Age-Related Macular Degeneration and Autophagy From 2010 to 2024.
  67. Songorine inhibits mitophagy in chronic heart failure via the TBC1D15/Fis1/Rab7A pathway.
  68. Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.
  69. cAMP-MFN2 signaling suppresses cochlear cell senescence and age-related hearing loss.
  70. Soluble guanylate cyclase stimulator vericiguat alleviates skeletal muscle injury and exercise capacity decline in ApoE-/- mice by inhibiting oxidative stress and repairing mitophagy.
  71. Decreased OPA1 Expression Increases Neuronal Vulnerability to Ischaemic Stroke during Ageing: Role of Timm8b as a Therapeutic Target.
  72. Disruption of Mitochondrial Dynamics and Integrity Drives Divergent Metabolic Flexibility and Resilience in Podocytes.
  73. Microbial Metabolite, Macro Impact: Urolithin A in the Nexus of Insulin Resistance and Colorectal Tumorigenesis.
  74. Imbalance in MICOS Proteins in Rat Liver Mitochondria in an Induced Hyperthyroidism Model.
  75. The Potential of Ectoine as a Brain Anti-Aging Agent in Rat Model of D-Galactose-Accelerated Aging May Be Mediated Through Crosstalk Between Redox/Mitochondrial Homeostasis/Autophagic/Apoptotic Pathways.
  76. A mitochondria-related gene-based signature predicts pancreatic ductal adenocarcinoma clinical outcome and revealed CAMK2A/THEM4 regulates progression phenotypes and mitophagy in vivo and in vitro.
  77. LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner.
  78. Cell-Free DNA and Mitochondria in Parkinson's Disease.
  79. Fat-targeted small molecule alleviates abnormal adipose tissue remodeling in obesity via SIRT3-driven mitophagy and inflammasome inhibition.
  80. Integrated bioinformatic and in vivo analysis confirms the cardioprotective role of OPA1.
  1. J Biochem. 2025 Dec 10. pii: mvaf079. [Epub ahead of print]
    Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.
    Kei Okatsu, Shuya Fukai.
      Mitochondrial quality control plays a critical role in maintaining cellular homeostasis by eliminating dysfunctional mitochondria. The PINK1/Parkin-dependent mitophagy mediates the selective clearance of damaged mitochondria. Dysfunction of PINK1 and Parkin is closely linked to Parkinson's disease. Upon mitochondrial depolarization, PINK1 accumulates on the outer membrane and phosphorylates both ubiquitin and the UBL domain of Parkin to initiate a positive feedback loop of ubiquitination. Parkin catalyzes the assembly of heterogeneous ubiquitin chains on outer mitochondrial membrane proteins, which serve as signals for autophagy adaptors. These adaptors are regulated by kinases such as TANK-binding kinase (TBK1). Deubiquitinating enzymes such as USP30 act as negative regulators. Recent structural and biochemical studies have advanced our understanding of the PINK1/Parkin-dependent mitophagy. Nonetheless, important questions remain regarding the regulatory mechanisms of PINK1, the catalytic mechanism of ubiquitin chain formation by Parkin, and the recognition of ubiquitin chains by autophagy adaptors. Here, we review the current understanding and outstanding questions on the molecular mechanisms underlying the PINK1/Parkin-dependent mitophagy with a focus on ubiquitin signaling.
    Keywords:  autophagy; kinase; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1093/jb/mvaf079
  2. Biol Open. 2025 Dec 10. pii: bio.062106. [Epub ahead of print]
    Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.
    Hilario Ruelas-Ramírez, Ariann E Mendoza-Martínez, P Abril Medina-Flores, Soledad Funes.
      Mitophagy is essential for mitochondrial quality control, selectively removing damaged or superfluous mitochondria to maintain cellular health and metabolic homeostasis. While positive regulators of mitophagy are relatively well characterized, the mechanisms governing its downregulation remain less understood. In this study, we investigate the role of Saccharomyces cerevisiae Slm35-a protein previously involved in oxidative stress response-in the regulation of mitophagy. We discovered that Slm35 is a soluble mitochondrial matrix protein and functions as a novel negative regulator of mitophagy and the mitochondrial retrograde (RTG) signaling pathway. Our results show that Slm35 modulates mitophagy through the RTG pathway, independently of Atg32 proteolytic processing by Yme1 or mitochondrial membrane potential (MMP) dissipation. Notably, Slm35 is crucial for the dynamic regulation of the RTG pathway in mitophagy-inducing conditions. These findings highlight the importance of Slm35 in fine-tuning mitochondrial quality control in response to metabolic cues and suggest a critical role for dynamic RTG pathway regulation in mitophagy control.
    Keywords:  Atg32; Mitochondria; Mitochondrial retrograde signaling; Mitophagy; Yeast
    DOI:  https://doi.org/10.1242/bio.062106
  3. Med Oncol. 2025 Dec 11. 43(1): 46
    Association of thymoquinone-induced changes in PINK1, DRP1, TFEB, and cytochrome c expression with mitochondrial dynamics and apoptosis in HepG2 and HDF cells.
    Bertan Emrah, Vural Korkut Senay.
      Healthy mitochondria and mitochondrial quality control are essential for vital cell activities. Cell health is fundamentally maintained by the coordinated regulation of processes such as mitochondrial fusion, fission, and mitophagy. Their disruption plays a role in cancer pathogenesis, as well as in many diseases. This study investigated the effects of thymoquinone (TQ), a bioactive compound from Nigella sativa, on mitochondrial dynamics and quality control in Hepatocellular Carcinoma Cells (HepG2) and Human Dermal Fibroblasts (HDF). Results from molecular techniques such as the MTT assay, colony formation assay, wound healing assay, DAPI staining, and JC-1 staining, as well as Real-Time Polymerase Chain Reaction (RT-PCR) and Western blot analysis, were evaluated. TQ treatment caused dose-dependent decreases in cell viability and migration in both cell types, according to the MTT and wound healing assay results. While nuclear morphology assessments with DAPI staining served as a parameter for apoptotic changes, JC-1 analysis revealed a significant loss of mitochondrial membrane potential (ΔΨm) in HepG2 cells, while a relatively milder decrease was observed in HDF cells. At the molecular level, TQ exposure increased Cytochrome c (Cyt c) and Transcription Factor EB (TFEB) levels in both cell lines, but Dynamin-Related Protein 1 (DRP1) upregulation was more pronounced in HDF cells. Specifically, Western blot results showed an increase in PTEN-Induced Kinase 1 (PINK1) protein in HepG2 cells, but not in HDF cells. These findings suggest that TQ can trigger the mitochondrial stress response in HepG2 cells through DRP1-dependent fission, TFEB-associated lysosomal activation, and PINK1-associated mitophagy signaling. The stronger suppression of ΔΨm and PINK1 induction in HepG2 suggests an increased likelihood of activation of the intrinsic apoptotic pathway, while the partial preservation of mitochondrial integrity in HDF cells suggests a mild adaptation to stress. Further studies on mitophagy flux, Cyt c intracellular distribution, and TFEB nuclear translocation will be needed to define the mechanisms underlying these cell-type-specific responses.
    Keywords:  Cytochrome c; DRP1; HDF; HepG2; PINK1; TFEB; Thymoquinone
    DOI:  https://doi.org/10.1007/s12032-025-03180-8
  4. J Mol Neurosci. 2025 Dec 13. 75(4): 162
    Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.
    Ga Hyun Park, Hye In Park, Donghyuk Shin, Kwang Chul Chung.
      While Parkinson's disease (PD) is predominantly sporadic, various mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been linked to the autosomal recessive form of PD. PINK1, a serine/threonine protein kinase, holds a pivotal role in mitophagy - a process that selectively eliminates damaged mitochondria, overseeing mitochondrial quality control and ultimately safeguarding against neuronal cell loss in PD. Understanding the regulation of PINK1 stability is essential in comprehending PD pathology, given its involvement in a pro-survival pathway. Although some components of the ubiquitin-proteasome system (UPS) are recognized for mediating the proteolysis of PINK1, the specific enzyme(s) responsible for positively influencing PINK1 stability have remained elusive. In this study, we demonstrated that ubiquitin-specific protease 20 (USP20) functions as a novel deubiquitinating enzyme targeting PINK1. We found that USP20 positively regulates PINK1 levels by hydrolyzing Lys 48-linked polyubiquitin chains, promoting mitophagy under the treatment of mitochondrial depolarizing agent carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Furthermore, CCCP treatment accelerates the deubiquitinating activity of USP20, facilitating the degradation of impaired mitochondria and enhancing mitochondrial quality control via PINK1 accumulation. Taken together, these findings unveil a novel enzyme, USP20, positively impacting PINK1 level and promoting CCCP-induced mitophagy. In addition, this study establishes a comprehensive map depicting how PINK1 can be regulated both positively and negatively through the coordinated action of multiple members in the UPS.
    Keywords:  CCCP; Deubiquitinating enzyme; Mitophagy; PINK1; Parkinson’s disease; USP20; Ubiquitination
    DOI:  https://doi.org/10.1007/s12031-025-02457-x
  5. Ageing Res Rev. 2025 Dec 08. pii: S1568-1637(25)00333-2. [Epub ahead of print] 102987
    Mitochondrial Dynamics in Neurodegenerative Diseases: Research Hotspots and Trends from 2005 to 2025.
    Shiliang Hu, Zhen Yang, Kaiming Bao, Wenlong Hou, Yuanyuan Qin, Chu Wu, QingMei Wang, Xun Luo, Li Luo.
       BACKGROUND: Dysregulation of mitochondrial dynamics, including fusion/fission, transport, mitophagy and biogenesis, plays a crucial role in neurodegenerative diseases. However, a systematic quantitative mapping of the knowledge structure (i.e., key research themes, foundational references, and citation/collaboration clusters) and evolving research trends (i.e., research hotspots over time) in this research field is lacking.
    METHODS: Empirical and review article on mitochondrial dynamics in neurodegenerative diseases, which published in English from 2005 to 2025, were retrieved from the Web of Science Core Collection and Scopus. BibliometriX, VOSviewer, and CiteSpace were applied to perform the bibliometric analysis and science mapping. Scientific performance analyses, collaborative networks of authors/institutions/countries, reference co-citation networks, keyword bursts analysis were conducted.
    RESULTS: A total of 834 documents were included, revealing a rapid growth in scientific productivity from 2005 to 2025. The United States, China, and Germany were the most productive countries, with institutions such as Case Western Reserve University and Texas Tech University serving as major hubs. Co-citation and keyword burst analyses reveal a distinct temporal shift: from foundational studies of fusion/fission machinery and oxidative stress toward an integrated Mitochondrial Quality Control paradigm encompassing mitophagy, dynamics, and biogenesis. Key emerging hotspots include mitochondrial biogenesis, mitochondrial transport, and quality control mechanisms. Translational frontiers prioritize enhancing PINK1/Parkin-mediated mitophagy, inhibiting Drp1-driven excessive fission, and activating PGC-1α-dependent biogenesis.
    CONCLUSION: This bibliometric study maps the intellectual structure and evolutionary trajectory of mitochondrial dynamics research in neurodegenerative diseases. It documents a field-wide paradigm shift toward a translational agenda centered on the MQC framework. Furthermore, the findings highlight the necessity of integrating pharmacological interventions with lifestyle modifications and precision medicine approaches to overcome translational barriers and develop effective disease-modifying strategies.
    Keywords:  Mitochondrial dynamics or mitochondrial quality control or mitophagy or Mitochondrial biogenesis or Bibliometric analysis or neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.arr.2025.102987
  6. Front Pharmacol. 2025 ;16 1724858
    Commentary: Hyperoside alleviates myocardial ischemia-reperfusion injury in heart transplantation by promoting mitochondrial fusion via activating the Stat3-Tom70-Opa1 pathway.
    Qin Yang, Yingjie Liu, Xinzheng Tang.
      
    Keywords:  hyperoside; mitochondrial dynamics; mitochondrial fusion; myocardial ischemia-reperfusion injury (MIRI); oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2025.1724858
  7. Cell Signal. 2025 Dec 06. pii: S0898-6568(25)00709-0. [Epub ahead of print]139 112294
    Reprogramming mitochondrial homeostasis in renal ischemia-reperfusion injury.
    Kangyu Wang, Hao Wang, Yalong Zhang, Zijian Zhang, Li Wang, Jianwei Yang, Jiangwei Man, Li Yang.
      Acute kidney injury (AKI) caused by renal ischemia-reperfusion injury (RIRI) is primarily a mitochondrial disorder characterized by disrupted dynamics, impaired biogenesis, and defective quality control. Excessive DRP1-mediated fission, suppression of the AMPK-SIRT-PGC-1α axis, and failure of the PINK1-Parkin mitophagy system converge to drive tubular dysfunction and ferroptosis. Here, we integrate recent insights into a "mitochondrial reprogramming" framework encompassing three axes-dynamic remodeling, metabolic renewal, and proteostatic reinforcement. Therapeutic strategies targeting these axes, such as DRP1 inhibition, AMPK-SIRT-PGC-1α activation, and reinforcement of mitophagy and MAM integrity by agents like melatonin, puerarin, or Schisandrin B, have shown promise in restoring mitochondrial resilience. Furthermore, mitochondrial biomarkers and imaging tools (mtDNA, mitochondrial peptides, [18F]BCPP-EF PET) may enable phenotype-guided interventions. This review outlines the "RIRI-Mitochondria-AKI-CKD continuum," emphasizing that mitochondrial maladaptation bridges acute injury and chronic fibrosis, highlighting mitochondria as precision therapeutic targets in AKI.
    Keywords:  Biomarkers; Ferroptosis; Mitochondria; Mitophagy; Renal ischemia–reperfusion
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112294
  8. Biochem Biophys Res Commun. 2025 Dec 08. pii: S0006-291X(25)01806-6. [Epub ahead of print]795 153090
    The role of Drp1-Pink1-Parkin mediated mitophagy in cisplatin-induced damage to primary cochlear SV pericytes.
    Ke-Ke Zhang, Qian-Hui Wan, Yan-Ping Wang, Li Li, Jun-Qiang Si.
       OBJECTIVE: This study aimed to investigate the crosstalk between mitochondrial fission and mitophagy in cochlear stria vascularis pericytes under cisplatin-induced ototoxic conditions.
    METHOD: In this study, pericytes were divided into Control group, CDDP group, and pcDNA3.1-Drp1 +CDDP group. The changes in mitochondrial ultrastructure of pericytes were observed by transmission electron microscopy; the expression of Drp1, Pink1, Parkin and LC3B proteins was detected by Western blot and immunofluorescence; the changes in co-localization of TOM20 and LC3B were detected by immunofluorescence; the changes in reactive oxygen content of pericytes were detected by DCFH-DA fluorescent probe; and the changes in mitochondrial membrane potential of pericytes were detected by JC-1 fluorescent probe.
    RESULTS: The results showed that Overexpression of Drp1 in pericytes increased the expression of Drp1, Pink1, Parkin and LC3B proteins, increased the co-localization ratio of TOM20 and LC3B, decreased the content of reactive oxygen species in pericytes, increased the mitochondrial membrane potential, and improved the mitochondrial structural damage of pericytes caused by cisplatin.
    CONCLUSION: Cisplatin inhibits mitochondrial division and autophagy through Drp1-Pink1-Parkin, causing damage to pericytes.
    Keywords:  Drp1; Mitochondria; Parkin; Pericytes; Pink1
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153090
  9. Front Aging Neurosci. 2025 ;17 1678460
    Exercise regulates mitophagy to alleviate parkinsonian neurodegeneration.
    Chang Liu, Wei He, JianHua Zhang.
      Parkinson's disease (PD) is a common neurodegenerative disorder with a rising incidence in aging populations, substantially diminishing patients' quality of life. Mitochondria are central to neuronal energy metabolism, and mitophagy plays a pivotal role in maintaining mitochondrial quality by removing damaged organelles. In PD, impaired mitophagy leads to the accumulation of dysfunctional mitochondria, exacerbating oxidative stress and bioenergetic deficits and thereby accelerating disease progression. In recent years, exercise has emerged as a safe and cost-effective intervention that alleviates PD symptoms. Exercise can activate mitophagy through key signaling pathways-including AMP-activated protein kinase (AMPK)/Unc-51-like kinase 1 (ULK1) and PTEN-induced kinase 1 (PINK1)/Parkin-thereby enhancing mitochondrial function and antioxidant capacity. This review synthesizes current evidence on how exercise modulates mitophagy to confer neuroprotection in PD, providing conceptual and practical insights for non-pharmacological management strategies in neurodegenerative disease.
    Keywords:  AMPK signaling; PINK1/Parkin pathway; Parkinson’s disease; exercise intervention; mitophagy
    DOI:  https://doi.org/10.3389/fnagi.2025.1678460
  10. Mitochondrion. 2025 Dec 04. pii: S1567-7249(25)00104-7. [Epub ahead of print]87 102107
    Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
    Hélène Calais, Giulia Bertolin.
      Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria through translocases such as TOMM and TIMM complexes. Upon entry, they can reach their final mitochondrial compartment, namely the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. In this review, we will first explore the main mitochondrial protein import mechanisms. Then, we will focus on how import deficiencies may trigger stress paradigms. Stress response pathways are activated to restore correct cellular homeostasis. We will explore four interconnected pathways at the cellular or mitochondrial scale, which can compensate for import alterations. These are the DELE1-HRI axis combined with the ISR, the UPRam, the UPRmt, and mitophagy. Their activation depends on the extent of import alteration, with ISR and UPRmt pathways activated in conditions of low stress. If stress levels are too high, the elimination of dysfunctional mitochondria by mitophagy is triggered. Last, we will explore how mitochondrial import deficiencies are a feature common to multifaceted pathologies, such as neurodegenerative diseases and cancer. We will also present pharmacological compounds mimicking stress response mechanisms and that could be used as a therapeutic option in the near future to restore efficient mitochondrial protein import rates. Overall, this review highlights the critical role of mitochondrial protein import in cellular and mitochondrial stress response, and in disease pathogenesis. It also emphasizes the potential of mitochondrial protein import as a therapeutic target, despite the surprising absence of direct pharmacological treatments to date.
    Keywords:  DELE1/HRI; ISR; Mitochondrial protein import; Pharmacological modulation; UPRam; UPRmt
    DOI:  https://doi.org/10.1016/j.mito.2025.102107
  11. Mol Ther. 2025 Dec 10. pii: S1525-0016(25)01022-6. [Epub ahead of print]
    Targeting endothelial mitochondrial dynamics in glaucoma: A novel therapeutic opportunity.
    Anil Chekuri.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2025.11.036
  12. Phytomedicine. 2025 Nov 29. pii: S0944-7113(25)01262-0. [Epub ahead of print]150 157627
    Isorhamnetin attenuates lipopolysaccharide-induced myocardial inflammatory injury by inhibiting PPARγ and preserving mitochondrial homeostasis.
    Zhongchao Gai, Ranran Wang, Linlin Xiao, Sijia Yan, Chengyuan Min, Guoli Gong, Jieqiong Zhao.
      Myocarditis refers to inflammation of the myocardium caused by infections, immune system activation, or exposure to drugs, resulting in cell death, tissue damage, and impaired heart function. Isorhamnetin (ISOR), a natural flavonoid found in the leaves and fruits of several medicinal plants, has broad pharmacological properties. However, the potential of ISOR in the treatment of myocarditis remains unclear. Here, we report that ISOR could alleviate lipopolysaccharide (LPS)-induced cardiac inflammation in mice. In addition, ISOR attenuated LPS induced apoptosis and pyroptosis, decreased reactive oxygen species (ROS) production, and improved the viability of H9c2 cells. Furthermore, LPS-induced cardiomyocyte inflammation was associated with dysregulated mitochondrial function, and ISOR protected cardiomyocytes from inflammatory damage by promoting mitochondrial homeostasis. Molecular docking analyses revealed Peroxisome Proliferator Activated Receptor Gamma (PPARγ) as a potential target of ISOR in cardiomyocytes. Mechanistically, PPARγ mitigated the LPS-induced dysregulation of mitophagy and mitochondrial biogenesis through modulating PTEN Induced Kinase 1 (PINK1), Sequestosome 1 (SQSTM1/P62), PPARG Coactivator 1 Alpha (PGC-1α), and Transcription Factor A, Mitochondrial (mtTFA). Our results suggested that ISOR could function as an inhibitor of PPARγ to preserve mitochondrial homeostasis, and further mitigate inflammatory injury to cardiomyocytes. These findings provide new ideas for preventing and treating myocardial inflammatory injury.
    Keywords:  Inflammatory injury; Isorhamnetin; Mitochondria; Myocarditis; Pparγ
    DOI:  https://doi.org/10.1016/j.phymed.2025.157627
  13. World J Stem Cells. 2025 Nov 26. 17(11): 114306
    Exosomal delivery of GrpE-like 1 from synovial mesenchymal stem cells activates PINK1-mediated mitophagy for cartilage repair in osteoarthritis.
    Soumya Deep Phadikar, Ramya Lakshmi Rajendran, Sathish Muthu, Prakash Gangadaran, Byeong-Cheol Ahn.
      GrpE-like 1 (GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells (SMSC) prevent mitochondrial dysfunction associated with osteoarthritis (OA) by activating PINK1-mediated mitophagy, restoring chondrocyte function, and preserving the extracellular matrix both in vitro and in vivo. Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagy-related gene that is downregulated in OA. Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production, reduced lipid peroxidation and reactive oxygen species, increased mitophagy markers (PINK1, Parkin, LC3-II/I), decreased p62 levels, and alleviated cartilage degeneration in a rat destabilization model. A causal role for mitophagy is supported by co-immunoprecipitation experiments confirming a GRPEL1-PINK1 interaction, and by PINK1 knockdown, which diminishes the protective effects of GRPEL1. These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.
    Keywords:  Cartilage repair; Exosomes; GrpE-like 1; Mitochondrial quality control; Mitophagy; Osteoarthritis; PINK1; Synovial mesenchymal stem cell
    DOI:  https://doi.org/10.4252/wjsc.v17.i11.114306
  14. Nutrients. 2025 Nov 25. pii: 3680. [Epub ahead of print]17(23):
    Therapeutic Modulation of Mitophagy by Cafestol in Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis.
    Wen-Rui Hao, Chun-Chao Chen, Guan-Ci Huang, Jia-Hong Lin, Huan-Yuan Chen, Ju-Chi Liu, Tzu-Hurng Cheng, Jin-Jer Chen.
      Background/Objectives: Mitophagy, the selective removal of damaged mitochondria, plays a pivotal role in regulating cardiac hypertrophy and fibrosis under pressure overload. Targeting mitophagy may help mitigate adverse cardiac remodeling. This preclinical study examined the effects of cafestol, a coffee-derived diterpene, on pressure overload-induced cardiac hypertrophy and fibrosis in mice, with emphasis on mitophagy modulation and mitochondrial ultrastructure. Methods: Male normotensive mice underwent transverse aortic constriction (TAC) and received cafestol at 2, 10, or 50 mg/kg/day via oral gavage for 28 days. Cardiac function was assessed by echocardiography. Histological and molecular analyses quantified fibrosis, inflammation, and apoptosis. Protein expression of CD68, CTGF, DDR2, α-SMA, CD44, galectin-3 (Gal3), collagen I, GAPDH, Bcl-2, Bax, cleaved caspase-3, GRP78, p-ERK/ERK, ATF4, p-mTOR/mTOR, and p62 was evaluated. Transmission electron microscopy (TEM) was used to assess autophagosome formation and mitochondrial morphology. Results: TAC induced significant cardiac hypertrophy and fibrosis, accompanied by elevated expression of fibrotic (CTGF, DDR2, α-SMA, collagen I), inflammatory (CD68, CD44, Gal3), apoptotic (Bax, cleaved caspase-3), and endoplasmic reticulum stress markers (GRP78, ATF4). TEM revealed increased autophagosome accumulation and disrupted mitochondrial architecture. Cafestol treatment reduced collagen deposition, immune cell infiltration, and apoptotic signaling; enhanced Bcl-2 expression; and restored p62 levels. TEM findings demonstrated decreased autophagosome burden and preserved mitochondrial structure, consistent with improved mitophagic flux and mitochondrial homeostasis. Conclusions: Cafestol mitigated pressure overload-induced cardiac remodeling in mice by modulating mitophagy, suppressing fibrotic and inflammatory responses, and preserving mitochondrial integrity. These findings support further investigation of cafestol's mechanisms and safety profile in preclinical models of cardiovascular disease.
    Keywords:  cafestol; fibrosis; mitophagy; pressure overload
    DOI:  https://doi.org/10.3390/nu17233680
  15. J Thromb Haemost. 2025 Dec 05. pii: S1538-7836(25)00846-3. [Epub ahead of print]
    ZC3H13-mediated m6a methylation mitigates endothelial injury in venous thrombosis by inhibiting elevated mitochondrial fission.
    Hui Lu, Yaohua Cai, Yanyi Tao, Yunqing Xia, Tingting Wu, Yu Hu, Liang V Tang.
       BACKGROUND: Endothelial injury is the core factor of venous thrombosis. m6A plays a critical role in metabolism and cellular processes. Moreover, the balance of mitochondrial dynamics is essential in regulating cellular growth, apoptosis, and mobility. Now, The roles of m6A modification and mitochondrial dynamics in regulating venous endothelial cells remains elusive.
    METHODS: M6A levels were evaluated by m6A dot blot and quantification analysis. Gain- and loss-of-function and rescue assays were performed to clarify gene functions. To investigate the mitochondrial dynamics in venous endothelium, mitochondrial morphology and function analysis were performed. The target gene of ZC3H13 was identified through RNA-seq and MeRIP-seq. Mechanism of ZC3H13-mediated m6A modification was explored through MeRIP-qPCR, luciferase reporter assay, RNA stability assay, and RNA immunoprecipitation assay.
    RESULTS: Downregulated ZC3H13 expression and elevated mitochondrial fission were observed in injured venous endothelium. Functional verification has clarified ZC3H13 regulated endothelial cells by modulating mitochondrial fission. Furthermore, ZC3H13-mediated m6A modification profile was revealed and DYRK1B was identified as its target in endothelial cells. Decreased m6A modification mediated by downregulation of ZC3H13 upregulated DYRK1B mRNA expression through inhibiting DYRK1B mRNA decay in a YTHDF-2-dependent manner. Functional verification also confirmed the functions of DYRK1B in regulating endothelial cells by modulating mitochondrial fission. Moreover, endothelial-targeted ZC3H13 overexpression attenuated venous endothelial injury, which contributed to the reduced thrombotic risk observed in mice.
    CONCLUSIONS: The findings of the current study showed that ZC3H13 mitigates endothelial injury by inhibiting excessive mitochondrial fission through the m6A/YTHDF2/DYRK1B axis.
    Keywords:  ZC3H13; endothelial injury; m6A; mitochondrial fission; venous thrombosis
    DOI:  https://doi.org/10.1016/j.jtha.2025.11.007
  16. Theranostics. 2026 ;16(4): 1681-1700
    Mitochondria-specific targeting of noncanonical EGR1 ntmRNA-coordinated mitophagy receptor BNIP3 homodimerization disrupts mitochondrial metabolism and suppresses hepatocellular carcinoma growth in vitro and in vivo.
    Yan Li, Lei Zhou, Mengmeng Liu, Hui Li, Ying Meng, Xue Wen, Yijing Zhao, Shanshan Liu, Zi Yan, Changhao Fu, Shan Zong, Wei Li, Andrew R Hoffman, Jiuwei Cui, Ji-Fan Hu.
      Background: Hypoxia-driven metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC) and depends critically on mitochondrial signaling. We sought to identify RNA-based molecular factors that orchestrate the hypoxia-mitochondria crosstalk and regulate metabolic adaptation in HCC cells. Methods: An integrated mtRNA-seq and mitochondria-specific LwaCas13a-BN-MLS RNA targeting approach was employed to profile RNA molecules aberrantly enriched in HCC mitochondria. Mitophagy was assessed via mt-Keima assay, immunofluorescence, transmission electron microscopy, and Western blotting of key autophagic markers. RNA-protein interactions were examined using RNA immunoprecipitation (RIP), electrophoretic mobility shift assays (EMSA), and computational structural modeling. In vitro and in vivo tumorigenicity was evaluated using colony formation, transwell invasion, wound healing, and subcutaneous xenograft models in nude mice. Results: Nuclear-encoded EGR1 mRNA was aberrantly translocated to mitochondria, where it functions as a non-translating mRNA (ntmRNA) essential for mitophagy. Mitochondria-specific EGR1 targeting disrupted mitochondrial homeostasis by accumulating damaged mitochondria, lowering ATP, increasing ROS, reducing membrane potential, diminishing spare respiratory capacity, and impairing hypoxia-induced mitophagy. Mechanistically, EGR1 ntmRNA promoted mitophagy through the HIF-1α/BNIP3/NIX axis by recruiting BNIP3 to mitochondria and coordinating its homodimerization via a 3'-UTR MRE. A synthetic MRE oligonucleotide rescued BNIP3 dimerization after EGR1 depletion. Finally, we demonstrated that EGR1 loss suppressed malignant phenotypes in vitro and reduced xenograft tumor growth in vivo. Conclusions: This study reveals a noncanonical role for EGR1 mRNA as an epigenetic regulator of mitophagy in HCC, thus expanding the functional repertoire of mRNA molecules beyond protein coding. Targeting this noncanonical EGR1 ntmRNA-BNIP3 homodimerization mechanism may suggest new therapeutic strategies for treating HCC.
    Keywords:  BNIP3 dimerization; EGR1 ntmRNA; hepatocellular carcinoma; hypoxia; mitochondria; mitophagy
    DOI:  https://doi.org/10.7150/thno.117745
  17. J Thorac Dis. 2025 Nov 30. 17(11): 9586-9597
    Involvement of mitochondrial unfolded protein response and activating transcription factor 4 in the mitochondrial damage pathway of BEAS-2B cells induced by cigarette smoke extracts.
    Jie Jin, Tiantian Cen, Minxuan Huang, Feng Xu, Qunli Ding, Dan Lv, Shanshan Wang, Lin Fei, Hongying Ma, Panfeng Fu.
       Background: Cigarette smoke extract (CSE) induces reactive oxygen species (ROS) generation in human bronchial epithelial cells, leading to mitochondrial dysfunction and subsequently triggering the mitochondrial unfolded protein response (UPRmt) mediated by the bZIP transcription factor activating transcription factor 4 (ATF-4). This study aimed to investigate whether UPRmt and ATF-4 are involved in the pathway of mitochondrial function impairment in BEAS-2B cells caused by CSE.
    Methods: BEAS-2B bronchial epithelial cells were treated with different concentrations of CSE, and mitochondrial function was detected by JC-1 staining and MitoSoxRed staining. The expression and localisation of translocase of inner mitochondrial membrane 23 (Tim23) and ATF-4 were detected by Western blot method and immunofluorescence staining with laser confocal microscopy.
    Results: The study showed decreased membrane potential and mitochondrial ROS accumulation in BEAS-2B cells after CSE treatment, which indicated that CSE caused mitochondrial dysfunction and oxidative stress. The expression of Tim23 was up-regulated after CSE exposure; this alteration hints at a potential activation of mitochondrial stress pathways. The expression of ATF-4 showed a positive correlation with the time of CSE treatment, and the expression in the nucleus was increased, which indicated that CSE altered the expression and localisation of Tim23 and ATF-4.
    Conclusions: CSE leads to a decrease in mitochondrial membrane potential and an increase in ROS generation, and triggers alterations in the expression of Tim23 and ATF-4. These findings are consistent with the model that CSE may impair mitochondrial homeostasis, potentially through mechanisms involving mitochondrial stress responses (such as UPRmt) and ATF-4 signaling.
    Keywords:  BEAS-2B; Cigarette smoke extract (CSE); activating transcription factor 4 (ATF-4); mitochondrial unfolded protein response (UPRmt)
    DOI:  https://doi.org/10.21037/jtd-2025-460
  18. Clin Sci (Lond). 2025 Dec 08. pii: CS20258287. [Epub ahead of print]139(23):
    Targeting mitochondria to protect the heart: a matter of balance?
    Fouad A Zouein, George W Booz.
      Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state. With ischemia/reperfusion (I/R) of the heart, fission is enhanced and is associated with mitochondrial swelling, depolarization, and production of reactive oxygen species, as well as apoptosis. Accumulating evidence indicates that blocking fission is effective in reducing I/R-induced tissue damage and contractile dysfunction. In theory, enhancing fusion should also serve to prevent I/R-related heart damage. In this perspective article, we present evidence from preclinical studies over the last several years supporting the conclusion that targeting mitochondrial dynamics is a promising pharmacological strategy to protect the heart. Such an approach has great value in limiting heart damage from not only myocardial infarction but also medical interventional reperfusion, alcohol consumption, chemotherapy, and sepsis.
    Keywords:  cardiac myocyte; ischemia-reperfusion injury; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; myocardial infarction
    DOI:  https://doi.org/10.1042/CS20258287
  19. G3 (Bethesda). 2025 Dec 08. pii: jkaf298. [Epub ahead of print]
    Identification of an uncharacterized gene as a mitochondrial methionine tRNA-synthetase in Caenorhabditis elegans.
    Bharat Vivan Thapa, Mohit Das, David I Taylor, James P Held, Maulik R Patel.
      Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPRmt) activators in C. elegans, we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes for a methionine tRNA synthetase (MetRS). Here, we characterize the UPRmt induction by Y105E8A.20, which we call mars-2, and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show that impaired mars-2 activity leads to reduced mitochondrial-encoded protein abundance, depletion of mitochondrial membrane potential, fragmented mitochondrial morphology, and mild developmental delay, although the animals remain viable. Hence, this hypomorphic mars-2(P447V) strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.
    Keywords:   Caenorhabditis elegans ; WormBase; mars-2; metionine tRNA-synthetase; mitochondria; mitochondrial unfolded protein response; mtDNA; tRNAs; translation
    DOI:  https://doi.org/10.1093/g3journal/jkaf298
  20. J Biochem Mol Toxicol. 2025 Dec;39(12): e70642
    Protective Effect of SESN2 on Glutamate Neurotoxicity via Keap1-Nrf2 Pathway-Mediated Mitophagy.
    Xiu-Mei Zhang, You-Chun Li, Wen Zhou, Qiong Jiang.
      Glutamate (Glu) possesses functional significance concerning neurological disorders by producing neurotoxicity as a major excitatory amino acid neurotransmitter. Sestrin2 (SESN2) has been affirmed to elicit wide neuroprotective properties as a highly conserved stress-responsive protein. Therefore, this project sets out to ascertain the impacts of SESN2 on Glu neurotoxicity and the concealed operating mechanism. Cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay kit, and Western blot estimated cell viability, cytotoxicity, and SESN2 expression. Commercial kits and fluorescence probes were employed to assess the degree of oxidative stress. The apoptotic changes were evaluated by terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) and Western blot. Mitochondrial function was measured by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide (JC-1) staining, MitoSOX staining, and Western blot analysis of mitophagy-related proteins and immunofluorescence. Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related proteins were also examined with Western blot. SESN2 expression was elevated in HT-22 cells upon stimulation with Glu. SESN2 upregulation reduced the viability loss, LDH release, oxidative stress, and apoptosis in HT-22 cells imposed by the Glu challenge, while a contrary trend was observed when SESN2 was downregulated. Moreover, hyperexpressed SESN2 activated the Keap1-Nrf2 pathway to promote mitophagy in Glu-exposed HT-22 cells. Deletion of Nrf2 partly abolished the effects of SESN2 elevation on the mitophagy, and mitophagy blocker Mdivi-1 partly reverted the influences of SESN2 overexpression on the viability, LDH release, oxidative stress, and apoptosis in Glu-stimulated HT-22 cells. SESN2 might mediate mitophagy via the Keap1-Nrf2 pathway to confer neuroprotection toward Glu-provoked toxicity.
    Keywords:  Keap1‐Nrf2; SESN2; glutamate; mitophagy; neuroprotection
    DOI:  https://doi.org/10.1002/jbt.70642
  21. Autophagy. 2025 Dec 10.
    ESRRA-ATG5-Mediated mitophagy enhances arginine metabolism to alleviate diabetic kidney disease.
    Hongtu Hu, Qian Yang, Jijia Hu, Yanqing Fan, Zongwei Zhang, Keju Yang, Weiwei Li, Zhuan Peng, Zhaowei Chen, Guohua Ding, Wei Liang.
      Diabetic kidney disease (DKD) is increasingly recognized as a consequence of impaired mitochondrial quality control in renal tubular epithelial cells (TECs). In this study we show that the nuclear receptor ESRRA (estrogen related receptor alpha) transcriptionally activates ATG5 (autophagy related 5) to sustain PINK1 (PTEN induced kinase 1)-dependent mitophagy and preserve tubular homeostasis. ESRRA and ATG5 expression were markedly reduced in human DKD biopsies, and their abundance correlated positively with estimated glomerular filtration rate and inversely with albuminuria. Conditional deletion of Esrra in mouse tubules or CRISPR-Cas9 knockout in primary TECs suppressed mitophagy, exacerbated mitochondrial dysfunction and aggravated tubulointerstitial fibrosis, whereas tubular Esrra re-expression or Atg5 overexpression restored mitophagy and attenuated renal injury. Multi-omics and mechanistic assays identified the natural polyphenol salvianolic acid C (SAC) as a high-affinity ESRRA agonist that binds Asp326, Phe382 and Ala396, stabilizes the receptor and upregulates ATG5. SAC dose-dependently improved proteinuria, renal function, mitochondrial respiration and insulin sensitivity in db/db and high-fat diet-streptozotocin DKD models without overt toxicity. Metabolomic profiling revealed that ESRRA-ATG5-driven mitophagy targets ARG2 (arginase 2) for autophagy-lysosomal degradation, thereby shifting L-arginine flux from urea production toward nitric-oxide synthesis; exogenous L-arginine partly rescued renal injury in Esrra-deficient mice. Collectively, this study uncovers an ESRRA-ATG5 axis that couples selective mitophagy to L-arginine metabolism as a pivotal defense against DKD, and identifies SAC as a first-in-class, naturally derived ESRRA activator with therapeutic potential.
    Keywords:  ATG5; Arginine metabolism; ESRRA; diabetic kidney disease; mitophagy; salvianolic acid C
    DOI:  https://doi.org/10.1080/15548627.2025.2601874
  22. Oral Dis. 2025 Dec 12.
    Mitophagy in Botulinum Toxin Type A-Induced Muscle Atrophy.
    Qian-Ying Mao, Zhuo Chen, Shang Xie, Ruo-Lan Xiang, Zhi-Gang Cai.
       OBJECTIVE: Botulinum toxin type A (BTXA) is widely used in oral and maxillofacial surgery to treat masseter hypertrophy and bruxism, inducing transient masseter atrophy, but the underlying mechanisms remain unclear. Mitophagy, essential for muscle fiber homeostasis, plays a critical role in muscle atrophy. This study aims to investigate whether mitophagy mediates BTXA-induced masseter muscle atrophy.
    METHODS: Rats received BTXA injections into masseter for 2 and 8 weeks. Muscle fiber composition was assessed via histology and immunofluorescence. Mitophagy markers (LC3-II, p62, beclin-1, Tomm20) were quantified by western blot. Mitochondrial function was evaluated via ATP content and mitochondrial DNA (mtDNA) copy number.
    RESULTS: BTXA injection led to transient masseter muscle atrophy. During this process, the proportion of type IIA muscle fibers significantly increased, while the proportion of type IIB fibers decreased. Additionally, at 2 weeks post-BTXA injection, the expression levels of LC3-II, p62, and beclin-1 were notably upregulated, whereas Tomm20 expression was downregulated. Furthermore, a significant reduction in ATP content and mtDNA copy number was observed at the same time point, indicating impaired mitochondrial function.
    CONCLUSION: These findings suggest that mitophagy plays a crucial role in BTXA-induced masseter muscle atrophy, providing new insights into the mechanisms underlying BTXA treatment.
    Keywords:  botulinum toxin type A; masseter muscle; mitophagy; muscle atrophy
    DOI:  https://doi.org/10.1111/odi.70168
  23. Cells. 2025 Dec 01. pii: 1904. [Epub ahead of print]14(23):
    Antiretroviral Drugs Impact Autophagy Differently in Primary Human Astrocytes.
    Laura Cheney, Grace McDermott, Hillary Guzik, Joan W Berman.
      While antiretroviral therapy (ART) has significantly improved the morbidity of HIV infection, ART may contribute to the pathogenesis of HIV associated neurocognitive impairment (HIV-NCI) by interfering with autophagic processes in astrocytes. Autophagy and mitophagy remove unwanted/damaged material and mitochondria from the intracellular environment, respectively. Dysregulated autophagy in astrocytes, abundant CNS cells with crucial homeostatic functions, contributes to many neurodegenerative diseases. Few studies have examined effects of ART on autophagy in astrocytes. We treated primary human astrocytes with a common ART regimen and performed LC3B-II and p62 turnover assays. ART significantly inhibited both LC3B-II and p62 turnover. Since p62, one autophagy receptor that mediates mitophagy, autophagic clearance of mitochondria, turnover was inhibited, we also examined mitophagy. While ART decreased BNIP3L/Nix homodimers, there were no changes in PINK1, Parkin, Mt-CO2, mitochondrial mass, or mitochondria-lysosome colocalization, indicating that ART did not inhibit mitophagy. We show that antiretroviral drugs have distinct effects on autophagic processes in astrocytes, which represents an alteration in their homeostasis, a major function of autophagy. This likely contributes to HIV-NCI. Understanding these impacts is important for improving ART for PWH, who have, by necessity, ongoing ART exposure. It also facilitates development of therapies for HIV-NCI that may include modulation of autophagy.
    Keywords:  BNIP3L/Nix; HIV associated neurocognitive impairment; LC3B; PINK1-Parkin; antiretroviral therapy; astrocytes; macroautophagy; mitophagy; p62; selective autophagy
    DOI:  https://doi.org/10.3390/cells14231904
  24. Food Chem Toxicol. 2025 Dec 09. pii: S0278-6915(25)00663-5. [Epub ahead of print] 115895
    The toxic effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming are associated with impaired mitochondrial dynamics balance.
    Chanisa Thonusin, Chayodom Maneechote, Siriporn C Chattipakorn, Nipon Chattipakorn.
      The toxicity of doxorubicin and trastuzumab can lead to heart failure. Its pathophysiology is correlated with cardiac metabolic reprogramming. Therefore, we investigated the effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming. Since mitochondrial dynamics imbalance is associated with cardiotoxicity, we evaluated the effects of restoring balance of mitochondrial dynamics on reducing cardiotoxicity. Male Wistar rats received either vehicle, 6 doses of 3 mg/kg of doxorubicin, or 4 mg/kg/day of trastuzumab. Doxorubicin-treated rats and trastuzumab-treated rats were also co-treated with either vehicle, 1.2 mg/kg/day of MDiVi1 (mitochondrial fission inhibitor), or 2 mg/kg/day of M1 (mitochondrial fusion promoter). The treatment duration was 30 and 7 days for doxorubicin and trastuzumab studies, respectively. Thereafter, cardiac function was determined. The rats were then euthanized to collect cardiac ventricular tissues for targeted metabolomics via liquid chromatography coupled with mass spectrometry. We found that doxorubicin and trastuzumab caused increased glycolysis, increased ketone body metabolism, decreased fatty acid utilization, decreased succinate oxidation, and decreased ATP production. These changes were more severe in doxorubicin-treated rats. Restoring mitochondrial dynamics balance by MDiVi1 or M1 improved cardiac metabolic reprogramming. These novel findings highlighted the toxic effects of doxorubicin and trastuzumab on cardiac metabolic reprogramming and their association with mitochondrial dynamics. Also, metabolomics might be used as a tool for treatment monitoring in doxorubicin- and trastuzumab-induced cardiotoxicity.
    Keywords:  Cardiotoxicity; Doxorubicin; Heart failure; Metabolic reprogramming; Mitochondrial dynamics; Trastuzumab
    DOI:  https://doi.org/10.1016/j.fct.2025.115895
  25. Int J Biol Sci. 2026 ;22(1): 178-200
    SIRT6-Mediated Regulation of TFAM: A Central Mechanism Connecting Nuclear and Mitochondrial Transcriptional Processes and Mitophagy.
    Meimei Jiang, Jiehan Li, Ning Ding, Guiyun Jia, Siming Wu, Nannan Liu, Ying Kang, Ge Zhang, Jiawei Wu, Lingling Zhang, Yingjie Zhang.
      Nuclear and mitochondrial transcriptional regulation represent distinct mechanisms of gene expression control, both of which have garnered significant scientific attention. However, the interplay between these two regulatory processes remains poorly understood and underexplored. Our research uncovers a novel link between nuclear and mitochondrial transcription by identifying SIRT6 as an upstream regulator of the mitochondrial transcription factor TFAM, acting both indirectly and directly. Mechanistically, SIRT6 deacetylates FoxA1 at the K267 site, blocks the binding of FoxA1 to the promoter region of TFAM, leading to reduced TFAM expression. In parallel, SIRT6 translocates to the mitochondria and directly deacetylates TFAM at the K154 site, suppressing its transcriptional activity. Furthermore, SIRT6 downregulates the expression level of mitochondrial genes and proteins, inducing mitochondrial dysfunction and mitophagy by targeting TFAM. Additionally, TFAM promotes the growth and metastasis of colon cancer in vitro and in vivo, while SIRT6 was inhibited. In conclusion, our findings provide compelling evidence that SIRT6 establishes a network linking nuclear and mitochondrial transcription through the regulation of TFAM, identifying TFAM as a potential therapeutic target for cancer.
    Keywords:  FoxA1; SIRT6; TFAM; mitochondrial dysfunction; mitophagy; transcription regulation
    DOI:  https://doi.org/10.7150/ijbs.120007
  26. Exp Eye Res. 2025 Dec 09. pii: S0014-4835(25)00575-5. [Epub ahead of print] 110802
    Autophagy and Mitophagy in Diabetic Retinopathy: The Effects and Mechanism of Action on the Neurovascular Unit.
    Yuyan Ren, Huazhi Zhang, Lanqing Ping, Jingwen Tang, Yilan Li, Ziying Wang, Yapeng Wang.
      While diabetic retinopathy (DR) is the primary cause of vision impairment and blindness in people with diabetes, current treatments fail to target early pathogenic mechanisms to halt disease progression. The development of DR involves complex cellular stress responses associated with metabolic dysregulation. Recent studies have highlighted the critical functions of autophagy, particularly mitophagy, in DR and how it contributes to the malfunction of the retinal neurovascular unit (NVU) and disease progression. Emerging insights have elucidated the interplay between autophagy, ER stress, and regulatory genes such as DRAM2, with pivotal roles for mitophagy-related pathways, including PINK1/Parkin and BNIP3/NIX-FUNDC1. This review systematically organizes and analyzes recent advances in research on how autophagy and mitophagy regulate ER stress, mitochondrial homeostasis, and the function of diverse NVU cell types. We present evidence that dysregulation of these processes compromises NVU integrity and accelerates DR progression. By clarifying the molecular links between autophagy, mitophagy, and NVU dysfunction, this review offers new insights for developing precision interventions and innovative therapies for early intervention of DR.
    Keywords:  Diabetic retinopathy (DR); autophagy; mitophagy; retinal neurovascular unit (NVU)
    DOI:  https://doi.org/10.1016/j.exer.2025.110802
  27. Int J Mol Sci. 2025 Dec 01. pii: 11641. [Epub ahead of print]26(23):
    Liproxstatin-1 Protects SH-SY5Y Cells by Inhibiting H2O2-Induced Excessive Mitophagy and Apoptosis.
    Tingting Yan, Feng Ding, Zhongyuan Fang, Yan Zhao.
      Oxidative stress is a critical factor in the pathogenesis of various neuronal disorders, causing cellular damage and mitochondrial dysfunction. This study aimed to explore the protective effects of liproxstatin-1 against H2O2-induced neural oxidative damage and elucidate the underlying mechanisms. Our findings demonstrated that 500 μmol/L H2O2 treatment induced mitochondrial dysfunction and apoptosis in SH-SY5Y cells, while 1 μmol/L liproxstatin-1 effectively mitigated these cytotoxic effects by restoring mitochondrial integrity and enhancing cell viability. Furthermore, 500 μmol/L H2O2 exposure significantly suppressed the activation of the protein kinase B/ mammalian target of rapamycin signaling pathway and triggered excessive mitophagy. Pretreatment with 1 μmol/L liproxstatin-1 attenuated the damage by H2O2, suggesting its protective role. Collectively, our results indicated that 500 μmol/L H2O2 induces cytotoxicity through oxidative damage, protein kinase B/ mammalian target of rapamycin pathway inhibition, and aberrant mitophagy, ultimately leading to apoptosis; meanwhile, 1 μmol/L liproxstatin-1 counteracted these effects by preserving mitochondrial function, suppressing excessive mitophagy, and inhibiting apoptotic pathways, thereby protecting SH-SY5Y cells from H2O2-induced cytotoxicity.
    Keywords:  AKT/mTOR; H2O2; apoptosis; liproxstatin-1; mitophagy
    DOI:  https://doi.org/10.3390/ijms262311641
  28. J Nanobiotechnology. 2025 Dec 06.
    Fisetin carbon dots alleviate periodontitis by enhancing mitophagy through regulation of sirtuin 3 SUMOylation.
    Yu Deng, Xinyu Jiang, Zhenzhen Che, Yaqi Shang, Mengting Hu, Wentian Wang, Weixian Yu, Bai Yang, Xinchan Liu.
      Periodontitis is a chronic inflammatory disease strongly linked to the sustained accumulation of reactive oxygen species (ROS). Eliminating excessive ROS and modulating the periodontal microenvironment to suppress inflammation represents a promising therapeutic approach for the treatment of periodontitis. Fisetin (FIS) is a naturally occurring flavonoid known for its strong antioxidant and anti-inflammatory effects. However, its poor water solubility and low bioavailability limit its therapeutic efficacy. Carbon dots (CDs), as an emerging nanomaterial, offer advantages such as simple synthesis, good biocompatibility, and low cost. To overcome the limitations of FIS, this study synthesized fisetin-derived carbon dots (FIS-CDs) via a hydrothermal method. The resulting FIS-CDs exhibits excellent water solubility, favorable biocompatibility, and demonstrates excellent ROS-scavenging capability without the need for further modification. In vitro FIS-CDs significantly reduced intracellular ROS levels, alleviate oxidative stress, maintain mitochondrial homeostasis, and suppress the generation of inflammatory cytokines. Furthermore, FIS-CDs exhibit excellent osteogenic potential. In vivo experiments confirmed that FIS-CDs markedly alleviated periodontal inflammation and oxidative damage, suppressed alveolar bone loss, and promoted regeneration of periodontal tissues. Mechanistically, FIS-CDs facilitate the activation of mitophagy by downregulating the SUMOylation of sirtuin 3 (SIRT3). This modulation contributes to the restoration of mitochondrial function, which in turn mitigates cellular injury and limits the secretion of inflammatory mediators. Collectively, these findings underscore the therapeutic promise of FIS-CDs as a safe and effective nanomaterial for periodontitis treatment and suggest a novel molecular target for future drug development.
    Keywords:  Carbon dots; Fisetin; Mitophagy; Periodontitis; SUMOylation; Sirtuin 3
    DOI:  https://doi.org/10.1186/s12951-025-03907-9
  29. Biochem Pharmacol. 2025 Dec 04. pii: S0006-2952(25)00869-X. [Epub ahead of print]244 117604
    Cinnamaldehyde suppresses ovarian cancer progression by activating ROS-mediated apoptosis and mitophagy.
    Chu Yi, Weifeng Feng, Guijuan Zhang, Jiali Luo, Yiliu Chen, Qing Feng, Yinbin Zhu, Yali Guo, Xianxin Yan, Min Ma.
      Cinnamaldehyde (CA), a natural bioactive compound derived from Cinnamomum species, has demonstrated broad-spectrum antitumor activity. However, its therapeutic potential and precise mechanisms in ovarian cancer (OC) remain incompletely elucidated. In this study, we systematically investigated the inhibitory effects of CA on OC and the underlying molecular mechanisms through both in vitro and in vivo approaches. In vitro experiments demonstrated that CA significantly induces reactive oxygen species (ROS) accumulation in OC cells, activates mitochondria-mediated apoptosis, and induces mitochondrial autophagy via the AMPK/ULK1/Beclin1 signaling axis. These synergistic effects collectively lead to significant suppression of OC cell proliferation. In a murine xenograft model of OC, CA administration substantially inhibited the growth of heterotransplanted tumors. Further in vivo analyses revealed a significant increase in the number of apoptotic cells and upregulation of the expression of the autophagy markers LC3B, PINK1, and Parkin in tumor tissues. Concurrently, the expression of the autophagic substrate p62 and the mitochondrial membrane protein TOMM20 decreased. These findings consistently corroborated the cellular mechanisms observed in vitro. This study provides the first evidence that CA suppresses OC progression via ROS-mediated dual mechanisms: apoptosis induction and mitophagy activation. Our results underscore the translational potential of CA as a promising therapeutic candidate and provide a robust experimental foundation for its further development against OC.
    Keywords:  Apoptosis; Cinnamaldehyde; Mitochondrial; Mitophagy; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.bcp.2025.117604
  30. J Agric Food Chem. 2025 Dec 08.
    Alleviating the Toxic Effects of Nitrite: Histidine Mitigates Hepatopancreas Damage by Suppressing Ferroptosis and Enhancing Mitochondrial Quality Control.
    Xin Zeng, Xiao-Qiu Zhou, Wei-Dan Jiang, Pei Wu, Hong-Yun Zhang, Yao-Bin Ma, Yang Liu, Xiao-Wan Jin, Hong-Mei Ren, Lu Zhang, Lin Feng.
      Nitrite accumulation in aquaculture systems exerts diverse toxic effects, jeopardizing aquatic animal health and sustainable production. Although dietary amino acid supplementation has shown potential in mitigating stress in fish, the protective role of histidine remains unclear. This study investigated the mechanism by which dietary histidine alleviates nitrite-induced hepatotoxicity in grass carp. Our findings reveal that histidine not only ameliorated nitrite-induced alterations in blood parameters but also enhanced the antioxidant capacity. Crucially, histidine attenuated hepatopancreatic and mitochondrial damage by suppressing ferroptosis and coordinating mitochondrial quality control. Mechanistically, histidine attenuated ferroptosis probably by regulating the Nrf2 pathway and iron metabolism. It also maintained mitochondrial homeostasis by promoting fusion, inhibiting fission, and inducing mitophagy via PINK1/Parkin and BNIP3 signaling. These findings highlight histidine's protective effects against nitrite-induced hepatopancreas injury and suggest 10.82 g/kg as the optimal dietary level for enhancing nitrite resistance in grass carp, providing valuable insights for developing antistress aquafeeds.
    Keywords:  ferroptosis; grass carp; hepatopancreas; histidine; mitochondrial quality control; nitrite exposure
    DOI:  https://doi.org/10.1021/acs.jafc.5c12483
  31. Theranostics. 2026 ;16(4): 1701-1719
    Impairment of mitochondrial quality control exacerbates diabetes-related atrial fibrillation by cGAS-STING signaling pathway and cardiomyocyte-macrophage crosstalk.
    Shan Meng, Jinfeng Duan, Jikai Zhao, Zijun Zhou, Boxuan Sun, Yinli Xu, Tao Huang, Tao Hong, Xin Chen, Tong Su, Liming Yu, Huishan Wang.
      Aims: Type 2 diabetes mellitus (T2DM) significantly elevates the likelihood of atrial fibrillation (AF); However, the precise mechanisms remain incompletely elucidated. Mitochondrial dysfunction is a hallmark of diabetic cardiomyopathy, and recent evidence suggests that activation of the cGAS-STING signaling pathway may contribute to metabolic inflammation in the atria. This study aims to investigate the role of mitochondrial DNA (mtDNA)-mediated cGAS-STING activation in promoting diabetes-associated atrial fibrillation (AF) through cardiomyocyte-macrophage crosstalk. Methods and results: Using a high-fat diet combined with streptozotocin through intraperitoneal injection, we induced a diabetic mouse model. We observed increased AF inducibility, oxidative stress, and mitochondrial ultrastructural abnormalities, along with elevated expression of STING pathway components and pro-inflammatory cytokines in atrial tissue. RNA sequencing and histological analyses confirmed dysregulation of mitochondrial quality control (MQC), including impaired mitophagy, imbalance in fusion and fission, and reduced mitochondrial biogenesis. In vitro, HL-1 atrial cardiomyocytes exposed to high glucose and palmitic acid showed excessive production of mtROS and cytosolic release of mitochondrial DNA (mtDNA), which in turn triggered cGAS-STING activation. A transwell co-culture system revealed that cardiomyocyte-derived mtDNA was engulfed by RAW 264.7 macrophages, promoting M1 polarization of macrophages and further amplifying inflammatory signaling. Importantly, pharmacological intervention with the mitochondrial antioxidant mito-TEMPO or cardiomyocyte-specific STING knockdown suppressed inflammatory responses, reversed atrial remodeling, and reduced AF susceptibility. Notably, STING overexpression sustained inflammatory pathways independently of suppressing oxidative stress, highlighting cGAS-STING signaling as a downstream effector of mitochondrial damage. Conclusion: Impairment of mitochondrial quality control promotes atrial inflammation and remodeling in diabetes through mtDNA-induced cGAS-STING activation and cardiomyocyte-macrophage communication. Targeting this pathway may offer a novel strategy for AF management in metabolically compromised hearts.
    Keywords:  Atrial fibrillation; Atrial myocytes-macrophage crosstalk.; Mitochondrial quality control; Type 2 diabetes; cGAS-STING signaling pathway
    DOI:  https://doi.org/10.7150/thno.124140
  32. Biochim Biophys Acta Rev Cancer. 2025 Dec 06. pii: S0304-419X(25)00252-5. [Epub ahead of print]1881(1): 189510
    Dysregulated mitochondrial dynamics in cancer: Unlocking new strategies to combat drug resistance.
    Teresa Rossi, Roberta Torcasio, Ludovica Ganino, Ilenia Valentino, Christian Boni, Massimo Gentile, Antonino Neri, Nicola Amodio, Mariaelena Pistoni.
      Mitochondria continuously alternate between fragmented and fused states, a process known as mitochondrial dynamics, which plays a pivotal role in essential cellular functions, including metabolism, apoptosis, reactive oxygen species production, and signal transduction. Disruptions in this dynamic equilibrium, frequently observed in aggressive cancers, can promote malignant transformation and tumor progression. A growing body of evidence indicates that dysregulated mitochondrial dynamics contribute to resistance against both conventional and targeted anticancer therapies. In this review, we explore the regulatory mechanisms governing mitochondrial dynamics, with a focus on the genetic and epigenetic modulation of key drivers such as DRP1, MFN1/2 and OPA1. We also discuss how altered mitochondrial dynamics converge into diverse mechanisms of drug resistance in cancer. Overall, these insights underscore aberrant mitochondrial dynamics as a potential biomarker of therapeutic resistance, and position mitochondrial dynamics-related GTPases, particularly DRP1 and Mitofusins, as exploitable targets for novel treatments in advanced solid and hematologic malignancies.
    Keywords:  Cancer therapy; DRP1; Drug resistance; MFF; MFN2; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189510
  33. Phytomedicine. 2025 Dec 05. pii: S0944-7113(25)01303-0. [Epub ahead of print]150 157668
    Swietenine attenuates renal tubular injury by activating mitophagy in diabetic nephropathy.
    Feilong Pei, Jingyu Duan, Lin Tan, Cuicui Gu, Jiale Miao, Shuang Liu, Chunping Zhang.
       BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes, characterized by high prevalence and mortality rates. Tubular damage is a significant pathological aspect of DN. Mitophagy plays a crucial role in tubular damage associated with DN. Swietenine (Swi) is the main bioactive compound isolated and purified from the fruits of S. macrophylla, and it has been shown to have anti-inflammatory, antioxidant, and anti-diabetic activities. Previous studies have indicated that Swi provides strong kidney protection in DN, but the underlying mechanisms by which Swi influences DN remain unclear.
    OBJECTIVE: This study aims to clarify the renal protective effects of Swi during the development of DN and explore its potential molecular mechanisms.
    METHODS: This study used high-fat diet and streptozotocin (HFD/STZ)-induced DN mice as an in vivo model, and human renal tubular epithelial cells (HK-2 cells) treated with high glucose combined with palmitic acid (HG/PA) as an in vitro model. After 8 weeks of treatment with Swi, serum and urine levels of renal function-related indicators were measured. Renal tissue sections were subjected to histopathological staining, and changes in mitochondrial morphology and number were observed using transmission electron microscopy (TEM). Levels of proteins associated with oxidative stress, apoptosis, autophagy, and mitophagy-related proteins were measured through via Western blotting (WB), immunofluorescence (IF) staining, flow cytometry, and fluorescent probes. Proteomics results based on tandem mass tag (TMT) were used to explore the potential mechanisms of Swi in DN. Finally, siRNA transfection was used to reveal the role of the Acsf2/PHB2/PINK1 pathway in HK-2 cells treated with HG and PA.
    RESULTS: Swi improved renal function in diabetic mice and alleviated insulin resistance, oxidative stress, and apoptosis levels in DN mice. Swi alleviated tubular injury and enhanced mitophagy levels in both in vivo and in vitro models. Additionally, Swi reduced mitochondrial reactive oxygen species (ROS) production and restored mitochondrial function. Importantly, the protective effects of Swi on HG/PA-induced HK-2 cells was abolished after siRNA transfection and the use of the mitophagy inhibitor Mdivi-1, further confirming that Swi alleviates diabetic kidney tubular injury by activating the Acsf2/PHB2/PINK1 signaling pathway.
    CONCLUSION: Swi enhances mitophagy through the Acsf2/PHB2/PINK1 pathway to alleviate diabetic kidney tubular damage. This study provides new evidence that Swi could be a potential drug for preventing and treating DN.
    Keywords:  Acsf2/PHB2/PINK1; Diabetic nephropathy; Mitophagy; Swietenine
    DOI:  https://doi.org/10.1016/j.phymed.2025.157668
  34. Sci Rep. 2025 Dec 10.
    Overexpression of PRDX2 alleviates chronic thromboembolic pulmonary hypertension by modulating inflammation and mitophagy.
    Chen Gong, Xiaoyan Lan, Yiming Xie, Xiaobing Wu, Fengxia Wu, Xing Chen, Huilei Zheng, Hong Wen, Feng Huang, Zhiyu Zeng.
      Chronic thromboembolic pulmonary hypertension (CTEPH) results from thrombi-induced endothelial injury, inflammation, and oxidative stress in pulmonary vessels, leading to vascular remodelling, increased resistance, and elevated pulmonary arterial pressure. Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme involved in regulating cellular redox balance and inflammation, its role in CTEPH is not yet fully understood. The aim is to investigate the expression and functional role of PRDX2 in CTEPH and explore its potential mechanisms in modulating inflammation and mitochondrial autophagy. Proteomics was used to analyse peripheral blood samples from patients with CTEPH and healthy controls to identify differentially expressed proteins. A rat model of CTEPH was developed through the intravenous injection of amino-crosslinked polystyrene microspheres. PRDX2 expression was assessed in lung tissues and primary pulmonary artery endothelial cells (PAECs) using immunohistochemistry, Western blotting, and qRT-PCR. The effects of PRDX2 overexpression and silencing on inflammation and mitochondrial autophagy were evaluated using ELISA, Western blotting, and transmission electron microscopy. The expression of PRDX2 was significantly increased in the peripheral blood of patients with CTEPH and in the pulmonary vasculature of rats with CTEPH.Overexpression of PRDX2 in PAECs attenuated the inflammatory response by NF-κB signaling pathway. Additionally, overexpression of PRDX2 regulated the expression of mitophagy-related proteins (LC3II/I, Beclin-1, and p62) and restored mitochondrial morphology. Further verification in rats showed that PRDX2 overexpression significantly improved haemodynamic parameters and pulmonary vascular remodelling in CTEPH. Overexpression of PRDX2 alleviates pulmonary vascular remodeling in CTEPH by reducing inflammation and Modulating mitophagy, suggesting its protective role and potential as a therapeutic target for the disease.
    Keywords:  Chronic thromboembolic pulmonary hypertension; Inflammation; Mitochondrial autophagy; Peroxiredoxin 2; Pulmonary artery endothelial cells
    DOI:  https://doi.org/10.1038/s41598-025-31063-5
  35. Phytomedicine. 2025 Nov 22. pii: S0944-7113(25)01224-3. [Epub ahead of print]150 157589
    MARCH5-mediated MIEF2 ubiquitination and degradation contribute to gigantol to against hepatic steatosis and mitochondrial fission in alcoholic liver disease.
    Yangsheng Wu, Shijie Dai, Zheming Li, Lanman Xu, YuJia Zhang, Jiannan Qiu, Lin Chen, Yiyou Lin, Mingjiang Mao, Jianglei Xu, Shouye Li, Xiaofeng Yuan, Xiaobing Dou.
       BACKGROUND: Alcoholic liver disease (ALD) is among the most prevalent health issues caused by chronic alcohol consumption. The mitochondrial E3 ligase Membrane Associated Ring-CH-type Finger 5 (MARCH5, also known as MITOL) is involved in mitochondrial fission in ALD. Gigantol (Gig) has been reported to alleviate oxidative dysfunction and inflammation in liver injury, but its effects on ALD and the mechanisms underlying these effects are not completely comprehended. This study aimed to explore the potential effects and mechanisms of Gig against ALD.
    METHODS: In this research, we explored the impacts of Gig on ethanol-treated zebrafish larvae, C57BL/6 mice, and AML12 cells. In vitro and in vivo gain- and loss-of-function experiments were employed to investigate the functions of MARCH5 and MIEF2 in ALD and the mechanisms underlying their functions.
    RESULTS: Gig alleviated hepatic steatosis, cell death, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial fission in both animal and cell models. Functionally, MIEF2 depletion potently repressed fatty acid synthesis, cell apoptosis and mitochondrial fission in vitro, at least in part by inhibiting the ROS/JNK/CHOP pathway. Moreover, overexpression of MIEF2 effectively reversed the reduction in lipid accumulation, cell death, mitochondrial fission, and mitochondria-associated membrane (MAMs) formation caused by MARCH5 overexpression. Mechanistically, MARCH5 directly interacted with MIEF2 to cause its ubiquitination and proteasomal degradation, thereby regulating mitochondrial dynamics in AML12 cells. Additionally, liver-specific MARCH5 knockdown markedly aggravated liver injury induced by an ethanol-containing diet. Importantly, liver-specific knockdown of MARCH5 in ALD model mice abolished the protective effects of Gig on the liver, partly through the activation of the MIEF2/JNK/CHOP pathway.
    CONCLUSION: These results suggest that Gig may protect against hepatic steatosis and mitochondrial fission in ALD by targeting MARCH5 to mediate ubiquitination and degradation of MIEF2, which lays the foundation for research on the effects of Gig against liver illnesses.
    Keywords:  Alcoholic liver disease; Gigantol; MARCH5; MIEF2; Mitochondrial fission; Ubiquitination
    DOI:  https://doi.org/10.1016/j.phymed.2025.157589
  36. Phytomedicine. 2025 Dec 11. pii: S0944-7113(25)01296-6. [Epub ahead of print] 157661
    Corrigendum to "Kaempferol ameliorates BMSCs senescence in postmenopausal osteoporosis by targeting Sp1 to activate FUNDC1-mediated mitophagy" [Phytomedicine 148 (2025) 157456].
    Linghanqing Wang, Yangyang Qu, Zhehan Hu, Puzhou Lei, Xurong Tian, Xinyue Yang, Sida Chen, Cheng Li, Binbin Wei, Lei Li.
      
    DOI:  https://doi.org/10.1016/j.phymed.2025.157661
  37. Front Physiol. 2025 ;16 1687578
    Ion channels and atrial fibrillation: mitophagy as a key mediator.
    Xize Wu, Xiaorui Yan, Ruoxi Ma, Qiuying Wu, Xue Pan, Qihua Wu, Jiaqi Ren, Yuxi Huang, Shan Gao, Yue Li, Lihong Gong.
       Background: The prevalence of atrial fibrillation (AF) is increasing due to the aging population. Mitophagy is crucial for maintaining cardiomyocyte function, while ion channels play a key role in cardiac electrical activity. Dysfunction of ion channels can trigger AF. However, the role of mitophagy-related ion channel genes in AF remains unclear.
    Methods: AF-related datasets GSE41177 and GSE79768 were merged and batch-corrected for differential expression analysis. Mitophagy-related and ion channel-related genes were obtained from the MsigDB and GeneCards databases. Immune infiltration and functional enrichment analyses were performed. Sixty-five machine learning models were developed to identify Hub genes, with the optimal model selected based on receiver operating characteristic curves, F1 scores, and accuracy. An acute electrical remodeling model of atrial tachyarrhythmia was established in Sprague-Dawley rats by administering a mixture of acetylcholine-calcium chloride for 7 days. Hematoxylin-eosin, Masson, and Sirius red staining were used to detect histopathologic changes in the atrial myocardium. The expression of AF-related mitophagy ion channel genes and proteins was measured by qRT-PCR and Western blotting.
    Results: A total of 444 differentially expressed genes in AF were identified, and 9 AF-related mitophagy ion channel genes (AFRMICGs) were obtained (BAX, CTNNB1, DPYSL2, EPHX1, GLUL, GNB2, MIF, MYC, TLR4). Functional enrichment analysis indicated that the pathogenesis of AF is related to inflammation, immune response, ion channels, apoptosis, and various organelles and is associated with the PI3K/AKT, NF-kappa B, JAK-STAT, and mTOR pathways. Immune infiltration analysis showed higher resting dendritic cells and neutrophils and lower follicular helper T cells, M2 macrophages, and activated dendritic cells in AF patients. The glmBoost + Lasso model identified 4 Hub genes: BAX, GLUL, MIF, and TLR4. In vivo experiments showed disordered myocardial cell arrangement, collagen fiber proliferation, interstitial widening, fibrous septa formation, and uneven cytoplasmic staining. qRT-PCR results showed upregulation of BAX, MIF, TLR4, SLC8A1, and CaMKII genes, while the expression of Nav1.5, Kv1.5, hERG, Cav1.2, Cav1.3, Cav3.2, PINK1, Parkin, FUNDC1, BNIP3, NIX, MAP1LC3A, and MAP1LC3B genes was downregulated. Western blotting confirmed increased protein expression of BAX, MIF, and TLR4, whereas GLUL expression showed no significant difference at either the gene or protein level.
    Conclusion: BAX, MIF, and TLR4 are key genes linking mitophagy and ion channels in AF, which appear to influence the immune microenvironment by modulating immune cell infiltration.
    Keywords:  atrial fibrillation; bioinformatics; ion channels; mitochondrion; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2025.1687578
  38. Sci Rep. 2025 Dec 08. 15(1): 43339
    KDM6B induces demethylation of H3K27me3 in MFN1 to modulate aberrant mitophagy in sepsis-induced acute lung injury.
    Haoran Deng, Shiping Zhu, Xue Song, Yufei Guo, Xuchun Ding.
      Acute lung injury (ALI) commonly occurs as a complication of sepsis, significantly increasing mortality rates in septic patients. Macrophages play a critical role in sepsis pathogenesis. KDM6B, a histone demethylase, has been reported to regulate macrophage death in ALI. In this study, we investigated the impact of KDM6B on macrophage processes during sepsis-induced ALI and elucidated the underlying molecular mechanisms. A cecal ligation and puncture (CLP)-induced septic mouse model was established to assess KDM6B's effects on lung injury severity and survival outcomes. Raw264.7 macrophages were stimulated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) to create an in vitro cell injury model, followed by flow cytometric analysis for apoptosis detection, DCFH-DA staining for oxidative stress assessment, and western blot analysis for mitophagy evaluation. Chromatin immunoprecipitation assays were performed to determine KDM6B's regulatory effects on histone H3 lysine 27 (H3K27) methylation status in the MFN1 promoter region. Results demonstrated upregulated KDM6B expression in CLP-induced septic mouse lungs. In vitro experiments revealed that KDM6B knockdown significantly suppressed LPS/IFN-γ-induced apoptosis while promoting mitophagy in macrophages. In vivo analyses showed that KDM6B suppression attenuated lung injury severity, inflammatory responses, and improved survival rates in septic mice. Mechanistically, KDM6B knockdown increased H3K27me3 levels, reduced MFN1 expression, and increased H3K27me3 enrichment specifically at the MFN1 promoter region. These findings demonstrate that KDM6B silencing facilitates H3K27me3 modification at the MFN1 promoter to inhibit its transcription, subsequently suppressing macrophage apoptosis and promoting mitophagy, which collectively mitigates sepsis-induced ALI progression.
    Keywords:  H3K37me3; KDM6B; MFN1; Mitophagy; Sepsis-induced acute lung injury
    DOI:  https://doi.org/10.1038/s41598-025-27199-z
  39. Int J Mol Sci. 2025 Nov 29. pii: 11608. [Epub ahead of print]26(23):
    Role of Acetaldehyde and Dysregulated Mitophagic Lysosomal Processing in Chronic-Binge Ethanol-Induced Liver Injury.
    Devadoss J Samuvel, Emory Foerster, Li Li, Amir K Richardson, Patrick M Wooster, John J Lemasters, Zhi Zhong.
      Chronic binge drinking is common among patients with alcohol-associated steatohepatitis. Therefore, we tested the hypothesis that chronic binge ethanol exposure disrupts mitophagic processing and stimulates release of mitochondrial damage-associated molecular patterns (mtDAMPs), thereby promoting hepatic inflammation and fibrosis after chronic binge ethanol (CBE) exposure in mice using the National Institute of Alcohol Abuse and Alcoholism model. After CBE, hepatic steatosis, liver injury, inflammation, and hepatic stellate cell (HSC) activation occurred. Alda-1, an aldehyde dehydrogenase-2 activator, attenuated these changes. After CBE, mitochondrial depolarization (mtDepo) occurred in ~85% hepatocytes, and mitophagy-associated proteins increased, which Alda-1 blunted. By contrast, transcription factor-EB (master regulator of lysosomal biogenesis) and lysosomal markers decreased, indicating disrupted lysosomal processing. After mitophagy, mitochondrial biogenesis (MB) restores mitochondrial mass and function. After CBE, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (MB regulator), mitochondrial transcription factor-A, oxidative phosphorylation proteins, and fatty acid oxidation all decreased, which Alda-1 largely restored. After CBE, serum mtDAMPs (mitochondrial DNA and cytochrome c) increased 3- to 10-fold. In vitro, mitochondrial DNA stimulated macrophage and HSC activation, which was prevented by toll-like receptor-9 inhibition. In conclusion, CBE increases mtDepo in an acetaldehyde-dependent fashion, leading to mitophagic overburden, disruption of mitochondrial homeostasis, mtDAMP release, and ultimately development of liver inflammation and injury.
    Keywords:  Alda-1; acetaldehyde; alcohol-associated liver disease; lysosome; mitochondrial biogenesis; mitochondrial damage-associated molecular patterns; transcription factor-EB
    DOI:  https://doi.org/10.3390/ijms262311608
  40. Theranostics. 2026 ;16(3): 1410-1431
    PINK1/Parkin promotes liver regeneration via Sigma-1 ubiquitination to inhibit ER-Mitochondrial calcium transfer.
    Jian Xu, Yuechen Wang, Weizhe Zhong, Haoran Hu, Ye Zhang, Yiyun Gao, Ping Wang, Zhuqing Rao, Haoming Zhou, Xuehao Wang.
      Rationale: Liver regeneration is regulated by both metabolic processes and immune responses. Nonetheless, there is limited comprehension of the mechanisms involved. PINK1/Parkin-mediated mitophagy has been well documented, the role and underlying alternative mechanism of PINK1/Parkin in regulating mitochondrial metabolism during liver regeneration remains unclear. Methods: Liver tissues from mice undergoing hepatectomy were utilized to evaluate the expression levels of PINK1/Parkin. Hepatocyte-specific PINK1 knockout and transgenic mouse models were generated to investigate the impact of PINK1 on regeneration. Mass spectrometry, co-immunoprecipitation, and ubiquitination assays were performed to explore the underlying molecular mechanisms. Results: We observed PINK1/Parkin expression was markedly upregulated in hepatic tissue following liver resection. PINK1 depletion in hepatocytes caused impaired liver regeneration. Moreover, mitochondrial calcium overload was found be responsible for restricted TCA by inhibiting succinate dehydrogenase activity in PINK1 deficient hepatocytes. Interestingly, PINK1 deficiency leads to succinate accumulation and release from hepatocytes, which impairs liver regeneration by restricting macrophage pro-repair phenotypes. This effect was further confirmed by enhanced regeneration in myeloid SUCNR1 knockout mice. Mechanistically, Sigma-1 is a molecular chaperone of the endoplasmic reticulum calcium channel IP3R, which helps maintain its normal functional conformation. Parkin was able to bind Sigma-1 through its UBL domain, facilitating its k48-linked ubiquitination, which promotes Sigma-1 degradation and subsequently suppressing calcium transfer from the ER to mitochondria at the mitochondrial-associated ER membrane. Conclusions: Collectively, PINK1/Parkin signaling regulates hepatocellular mitochondrial ATP and succinate production by modulating ER-mitochondria calcium transfer to promote liver regeneration, revealing a promising therapeutic target for liver regeneration.
    Keywords:  MAM calcium channel; PINK1/Parkin; liver regeneration; sigma-1; succinate
    DOI:  https://doi.org/10.7150/thno.115726
  41. Sci Rep. 2025 Dec 09.
    Ubiquitin-specific protease 14 inhibition promotes mitophagy and attenuates neural apoptosis after spinal cord injury.
    Dingwei Wu, Dehui Chen, Huina Chen, Zhengxi Yu, Hao Feng, Linquan Zhou, Zhi Chen, Tengbin Shi, Rongcan Wu, Yelei Zhang, Lei Sun, Zhenyu Wang, Wenge Liu.
      
    Keywords:  DUBs; Mitophagy; Spinal cord injury; USP14; USP14 inhibition
    DOI:  https://doi.org/10.1038/s41598-025-31745-0
  42. Int J Parasitol. 2025 Dec 09. pii: S0020-7519(25)00227-9. [Epub ahead of print]
    Callunene, mitophagy, and flagellum removal in trypanosomatids.
    Andreu Saura, Vilém Blahout, Edubiel A Alpizar-Sosa, Haoshen Wen, Aditya Reddy, Galina Prokopchuk, Julius Lukeš, Tereza Kubátová, Wim Dehaen, Silvie Rimpelová, Alexei Yu Kostygov, Pavla Perlíková, Vyacheslav Yurchenko.
      Callunene, a natural component of heather (Calluna vulgaris) nectar, has previously been shown to protect bumblebees from infection by the trypanosomatid Crithidia bombi. Here, we demonstrate that callunene exhibits antiparasitic activity against several trypanosomatid species, including Crithidia bombi, Leishmania mexicana, and Trypanosoma brucei. Notably, callunene's in vitro efficacy against T. brucei was comparable to that of nifurtimox, although its cytotoxicity toward human cells may limit direct therapeutic application. Using a biotinylated callunene analogue in the pull-down assay, we identified NIPSNAP, a mitochondrial protein involved in mitophagy regulation, as a primary molecular target of this compound in C. bombi. Moreover, callunene alters acidocalcisome abundance, further connecting its role to regulation of mitochondrial physiology. Given its effects on mitochondria and ability to interact with NIPSNAP, callunene represents a promising chemical probe for studying mitophagy, a poorly understood process in trypanosomatids, and may provide new insights into mitochondrial biology of these parasites.
    Keywords:  Callunene; Crithidia bombi; flagellum removal; mitophagy
    DOI:  https://doi.org/10.1016/j.ijpara.2025.12.002
  43. Int J Biol Sci. 2026 ;22(1): 308-326
    Piezo1-driven mechanotransduction regulates mitochondrial biogenesis by AMPK/SIRT1-mediated PGC-1α deacetylation to ameliorate bone loss in disuse osteoporosis.
    Jianpeng Chen, Dengying Wu, Chengbin Huang, Zijian Yan, Jiahao Wang, Siteng Li, Xuankuai Chen, Yanbin Zhu, Yingze Zhang.
      Disuse osteoporosis (DOP), a skeletal disorder triggered by insufficient mechanical loading, manifests as progressive bone mass deterioration and microarchitectural weakening. Piezo1, a key mechanosensitive ion channel expressed in bone cells, is implicated in maintaining skeletal homeostasis. Using a murine hindlimb unloading (HLU) model simulating microgravity-induced bone loss, we observed significant downregulation of Piezo1 expression in bone tissue and isolated bone marrow-derived mesenchymal stem cells (BMSCs). Systemic administration of the Piezo1 agonist Yoda1 attenuated HLU-induced osteopenia and improved bone formation capacity. Mechanistic studies in BMSCs demonstrated that Piezo1 activation promoted mitochondrial biogenesis. This effect required AMPK/SIRT1 signaling-dependent deacetylation of PGC-1α, leading to enhanced mitochondrial function, improved osteogenic differentiation, and reduced apoptosis. Critically, pharmacologic inhibition of SIRT1 abolished the osteoprotective effects of Yoda1 in vivo. These findings establish that mechanical unloading impairs Piezo1-mediated mechanotransduction in BMSCs, contributing to disrupted skeletal homeostasis, which can be mitigated by exogenous Piezo1 activation. Our results define a mechanism where Piezo1 integrates mechanical signals into the AMPK/SIRT1/PGC-1α signaling cascade to regulate mechanoadaptive bone formation, highlighting Piezo1 activation as a potential mechanism-based therapeutic strategy for disuse osteoporosis.
    Keywords:  AMPK/SIRT1; PGC-1α deacetylation; Piezo1; disuse osteoporosis; mitochondrial biogenesis
    DOI:  https://doi.org/10.7150/ijbs.124043
  44. Cells. 2025 Nov 26. pii: 1861. [Epub ahead of print]14(23):
    β-Cell Mitochondrial Dysfunction: Underlying Mechanisms and Potential Therapeutic Strategies.
    Radwan Darwish, Yasmine Alcibahy, Ghena Abu-Sharia, Alexandra E Butler.
      Mitochondria are essential for β-cell function, coupling glucose metabolism to ATP production and insulin secretion. In diabetes, β-cell mitochondrial dysfunction arises from oxidative stress, impaired quality control and disrupted dynamics, leading to reduced oxidative phosphorylation, defective insulin release and progressive cell loss. Key transcriptional regulators link genetic susceptibility to mitochondrial dysfunction in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These disruptions impair mitophagy, mitochondrial translation and redox homeostasis. Therapeutic strategies that restore mitochondrial function, including mitophagy enhancers, mitochondrial antioxidants, and transcriptional regulators, have shown potential in preserving β-cell integrity. As mitochondrial failure precedes β-cell loss, targeting mitochondrial pathways may represent a critical approach to modifying diabetes progression.
    Keywords:  diabetes; mitochondria; mitochondrial dysfunction; mitophagy; β-cell
    DOI:  https://doi.org/10.3390/cells14231861
  45. FEBS J. 2025 Dec 07.
    The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
    Jiaxin Qian, Annika Nutz, Katja Hansen, Lea Bertgen, Mirita Franz-Wachtel, Boris Macek, Johannes M Herrmann, Doron Rapaport.
      The biogenesis of mitochondria relies on the import of newly synthesized precursor proteins from the cytosol. Tom70 is a mitochondrial surface receptor which recognizes precursors and serves as an interface between mitochondrial protein import and the cytosolic proteostasis network. Mitochondrial import defects trigger a complex stress response, in which compromised protein synthesis rates are a characteristic element. The molecular interplay that connects mitochondrial (dys)function to cytosolic translation rates in yeast cells is however poorly understood. Here, we show that the deletion of the two Tom70 paralogs of yeast (TOM70 and TOM71) leads to defects in mitochondrial biogenesis and slow cell growth. Surprisingly, upon heat stress, the deletion of ZUO1, a chaperone of the ribosome-associated complex (RAC), largely prevented the slow growth and the reduced translation rates in the tom70Δ/tom71Δ double deletion mutant. In contrast, the mitochondrial defects were not cured but even enhanced by ZUO1 deletion. Our study shows that Zuo1 is a critical component in the signaling pathway that mutes protein synthesis upon mitochondrial dysfunction. We propose a novel paradigm according to which RAC serves as a stress-controlled regulatory element of the cytosolic translation machinery.
    Keywords:  Tom70; mitochondria; protein import; proteostasis; ribosome‐associated complex
    DOI:  https://doi.org/10.1111/febs.70356
  46. J Immunol. 2025 Dec 08. pii: vkaf325. [Epub ahead of print]
    The role of mitophagy during hematopoiesis in an invertebrate, Pacifastacus leniusculus.
    Waruntorn Luangtrakul, Kenneth Söderhäll, Irene Söderhäll.
      Freshwater crayfish as most aquatic crustaceans live for up to 20-30 years on the bottom of lakes and rivers, constantly exposed to millions of microorganisms. Consequently, they must have an effective immune system to combat and eliminate pathogens. The main immune cells are the hemocytes, and they are regularly consumed during the animal's whole life and are continuously produced through hematopoiesis. We used DMSO as a tool to induce differentiation of hematopoietic stem cells and we can show that differentiation of hematopoietic stem cells to mature hemocytes in a freshwater crayfish is preceded by degradation of mitochondria by mitophagy and this process could be inhibited by a mitophagy inhibitor. The differentiation process was regulated by β-catenin signaling in similarity to differentiation of human neutrophils. A better understanding of the molecular mechanisms that regulate hemocyte development in these animals will provide new insights into the evolution of the innate immune system and hematopoiesis in general.
    Keywords:  crustaceans; hematopoiesis; innate immunity; invertebrate
    DOI:  https://doi.org/10.1093/jimmun/vkaf325
  47. ACS Infect Dis. 2025 Dec 08.
    Berberine Suppresses Pathogenic Fungus Aspergillus fumigatus Hyphal Growth via Mitochondrial Fragmentation-Induced ROS Elevation and Hog1-MAPK Activation.
    Hengxiu Wang, Hongchen Wang, Yue Yang, Tianming Wang, Changzhong Wang, Daqiang Wu, Caixia Zheng, Wenfan Wei.
      Berberine (BER), a natural isoquinoline alkaloid, exhibits broad-spectrum antifungal activity, yet its mechanism against Aspergillus fumigatus─a leading cause of invasive fungal infections─remains poorly understood. Here, we aim to unveil the mechanism of BER against the pathogenicity of A. fumigatus through mitochondrial dynamics and related pathways. In vitro assays revealed that berberine treatment triggered mitochondrial fragmentation, resulting in reactive oxygen species (ROS) overaccumulation. Subsequent proteomic analyses identified Hog1-MAPK as the central signaling hub activated by ROS stress. Upon activation, Hog1 localizes to the nucleus. ROS scavenging (N-acetylcysteine (NAC) treatment) abolished BER's antifungal effects, confirming the ROS-Hog1-cell cycle axis. Crucially, in a murine invasive aspergillosis model, BER reduced the fungal burden in lungs and improved survival rates. Thus, we demonstrate that berberine suppresses A. fumigatus growth by disrupting mitochondrial dynamics, elevating reactive ROS, and activating the Hog1-MAPK signaling cascade, ultimately inducing cell cycle arrest. Our findings unveil a previously unrecognized mechanism linking mitochondrial morphology dysregulation to cell cycle control in fungi and establish BER as a promising therapeutic agent targeting mitochondrial-ROS-Hog1 signaling in A. fumigatus infections.
    Keywords:  Aspergillus fumigatus; Hog1-MAPK; berberine; cell cycle arrest; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsinfecdis.5c00749
  48. Int J Mol Sci. 2025 Nov 24. pii: 11329. [Epub ahead of print]26(23):
    Modulatory Potential of Alpinetin on Inflammation, Oxidative Stress, Apoptosis, and Mitochondrial Dynamics in a Rat Middle Cerebral Artery Occlusion Model of Ischemic Stroke.
    Sitthisak Thongrong, Ratchaniporn Kongsui, Lars Klimaschewski, Jinatta Jittiwat.
      Ischemic stroke initiates a complex cascade of pathophysiological events-including energy failure, excitotoxicity, oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction-that together lead to extensive neuronal damage. Effectively targeting these interconnected mechanisms is crucial for achieving neuroprotection. Alpinetin, known for its antioxidant, anti-inflammatory, and cytoprotective properties, has shown promise as a potential therapeutic agent for cerebral ischemia in preliminary studies. However, the exact molecular mechanisms underlying its neuroprotective effects remain unclear. Therefore, this study aimed to investigate the multifaceted actions of alpinetin in a preclinically relevant right middle cerebral artery occlusion (Rt.MCAO) rat model, focusing on its impact on neuronal survival, inflammation, oxidative stress, apoptosis, and mitochondrial function. Forty male Wistar rats were randomly assigned to four groups: sham operation, Rt.MCAO + vehicle, Rt.MCAO + piracetam (250 mg/kg BW), and Rt.MCAO + alpinetin (100 mg/kg BW). We examined glial cell morphology, protein kinase B (Akt) expression, mitochondrial superoxide dismutase (MnSOD), myeloperoxidase (MPO), anti-apoptotic proteins, mitogen-activated protein kinase (p38 MAPK) and mitofusin-2 (Mfn2). Treatment with alpinetin for 3 days exerted robust neuroprotective effects by significantly reducing astrocytic and microglial activation through the downregulation of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1), restoring Akt expression, decreasing MPO activity, and enhancing MnSOD activity. Additionally, alpinetin modulated apoptotic signaling by lowering pro-apoptotic markers Bcl-2 Associated X-protein (Bax) and caspase-3 while increasing the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL). It also attenuated p38 MAPK activation and preserved mitochondrial integrity by mitigating the decline in Mfn2 levels. Overall, these findings highlight the therapeutic potential of alpinetin in targeting multiple pathological processes involved in ischemic brain injury, supporting its promise as an effective treatment for stroke.
    Keywords:  alpinetin; apoptosis; inflammation; ischemic stroke; mitochondrial dynamics; oxidative stress
    DOI:  https://doi.org/10.3390/ijms262311329
  49. Front Cell Dev Biol. 2025 ;13 1606805
    Mitochondrial AAA+ protease activity uncovers differential sensitivity of Drosophila blood cell lineages to systemic cues.
    Rajarshi Batabyal, Aman Sharma, Maneesha S Inamdar.
      Hematopoiesis involves balanced blood progenitor proliferation, differentiation, and death, in response to dynamic physiological cues. Previous studies have shown that Drosophila lymph gland blood progenitors reside in functionally distinct compartments. Mitochondrial fission-fusion balance and maturity also vary among progenitor compartments and affect cell fate and lineage choice. Here, we show that perturbing mitochondrial homeostasis in Drosophila blood cells (hemocytes), can have multiple long-range effects on lymph gland hematopoiesis. Specifically, depletion of the mitochondrial AAA+ proteases AFG3L2 or YME1L from the niche or blood progenitors, caused larval lethality. However, depletion from hemocytes alone, gave viable larvae but with a histolysed primary lobe, and an intact and expanded niche. Posterior lobes showed severe hyperproliferation and precocious differentiation. Genetic or pharmacological reduction of ROS restored LG size and differentiation status to control levels, while reducing Hippo pathway activity partially rescued the precocious differentiation. Our study provides the first insights into the roles of mitochondrial AAA+ proteases in mediating generation or modulation of systemic signals that control inter-compartmental cross talk between hemocytes and the hematopoietic organ. We propose that mitochondrial homeostasis in hemocytes is a key point of control that helps restrict progenitor differentiation. Given the conservation in AAA+ protease functions and in signaling pathways that control hematopoiesis, our studies will help gain insight into systemic control of mammalian hematopoiesis.
    Keywords:  AAA+ proteases; AFG3L2; ROS; YME1L; hematopoiesis; lymph gland
    DOI:  https://doi.org/10.3389/fcell.2025.1606805
  50. Neurol Res. 2025 Dec 12. 1-16
    Astrocyte S1P1 regulates mitochondrial autophagy in inflammation and neuronal injury after epilepsy.
    Lixiang Yang, Chao Cheng, Weifeng Miao, Zhaodi Liao, Weiyi Huang, Qijian Zhang, Yuanrun Zhu, Jun Sun, Junfei Shao.
       OBJECTIVE: The aim of this study is to explore the mechanism by which sphingosine 1-phosphate receptor 1 (S1P1) regulates mitochondrial autophagy through PHB2, thereby exacerbating inflammation and nerve damage after epilepsy.
    METHODS: This study investigated the mechanisms of S1P1 and PHB2 in neuroinflammation and neuronal damage caused by epilepsy using in vitro and in vivo experiments. In vitro, a magnesium-free epilepsy model was established to induce synchronous epileptic activity. In vivo, a pilocarpine-induced epilepsy model was used with S1P1 agonists (SEW2871) and inhibitors (W146). Protein expression was analyzed by Western blotting, qPCR, and immunofluorescence for gene expression, autophagy and inflammatory markers. NBT staining measured superoxide anion production, while ATP and DCFDA assays assessed ATP and ROS levels. Patch clamp techniques measured neuronal excitability. Behavioral tests included open field tests and EEG recordings to evaluate seizure activity and behavioral deficits.
    RESULTS: PHB2 expression was significantly upregulated in epileptic astrocytes, leading to increased mitochondrial autophagy and enhanced oxidative stress. Knocking out PHB2 reduced autophagy flux and decreased pro-inflammatory cytokines, indicating its role in exacerbating inflammation. S1P1-PHB2 pathway activation upregulated both S1P1 and PHB2, promoting mitochondrial autophagy and neuroinflammation, which exacerbated epilepsy symptoms.
    CONCLUSION: S1P1-PHB2 axis plays a crucial role in the neuroinflammation and neurodamage caused by epilepsy. S1P1, through PHB2, promotes mitochondrial autophagy, increases oxidative stress and releases pro-inflammatory cytokines, thereby leading to neural damage. By using the S1P1 antagonist W146 to inhibit autophagy and inflammatory responses, these effects can be alleviated.
    Keywords:  Mitochondrial Autophagy; PHB2; S1P1; epilepsy; inflammation
    DOI:  https://doi.org/10.1080/01616412.2025.2602687
  51. J Stroke Cerebrovasc Dis. 2025 Dec 06. pii: S1052-3057(25)00296-4. [Epub ahead of print]35(1): 108519
    Based on the PINK1/Parkin signaling pathway, the protective effect of salidroside on cerebral ischemia-reperfusion injury in male rats was investigated.
    Ting Dong, Haoyu Wang, Yanwei Li, Jun Tan.
       OBJECTIVE: Based on the male Sprague-Dawley rats middle cerebral artery occlusion model and SH-SY5Y hypoxia-reoxygenation model, this study systematically evaluated the neuroprotective effect of salidroside (SAL) on cerebral ischemia/reperfusion injury in rats, and explored its possible protective mechanism through PINK1/Parkin signaling axis regulating mitochondrial autophagy.
    MATERIALS AND METHODS: Using the middle cerebral artery occlusion (MCAO) model in male Sprague-Dawley rats and the SH-SY5Y cell hypoxia-reoxygenation model, we assessed neurological damage severity through the modified neurological severity scores (NSS). Brain histopathological changes were evaluated using hematoxylin-eosin staining, while the infarct volume in the ischemic brain was assessed with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Transmission electron microscopy was employed to observe mitochondrial ultrastructural alterations in the ischemic brain tissue. Western blotting was used for quantitative analysis of key autophagy-related molecules (PINK1, Parkin), and ROS, MDA, and ferrous ion kit were utilized to evaluate ferroptosis biomarker.
    RESULTS: The findings indicate that SAL effectively reduces infarction rates and ameliorates histopathological changes. SAL decreases the formation of reactive oxygen species, malondialdehyde, and ferrous ions by upregulating the expression of PINK1 and Parkin proteins, thereby mitigating apoptosis. Furthermore, SAL significantly inhibits ferroptosis in SH-SY5Y neuroblastoma cells subjected to OGD/R and reduces oxidative stress. The application of the mitochondrial autophagy inhibitor Mdivi-1 enhances the protective effect of SAL against ferroptosis in both MCAO and OGD/R models. Therefore, we draw the following conclusions: In the rat cerebral ischemia-reperfusion injury model and the SH-SY5Y cell oxygen-glucose deprivation/reoxygenation (OGD/R) model, iron death was found to be increased. Pre-treatment with salidroside was able to reduce the occurrence of iron death in both the cerebral ischemia-reperfusion injury model and the cellular OGD/R model.
    CONCLUSIONS: Salidroside may inhibit iron death by activating the PINK 1 / Parkin signaling pathway and thereby reduce cerebral ischemia-reperfusion injury. Targeted regulation of this pathway may become an important strategy to interfere with CIRI.
    Keywords:  Cerebral Ischemia-Reperfusion Injury(CIRI); Ferroptosis; GPX4; Mitochondrial Autophagy; Salidroside
    DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2025.108519
  52. Phytomedicine. 2025 Dec 03. pii: S0944-7113(25)01285-1. [Epub ahead of print]150 157651
    Lobetyolin alleviates microglial inflammation by activating CK2α/Opa1-mediated mitochondrial fusion in ischemic stroke.
    Na Qin, Rujuan Liu, Rong Deng, Wanqi Jia, Yuxi Yang, Jianyu Sun, Shiman Gao, Ting Zhu.
       BACKGROUND: The inflammatory response triggered by mitochondrial damage is considered one of the key pathogenic mechanisms of ischemic stroke (IS). Lobetyolin (LBT), the main active component of Codonopsis Radix, has pharmacological potential for inhibiting neuroinflammation, but its underlying mechanisms has not been fully defined.
    PURPOSE: The aim of this study was to investigate the neuroinflammatory inhibitory effect of LBT on mitochondrial disorders in IS and its underlying mechanisms.
    METHODS: In this study, key targets and biological pathways of IS were determined by RNA sequencing, and network pharmacology was used to predict key drug-disease targets. We established a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model and an oxygen-glucose deprivation/reperfusion (OGD/R) cellular model in vivo and in vitro. 2,3,5-Triphenyltetrazolium chloride (TTC) staining, cerebral blood flow measurements, neurological behavioural scoring and behavioural testing were performed to elucidate the neuroprotective effects of LBT. Moreover, the mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured to assess mitochondrial function. Mechanistically, molecular docking experiments, CETSA, DARTS and inhibitor experiments were performed to elucidate the potential mechanism by which LBT treats IS.
    RESULTS: LBT inhibited inflammatory responses, maintained mitochondrial function, promoted Opa1-mediated mitochondrial fusion, and exerted neuroprotective effects on IS in vivo and in vitro. The inhibition of Opa1 expression weakened the inhibitory effect of LBT on neuroinflammation in OGD/R-induced Bv2 cells. Mechanistically, the results of molecular docking, CETSA, and DARTS experiments revealed that CK2α is a direct target of LBT and interacts with Jak2, leading to the phosphorylation and activation of the Jak2-Stat3 signalling pathway. The inhibition of CK2α attenuated the phosphorylation of Stat3 and Jak2 by LBT and promoted Opa1-mediated mitochondrial fusion and mitochondrial function.
    CONCLUSIONS: This study demonstrated that LBT alleviates neuroinflammation by directly targeting CK2α and promoting Opa1-mediated mitochondrial fusion, which is a previously unrecognized mechanism underlying its neuroprotective effects. These findings revealed the potential of LBT as a therapeutic agent targeting CK2α/Opa1 for IS treatment, providing insights for the development of new strategies.
    Keywords:  CK2α; Inflammation; Ischemic stroke; Lobetyolin; Mitochondrial fusion; Opa1
    DOI:  https://doi.org/10.1016/j.phymed.2025.157651
  53. Biochem Pharmacol. 2025 Dec 06. pii: S0006-2952(25)00889-5. [Epub ahead of print]244 117624
    Agomelatine alleviates hypoxia-induced pulmonary arterial hypertension by activating mitophagy via the SIRT1/FoxO1/ULK1 signaling pathway.
    Jia-Yi Zhang, Rui Zhang, Jiaqi Liu, Ling Chen, Yu-Jie Sun, Yi-Ting He, Wei-Ping Xie, Lan Wang, Hui Kong, Meng-Yu He.
      Human melatonin receptor type 1/2 (MTR1/MTR2) are widely distributed throughout the body and play essential roles in regulating cardiovascular physiology. However, the therapeutic potential of agomelatine (AGM), a melatonin analog and nonselective MTR1/MTR2 agonist, in pulmonary arterial hypertension (PAH) remains unclear. The present investigation was designed to evaluate the ameliorative potential of AGM on pulmonary vascular remodeling in a SU5416/hypoxia (SuHx)-induced PAH rat model, and to elucidate the concomitant mechanistic pathways. Our experimental data demonstrated that AGM treatment significantly diminished right ventricular systolic pressure, mitigated right ventricular hypertrophy, and attenuated medial wall thickening of pulmonary arteries. Notably, immunofluorescence staining further revealed predominant localization of MTRs within the smooth muscle layer of pulmonary arteriole. In vitro, AGM significantly suppressed hypoxia-evoked proliferative and migratory responses in human pulmonary artery smooth muscle cells (PASMCs). Mechanistically, AGM enhanced mitochondrial reactive oxygen species generation and facilitated mitophagic flux, as corroborated by upregulated LC3-II protein expression, diminished p62 abundance, and increased mitochondrial-lysosomal colocalization. Transcriptomic analysis identified unc-51 like autophagy activating kinase 1 (ULK1) as a pivotal mediator of AGM-induced mitophagy. Genetic silencing of ULK1 abrogated the cytoprotective efficacy of AGM against hypoxia-evoked PASMC dysfunction. Further investigation revealed that AGM upregulated Sirtuin 1 (SIRT1) expression, leading to forkhead box protein 1(FoxO1) deacetylation. In contrast, inhibition of SIRT1 resulted in increased FoxO1 acetylation, which subsequently downregulated ULK1 expression and impaired mitophagy. Collectively, these findings establish that AGM exerts therapeutic effects in PAH by enhancing ULK1-dependent mitophagy through modulation of the SIRT1/FoxO1 signaling axis, underscoring its potential as a novel therapeutic candidate for PAH.
    Keywords:  Melatonin analog; Mitophagy; Pulmonary arterial hypertension; Pulmonary arterial smooth muscle cells; Unc-51 like autophagy activating kinase 1
    DOI:  https://doi.org/10.1016/j.bcp.2025.117624
  54. World J Clin Oncol. 2025 Nov 24. 16(11): 113193
    Ferroptosis, autophagy, and mitochondrial dynamics: Front burners in cancer therapeutics.
    Minal Garg, Niharika.
      This article comments on the article by Rana and Prajapati published in the recent issue. Cancer remains the most formidable public health problem and contributes to significant mortality worldwide. Tumor heterogeneity, toxicity and acquired resistance limit the efficacy of widely used cancer therapies such as radiotherapy, chemotherapy, gene therapy, and immunotherapy. Regulated cell death maintains cellular homeostasis and is a primary hallmark of cancer. Review by Rana and Prajapati discusses the mechanistic regulation of ferroptosis, autophagy, and mitochondrial dynamics in cancer and highlights the therapeutic possibilities of these regulated cell death pathways for developing more effective and targeted cancer therapies, mainly for aggressive and drug-resistant tumors. Considering the important regulatory role of ferroptosis, autophagy and its dynamic interplay with mitochondrial metabolism in tumor pathogenesis, therapy resistance and metastasis, reshaping of the tumor microenvironment with modulations in autophagy and mitochondrial function could sensitize ferroptosis-resistant tumors to anticancer drugs thereby increase the therapeutic efficacy of existing treatment regimens. Deeper understanding of the crosstalk may lead to the identification of non-invasive biomarkers for detecting ferroptosis-sensitive and resistant tumors, prediction of treatment response and the development of clinically translatable pharmacological strategies to maximize patient benefit while minimizing adverse outcomes.
    Keywords:  Anti-cancer drugs; Autophagy; Ferroptosis; Mitochondrial metabolism; Therapy resistance
    DOI:  https://doi.org/10.5306/wjco.v16.i11.113193
  55. Toxicol Appl Pharmacol. 2025 Dec 10. pii: S0041-008X(25)00463-6. [Epub ahead of print] 117687
    Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis.
    Sultan Alrashdi, Shimaa K Mohamed, Mohamad Elbaz, Elsayed K El-Sayed.
      Bladder ischemia, frequently associated with vascular insufficiency, contributes to lower urinary tract symptoms via oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial defect, and apoptosis. Ischemia-reperfusion (I/R) injury exacerbates these effects by generating excessive reactive oxygen species. Trimetazidine (TMZ), an anti-ischemic agent, has shown protective effects in several I/R models; however, its role in bladder injury remains insufficiently characterized. This study investigated the protective effect of TMZ against bladder I/R injury in rats, focusing on oxidative stress, inflammation, ER stress, mitochondrial biogenesis, microRNA regulation, and apoptosis. Forty rats were allocated into four groups: sham control, I/R, and two TMZ-pretreated groups (10 or 20 mg/kg/day, p.o., for 14 days) prior to I/R induction. Controls received Tween 80 vehicle. Bladder tissues were collected for biochemical, molecular, and histopathological analyses. TMZ showed protection by lowering MDA (~43.5-60.8 %) and enhancing GSH (~2-2.6 fold) and SOD activity (~2-3.2 fold). ER stress was attenuated, with reduced p-PERK (~29.4-63 %) and CHOP (~29.1-60 %), alongside upregulation of mirR-211 (~1.4-1.9 fold). TMZ restored mitochondrial biogenesis through increased SIRT1 (~1.9-2.4 fold), PGC1α (~2.1-4.3 fold), p-AMPK (~3-6.3 fold), and ATP (~2-2.8 fold). It also downregulated pro-apoptotic (Bax, Caspase 3) and pro-inflammatory (TNF-α, IL-1β) mediators. Histopathology revealed marked preservation of bladder architecture, particularly at 20 mg/kg. TMZ exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective effects in bladder I/R injury via modulation of oxidative stress, ER stress, mitochondrial pathways, and the mirR-211/CHOP axis. These findings suggest that TMZ may represent a promising therapeutic candidate for ischemia-associated bladder dysfunction, providing a mechanistic basis for future translational and clinical investigation.
    Keywords:  Bladder ischemia-reperfusion injury; Endoplasmic reticulum stress; Oxidative stress; SIRT1/AMPK/PGC1α pathway; Trimetazidine; mirR-211/CHOP axis
    DOI:  https://doi.org/10.1016/j.taap.2025.117687
  56. Structure. 2025 Dec 11. pii: S0969-2126(25)00446-0. [Epub ahead of print]
    An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial import.
    Maxwell J Bachochin, Kelly L McGuire, Brian D Cook, Qiaozhen Ye, Steven Silletti, Kevin D Corbett, Elizabeth A Komives, Mark A Herzik.
      Tom70 mediates mitochondrial protein import by coordinating transfer of cytosolic preproteins from Hsp70/Hsp90 to the translocase of the outer membrane (TOM) complex. In humans, the cytosolic domain of Tom70 (HsTom70c) is entirely α-helical and comprises modular TPR motifs divided into an N-terminal chaperone-binding and a C-terminal preprotein-binding domain. However, the mechanisms linking these functional regions remain poorly understood. Here, we present the 2.04 Å crystal structure of unliganded HsTom70c, revealing two distinct conformations-open and closed-within the asymmetric unit. These states are stabilized by interdomain crystal contacts and supported in solution by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Principal component and network analyses reveal a continuum of motion linking the NTD and CTD via key residues in helices α7, α8, and α25. Engagement of the CTD by viral protein Orf9b disrupts this network, stabilizing a partially closed intermediate and dampening distal NTD dynamics.
    Keywords:  HDX-MS; Orf9b; Tom70; X-ray crystallography; allostery; mitochondrial protein import; molecular dynamics; protein dynamics
    DOI:  https://doi.org/10.1016/j.str.2025.11.011
  57. J Cell Mol Med. 2025 Dec;29(23): e70983
    RETRACTION: Melatonin Modulates Mitophagy, Innate Immunity and Circadian Clocks in a Model of Viral-Induced Fulminant Hepatic Failure.
       RETRACTION: I. Crespo, P. Fernández-Palanca, B. San-Miguel, M. Álvarez, J. González-Gallego, and M.J. Tuñón, "Melatonin Modulates Mitophagy, Innate Immunity and Circadian Clocks in a Model of Viral-Induced Fulminant Hepatic Failure," Journal of Cellular and Molecular Medicine 24, no. 13 (2020): 7625-7636, https://doi.org/10.1111/jcmm.15398. The above article, published online on 29 May 2020 in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, Stefan N. Constantinescu; the Foundation for Cellular and Molecular Medicine; and John Wiley & Sons Ltd. Following publication, concerns were raised by third parties regarding duplications in panels C and F in Figure 1B. Additional concerns of duplication and splicing were also raised for Figures 2C and 3B, which were investigated and confirmed by the publisher; additionally, portions of Figure 4 were duplicated from Figure 3 of an earlier article by some of the same authors (González-Fernández et al. 2018 [https://doi.org/10.3389/fphar.2018.00556]). The authors provided their raw data, but this was not sufficient to resolve the concerns, and the authors were unable to provide a satisfactory explanation. The retraction has been agreed upon because of concerns that portions of the figures were duplicated, affecting the interpretation of the data and results presented.
    DOI:  https://doi.org/10.1111/jcmm.70983
  58. Plant Commun. 2025 Dec 09. pii: S2590-3462(25)00429-8. [Epub ahead of print] 101667
    The transcription factor ANAC017 links mitochondrial retrograde signaling with the ubiquitin-proteasome system to control mitochondrial function in Arabidopsis.
    Yang Zhao, Michael Ogden, Ronghui Pan, Jianping Hu, Staffan Persson, Monika W Murcha, Huixia Shou, Yan Wang, Ghazanfar Abbas Khan, James Whelan.
      Mitochondrial biogenesis requires the import of more than a thousand proteins encoded by nuclear DNA. The translocase of the outer mitochondrial membrane (TOM) complex serves as the primary gateway to specifically recognise precursor proteins, which are synthesized in the cytosol. Little is known about the regulation of the abundance of the TOM complex. Using forward genetics we identified key 26S proteasome subunits, including REGULATORY PARTICLE NON-ATPASE1A (RPN1A), that impact TOM complex subunits abundance through the ubiquitin-proteasome pathway. Loss of proteasome function through rpn1a mutation or MG132 treatment increased the abundance of TOM20 isoforms and induced mitochondrial stress marker genes. In contrast, overexpression of ANAC017, an endoplasmic reticulum anchored transcription factor that activates mitochondrial retrograde signaling under stress, lowered TOM20 abundance and reduced mitochondrial protein import. The rate of mitochondrial protein import and respiratory activity was also altered. Genetic analyses placed the proteasome downstream of ANAC017, since the decrease in TOM20 required the RPN1a subunit. Transcriptome profiling under antimycin A showed broad ANAC017 dependent reprogramming of ubiquitin proteasome system genes. A second tier formed by ANAC053 and ANAC078 bound promoters of proteasome subunits, including RPN1a, and was required to restrain TOM20 accumulation. These findings establish a two step transcriptional circuit that engages the ubiquitin proteasome system to tune TOM abundance and coordinate protein import with organelle function.
    Keywords:  Mitochondria; Proteasome; Protein turnover; Ubiquitination
    DOI:  https://doi.org/10.1016/j.xplc.2025.101667
  59. iScience. 2025 Dec 19. 28(12): 113996
    High matrix stiffness triggers the YAP-OPA1-TET1/3 loop to drive chemoresistance via enhanced nuclear-mitochondrial communication.
    Peng Wu, Sicheng Wang, Zanmin Hu, Haoyan Zhang, Yuqing Lin, Zizhao Li, Jiahong Wu, Yani Chen, Yujie Chen, Yuandong Xu, Jun Li, Yupeng Guan.
      Chemoresistance remains a major obstacle in prostate cancer therapy. This study demonstrates that high extracellular matrix stiffness promotes chemoresistance by disrupting mitochondrial-nuclear communication. Culturing prostate cancer cells on polyacrylamide hydrogels of varying stiffness revealed that a high-stiffness environment promotes mitochondrial fusion and enhances function. Mechanistic investigations revealed that high matrix stiffness activates YAP, leading to dysregulation of the Hippo signaling pathway, which subsequently upregulates the expression of OPA1 and induces mitochondrial fusion. This fusion triggers a reprogramming of glutamine metabolism. The resulting metabolite, α-ketoglutarate, activated DNA demethylases TET1 and TET3, causing epigenetic modifications of YAP target genes and further exacerbating Hippo pathway dysregulation. Together, this establishes a YAP-OPA1-TET1/3-mediated positive feedback loop between the nucleus and mitochondria that drives drug resistance. Crucially, targeting OPA1 disrupted this loop and reversed stiffness-induced chemoresistance. These findings reveal a novel mitochondrial-nuclear communication, offering new insights for overcoming chemoresistance in prostate cancer.
    Keywords:  bioinformatics; biological sciences; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113996
  60. BMC Pediatr. 2025 Dec 12. 25(1): 984
    Functional identification of two variants in unrelated Chinese patients with DNM1L-related mitochondrial disorders.
    Zhenkun Zhang, Zhehui Chen, Xiaofan Bie, Zhenhua Xie, Xian Li, Jing Liu, Mengjun Xiao, Qiang Zhang, Yaodong Zhang, Yanling Yang, Dongxiao Li.
       BACKGROUND: The DRP1 protein, a member of the dynamin superfamily of GTPases, is encoded by the dynamin-1-like (DNM1L) gene and plays a critical role in mitochondrial fission. There was significant clinical heterogeneity in DNM1L-related disorders.
    METHODS: Whole exome sequencing (WES) was used to identify potential genetic causes of the phenotype in probands. Bioinformatics analysis was performed to analyze the pathogenicity of the identified variants, and 3D protein modeling was constructed to predict their effects on protein structure. Preliminary studies of the functional effects of the variant sites on the encoded proteins were performed by in vitro experiments.
    RESULTS: Two de novo variants, c.1049G>C (p.Gly350Ala) and c.2161C>T (p.Gln721*), were detected in affected individuals. One patient presented with severe epileptic encephalopathy while the other exhibited a distinctive clinical phenotype of hemiparesis. In silico analysis, conservative analysis, and 3D homology modelling indicated that the p.Gly350Ala and the p.Gln721* variants are deleterious. Furthermore, the results of the artificial transfection experiments demonstrated that the p.Gly350Ala variant resulted in a reduction in DNM1L expression at both the transcriptional and protein levels (p < 0.05). In contrast, the p.Gln721* variant exhibited no significant alteration in protein levels (p = 0.08), although it did result in a reduction in mRNA levels.
    CONCLUSIONS: The present findings suggest that these variants may contribute to DRP1 deficiency, potentially triggering a range of DNM1L-related disease phenotypes. This study serves to expand the spectrum of variants associated with DNM1L-related disorders.
    Keywords:   DNM1L gene; Children; DRP1; Phenotypic spectrum; Variant; Whole exome sequencing
    DOI:  https://doi.org/10.1186/s12887-025-06299-9
  61. NPJ Sci Food. 2025 Dec 11.
    Haematococcus pluvialis ameliorates renal fibrosis by restoring mitophagy via PINK1-Parkin-p62-LC3 signaling.
    Yutong Wu, Cailian Chen, Jinmei Xie, Xiuting Chang, Yong Zhang, Yunjian Zheng, Yijun Yuan, Wenting Hu, Xi Xie.
      Renal fibrosis is a key pathological process of chronic kidney disease (CKD) and is associated with epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction. Haematococcus pluvialis (H. pluvialis), a unicellular green alga, is rich in natural antioxidants like astaxanthin and unsaturated fatty acids. This study aimed to explore the renal protective effects and the potential mechanisms of H. pluvialis in vivo and in vitro. The bioinformatics analysis combined with in vivo and in vitro studies revealed that H. pluvialis attenuated renal fibrosis by restoring mitophagy and reversing EMT. For in vivo experiments, H. pluvialis reduced renal ECM deposition and improved renal injury in the unilateral ureteral obstruction (UUO) rats. RNA-seq analysis and in vitro studies showed that H. pluvialis reversed the TGF-β1-induced EMT in HK-2 cells and improved mitochondrial energy metabolism. Immunofluorescence and molecular docking results suggested that H. pluvialis, especially astaxanthin and trans-3-indoleacrylic acid in it, restored mitophagy via PINK1-Parkin-p62-LC3 signaling and reduced pro-fibrotic factor secretion in HK-2 cells. This study supports the development of H. pluvialis as a functional food for CKD management, providing a new strategy to ameliorate renal fibrosis.
    DOI:  https://doi.org/10.1038/s41538-025-00654-x
  62. World J Psychiatry. 2025 Dec 19. 15(12): 108867
    Sini-Suanzaoren decoction regulates mitochondrial biogenesis mediated by MT-SIRT1 in the treatment of insomnia rats.
    Ru-Ting Li, Bi-Juan Lan, Zhuo-Yang Xiao, Qing-Huan Shi, Xin-Yi Chen, Feng Li.
       BACKGROUND: Insomnia is closely associated with anxiety and depression, with its pathogenesis involving biological, psychological, and social factors. Sini powder and Suanzaoren decoction are clinically effective traditional Chinese medicine formulas for insomnia, demonstrating promising bioactivity. However, the capability of the active components of Sini-Suanzaoren decoction (SNSZRD) to cross the blood-brain barrier (BBB) and their precise molecular mechanisms, particularly concerning the MT-SIRT1 pathway and mitochondrial function, remain largely unexplored.
    AIM: To elucidate the bioactive components of SNSZRD that are capable of BBB penetration and investigate the therapeutic mechanism of SNSZRD against insomnia.
    METHODS: The chemical components of SNSZRD were analyzed through liquid chromatography-mass spectrometry (LC-MS). Male Sprague-Dawley rats were intraperitoneally injected with DL-4-chlorophenylalanine (PCPA) to establish an insomnia model. Rats were divided into control, model, eszopiclone (positive control), and SNSZRD low-/medium-/high-dose groups. Molecular docking predicted BBB-penetrating components and their binding affinity for SIRT1. Key pathways were analyzed through open-field tests, elevated plus-maze tests, pentobarbital-induced sleep experiments, Haematoxylin and eosin staining, Nissl staining, ELISA, Western blot analysis, quantitative real-time PCR, and immunohistochemistry.
    RESULTS: LC-MS identified 1574 compounds in SNSZRD, of which eight prototype components (e.g., pachymic acid and senkyunolide G) could cross the BBB. Molecular docking revealed that these components formed stable hydrogen bonds with the SIRT1 protein. SNSZRD treatment significantly ameliorated PCPA-induced anxiety-like behaviors and sleep latency/sleep duration, as well as reduced neuronal degeneration and Nissl body loss in the hypothalamus of treated rats. Additionally, SNSZRD elevated serum melatonin and hypothalamus ATP levels and upregulated the mRNA and protein expression levels of arylalkylamine N-acetyltransferase, SIRT1, PPARγ coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A in the MT-SIRT1-mitochondrial biogenesis pathway.
    CONCLUSION: SNSZRD might exert its therapeutic effects on insomnia by modulating MT-SIRT1 axis-regulated mitochondrial biogenesis in rats and might serve as an effective therapeutic agent for insomnia.
    Keywords:  Insomnia rats; MT-SIRT1-mediated; Mitochondrial biogenesis; Sini-Suanzaoren decoction
    DOI:  https://doi.org/10.5498/wjp.v15.i12.108867
  63. Biol Direct. 2025 Dec 06.
    Autophagy and mitophagy in dermatological disease: a comprehensive review from molecular pathways to therapeutic frontiers.
    Luca D'Ambrosio, Maria Elisabetta Greco, Maurizio Forte, Daniele Vecchio, Sonia Schiavon, Flavio Di Nonno, Shazia Tahir, Vittorio Picchio, Claudia Cozzolino, Gianmarco Sarto, Marco Bernardi, Luigi Spadafora, Beatrice Simeone, Mattia Vinciguerra, Sebastiano Sciarretta, Giacomo Frati, Ernesto Greco, Concetta Potenza, Ilaria Proietti, Jacopo Morroni, Elisa Dietrich, Leonardo Schirone.
      Autophagy - the cell's built-in recycling and quality-control programme - touches every layer of cutaneous biology. In keratinocytes it sculpts the cornified envelope; in melanocytes it balances pigment synthesis and oxidative stress; in immune and appendageal cells it fine-tunes defence, repair and hair-follicle cycling. When this choreography falters, skin disorders emerge. This review journeys from basic mechanisms (ULK1 signalling, Beclin-1/VPS34 nucleation, LC3B lipidation, selective mitophagy) to their fingerprints in health and disease. We dissect how autophagy malfunctions drive psoriasis hyper-proliferation, atopic-dermatitis barrier leakiness, vitiligo depigmentation and the metabolic rewiring of melanoma. Non-melanoma cancers, infectious dermatoses, wound repair, ageing and photo-damage are mapped onto the same autophagic atlas. Therapeutically, the pathway is a double-edged sword. mTOR or caloric-restriction mimetics jump-start a protective flux; chloroquine derivatives and ULK1 blockers clip tumour survival circuits; cannabinoids, photodynamic therapy and immune-checkpoint combinations exploit context-specific toggling between induction and brake. Emerging biomarkers (LC3B-II, p62, AMBRA1) promise patient-stratified interventions. By weaving together molecular detail, pre-clinical insight and clinical translation, we show why autophagy is no longer a backstage process but a star player in dermatology - and how targeting its switches could reshape future treatment algorithms.
    Keywords:  Autophagy; Dermatological disease; Immunodermatology; Mitophagy; Skin disorders; Skin homeostasis
    DOI:  https://doi.org/10.1186/s13062-025-00703-1
  64. Circulation. 2025 Dec 10.
    S-Nitrosylation of Pyruvate Kinase Isoform 2 Drives Cardiac Fibrosis by Promoting Mitochondrial Fission.
    Shanshan Luo, Danyu Ye, Yan Zhang, Yu Wang, Miao Zhou, Mengqi Lv, Xiaoqian Wang, Ke Zhong, Yuxiao Zhang, Lulu Hu, Shixiu Sun, Zhiren Zhang, Bo Yu, Changhao Sun, Xiangqing Kong, Zhengrong Huang, Xin Chen, Yi Han, Liping Xie, Yong Ji.
       BACKGROUND: Cardiac fibrosis is a major determinant of adverse clinical outcomes of many heart diseases; currently, therapeutic strategy directly targeting fibroblasts is lacking. Nitric oxide-mediated nitrosative stress is associated with cardiac injury, and excessive nitric oxide can trigger S-nitrosylation (SNO) to specific cysteine thiol. This study aims to investigate the role of SNO in cardiac fibrosis and to identify potential therapeutic target.
    METHODS: SNO proteomic analysis was performed in cardiac tissue isolated from both mice subjected to transverse aortic constriction and spontaneous hypertensive rats. Elevated SNO of pyruvate kinase M2 (PKM2) was identified in cardiac fibroblasts, which was merely detected in cardiomyocytes. Cardiac fibroblast-specific PKM2 knockout mice and mice transfected with wild-type or SNO-resistant PKM2 mutant were used to determine the involvement of SNO of PKM2 (SNO-PKM2) in cardiac fibrosis. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to explore effectors mediating SNO-PKM2-induced activation of cardiac fibroblasts. A recently approved drug for rare blood disorder, mitapivat, was shown to dose-dependently relieve cardiac fibrosis.
    RESULTS: SNO of PKM2 at cysteine 49 and 326 increased in the heart tissue of patients with heart failure, heart tissue of murine cardiac fibrosis models, and cardiac fibroblasts stimulated with angiotensin II. SNO-PKM2 reduced pyruvate kinase activity and tetramerization of PKM2, and cardiac fibroblast-specific PKM2 knockout aggravated cardiac fibrosis, whereas cardiac fibroblast-specific PKM2 knockout mice transfected with SNO-resistant mutant rather than wild-type PKM2 had cardiac function. Mechanistically, SNO-PKM2 drove excessive mitochondrial fission and mitochondrial dysfunction through interfering with its interaction with actin regulatory protein gelsolin. TEPP-46, a pharmacological PKM2 activator, alleviated mitochondrial fission and cardiac fibrosis. Moreover, the US Food and Drug Administration-approved drug mitapivat showed preventive and therapeutical effects on cardiac fibrosis through activating PKM2.
    CONCLUSIONS: SNO-PKM2 specifically increases in cardiac fibroblasts and activated cardiac fibroblasts by inducing excessive mitochondrial fission through a gelsolin-dependent manner. Mitapivat is a potential therapeutic option for attenuating cardiac fibrosis.
    Keywords:  PKM2 protein, human; fibrosis; mitapivat; mitochondria
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.075903
  65. Biochem Biophys Res Commun. 2025 Dec 05. pii: S0006-291X(25)01818-2. [Epub ahead of print]795 153102
    The role and mechanism of asiaticoside in regulating smooth muscle cell mitochondrial Drp1 during neointimal hyperplasia and atherosclerosis.
    Mingyu Liu, Lu Wang, Lina Wang, Tao Yang, Fei Xiang, Junyao Lu, Sixuan Chen, Hui Li, Yaxin He, Wei Wang, Shuyuan Guo, Yuanyuan Guo.
      Early atherosclerosis is characterized by aberrant proliferation and migration of vascular smooth muscle cells (VSMCs). Asiaticoside (ASI), the primary bioactive constituent of Centella asiatica, has been demonstrated to possess anti-inflammatory and antioxidant properties. However, its mechanisms of action regarding VSMC proliferation and migration remain incompletely understood. Here, we demonstrate that asiaticoside inhibits platelet-derived growth factor-BB (PDGF-BB)-induced proliferation, migration, and phenotypic switching of VSMCs by regulating dynamin-related protein 1 (Drp1). In vivo, oral administration of asiaticoside (50 mg/kg) reduced lipid plaque deposition in atherosclerotic mice and attenuated neointimal hyperplasia in Sprague-Dawley (SD) rats. In vitro, treatment with asiaticoside (100 μM) significantly suppressed PDGF-BB-induced VSMC proliferation and migration. Western blot and quantitative polymerase chain reaction (qPCR) analyses showed that the expression of proliferation markers (Cyclin D1 and proliferating cell nuclear antigen [PCNA]) and migration markers (matrix metalloproteinase-9 [MMP9] and matrix metalloproteinase-2 [MMP2]) was markedly downregulated. Mechanistically, PDGF-BB stimulation upregulated mitochondrial Drp1 expression and promoted its translocation to mitochondria, resulting in mitochondrial fragmentation and dysfunction. Asiaticoside treatment effectively reversed these effects and preserved mitochondrial integrity. Furthermore, we preliminarily found that asiaticoside activates the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Thus, we propose that asiaticoside may inhibit VSMC proliferation, migration, and phenotypic switching via the AMPK/Drp1 axis. Our study highlights the potential therapeutic value of asiaticoside in the prevention and treatment of atherosclerosis and vascular restenosis.
    Keywords:  Asiaticoside; Atherosclerosis; Drp1; Neointimal hyperplasia; VSMCs
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153102
  66. J Ophthalmol. 2025 ;2025 6670966
    A Bibliometric Analysis of Research Progress on Age-Related Macular Degeneration and Autophagy From 2010 to 2024.
    Nana Meng, Leizhou Xia, Yiqing Gong, Chunhe Shi, Peirong Lu.
       Background: Autophagy regulates intracellular metabolism and is crucial in the development of age-related macular degeneration (AMD). Despite the growing number of studies on AMD and autophagy in recent years, bibliometric analyses in this field remain scarce. Therefore, a bibliometric analysis was applied to explore the research trends and hot spots of this field in this study.
    Methods: We collected publications on autophagy in AMD from the MEDLINE database, covering the period from January 2010 to October 2024. The "bibliometrix" R package (Version R 4.2.3) was utilized for bibliometric analysis, and WPS Excel, PowerPoint, and Word (12.1.0.18276) were used to manage data and create related tables.
    Results: A total of 349 articles were included. The amount of literature was on the rise from 2010 to 2024. China leads in article quantity, whereas the United States holds the most influence. Although Finland ranks the third position in publication volume, followed by China and the United States, Finland led research in this field, with the University of Eastern Finland being the most active and prolific institution and Kaarniranta Kai as the most productive and influential author. International Journal of Molecular Sciences and Autophagy is the journal with the most volume. The three most referenced studies primarily examine the interplay between inflammation, oxidative stress, and autophagy in retinal pigment epithelial cells. The analysis for keywords found that mitophagy has also received increasing attention in this field.
    Conclusions: This bibliometric analysis identifies current research hotspots in autophagy related to AMD and informs future research directions. Future trends in this field may involve identifying and developing novel autophagy-targeted therapies for the prevention and treatment of AMD.
    Keywords:  age-related macular degeneration (AMD); autophagy; bibliometric analysis; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1155/joph/6670966
  67. Br J Pharmacol. 2025 Dec 08.
    Songorine inhibits mitophagy in chronic heart failure via the TBC1D15/Fis1/Rab7A pathway.
    Wenxiu Liu, Xingju Zou, Yang Zheng, Chen Sun, Cheng Peng.
       BACKGROUND AND PURPOSE: Songorine (SGR) is an alkaloid extracted from Aconitum carichaelii Debx. and has a demonstrated role in cardiac dysfunction. Chronic heart failure (CHF) is a severe clinical syndrome leading to functional impairment and death, primarily due to the deterioration of energy metabolism in cardiomyocytes. However, the precise mechanisms responsible for SGR therapeutic effects in CHF are unclear.
    EXPERIMENTAL APPROACH: Transverse aortic constriction (TAC) surgery was adopted to mimic heart failure in mice. Matrix-assisted laser desorption/ionisation mass spectrum image (MALDI-MSI), in combination with tissue metabolomics, revealed the distribution of different metabolites in cardiac tissue. H9c2 cells were selected as a cell model for in vitro experiments. ROS content, mitochondrial membrane potential and lysosomal activity were measured in different experimental groups.
    KEY RESULTS: CHF mice exhibited cardiac dysfunction, mitochondrial damage and metabolic alterations after 4 weeks. Treatment with SGR significantly improved ejection fraction, decreased autophagic levels and affected the spatial distribution of fatty acylcarnitines, a series of metabolites associated with β-oxidation. These findings suggested that SGR possessed an ameliorative effect on pressure overload-induced CHF, potentially mitigating mitochondrial damage by modulating energy metabolism. SGR administration partially reversed these alterations and restored cardiac function, enhancing the phosphorylation of mTOR and potentially mitigating the separation of mitochondria and lysosomes via the TBC1D15/Fis1/Rab7A pathway. Finally, studies on the effects of siRNA further demonstrated the critical role of SGR in mitochondrial function.
    CONCLUSIONS AND IMPLICATIONS: This study provides valuable insights into the role of SGR in managing CHF via TBC1D15-mediated mitochondrial dysfunction.
    Keywords:  chronic heart failure; metabolomics; mitophagy; songorine
    DOI:  https://doi.org/10.1111/bph.70257
  68. Protein Cell. 2025 Dec 08. pii: pwaf109. [Epub ahead of print]
    Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.
    Yanan Lv, Xuejing Zhao, Di Li, Zhaoqi Hao, Yue Zhao, Yuhang Zhou, Yujing Zhang, Han Chen, Zhongbing Lu, Dong Li, Yuting Guo.
      Mitochondrial calcium fluxes serve as pivotal regulators of optimal organellar function and cellular viability, yet the spatiotemporal regulation of nanodomain Ca2+ transients at mitochondria-ER contact sites (MERCS) and their integration into adaptive mitochondrial stress signaling remain unresolved. In this study, we employed custom-built high temporal-spatial resolution GI/3D-SIM imaging techniques to achieve nanoscale resolution of calcium transients. We identify that MERCS-localized calcium oscillations gate retrograde stress signaling. Mechanistically, we demonstrate that augmented mitochondria-associated ER membrane (MAMs) connectivity unexpectedly attenuated global mitochondrial Ca2+ efflux, which triggering ATF5 shuttling-mediated transcriptional licensing and calcium-sensitive epigenetic reprogramming that synergistically activating stress-resilience programs. Quantitative protein expression and transcriptome analyses confirm that CsA-mediated calcium retention mimics MAMs induction preserves mitochondrial integrity and protecting cells from apoptosis in Aβ1-42-challenged neurons through synchronized UPRmt activation. Our findings reveal a novel mechanism by which MERCS decode proteotoxic stress into transcriptional and epigenetic adaptations, offering therapeutic potential for neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Mito-ER interaction; calcium transients; mitochondrial stress response; super-resolution microscopy
    DOI:  https://doi.org/10.1093/procel/pwaf109
  69. Front Immunol. 2025 ;16 1715738
    cAMP-MFN2 signaling suppresses cochlear cell senescence and age-related hearing loss.
    Yu Liu, Jinyuan Cao, Jie Cui, Haitong Chen, Shujing Qin, Qi Li, Zhongwu Su.
       Introduction: Age-related hearing loss (presbycusis) is the most common sensory deficit in the elderly, yet it lacks effective pharmacological treatments. The decline of the cyclic AMP (cAMP) signaling pathway is implicated in aging, but its functional role in the auditory system remains largely unknown.
    Methods: To investigate whether enhancing cAMP signaling could counteract presbycusis and elucidate the underlying molecular mechanism, we used a D-galactose-induced cellular senescence model and an in vivo aged mouse model. The effects of the cAMP analog dibutyryl-cAMP (dbcAMP) on cellular senescence, inflammation, mitochondrial function, and cochlear structure were evaluated. The role of Mitofusin-2 (MFN2) was further assessed using siRNA-mediated knockdown.
    Results: dbcAMP potently suppressed cellular senescence and the associated inflammatory phenotype. In addition, cAMP treatment alleviated mitochondrial dysfunction, as indicated by improved mitochondrial bioenergetics and morphology. The anti-senescence effects of cAMP were significantly blunted upon siRNA-mediated knockdown of Mfn2, establishing MFN2 as a key, though perhaps not the sole, component of this protective pathway. Importantly, systemic administration of dbcAMP to aged mice significantly preserved hearing function and protected cochlear hair cells. This in vivo protection was accompanied by an upregulation of cochlear MFN2 and a coordinated suppression of senescence and inflammation markers.
    Discussion: Our study reveals a critical protective role for the cAMP-MFN2 axis in auditory aging by suppressing cellular senescence. These findings identify this axis as a novel and promising therapeutic target for the treatment of age-related hearing loss.
    Keywords:  age-related hearing loss (ARHL); cAMP; inflammation; mitochondrial dynamics; mitofusin2
    DOI:  https://doi.org/10.3389/fimmu.2025.1715738
  70. Biochem Pharmacol. 2025 Dec 05. pii: S0006-2952(25)00835-4. [Epub ahead of print] 117570
    Soluble guanylate cyclase stimulator vericiguat alleviates skeletal muscle injury and exercise capacity decline in ApoE-/- mice by inhibiting oxidative stress and repairing mitophagy.
    Yu-Lin Li, Bo-Ang Hu, Puyuan Xiao, Lu Han, Zhou-Jie Tong, Xu Jia, Ya-Qiong Jiao, Ming Song, Zhi-Hao Wang, Wei Zhang, Yuan-Yuan Shang, Ming Zhong.
      Patients with atherosclerosis suffer from exercise capacity decline and skeletal muscle injury. Soluble guanylate cyclase stimulator vericiguat plays a protective role in the blood vessels and kidneys in addition to treating heart failure, but its effect on skeletal muscles remains unclear. This study aimed to investigated whether vericiguat can improve exercise capacity and mitigate skeletal muscle injury of atherosclerotic ApoE-/- mice. Vericiguat dose-dependently increased the forelimb grip strength, hanging impulse, and exhaustive running time, and reduced the levels of creatine kinase and lactatedehydrogenase, independently of improvements in plaque burden. In vericiguat group, the expression level of cGMP and PKG1α, the cross sectional area of skeletal muscles and the proportion of slow myofibers were dose-dependently increased. Vericiguat reduced the level of IL-6, TNF-α and MitoROS in skeletal muscles, and increased the level of SOD, GSH/GSSG ratio, mitochondrial content and membrane potential. In the mitophagy signaling pathway, the expression of p62 in skeletal muscles was decreased in vericiguat group, while the expression of PINK, Parkin, and LC3-II/I was increased. This study found that vericiguat could improve exercise capacity and mitigate skeletal muscle injury of atherosclerotic mice by repairing the impaired sGC-cGMP-PKG pathway, along with reducing skeletal muscle atrophy, inflammation and oxidative stress, and improving mitochondrial function and mitophagy.
    Keywords:  Atherosclerosis; Mitophagy; Oxidative Stress; Skeletal Muscle; Vericiguat
    DOI:  https://doi.org/10.1016/j.bcp.2025.117570
  71. Free Radic Biol Med. 2025 Dec 08. pii: S0891-5849(25)01419-4. [Epub ahead of print]
    Decreased OPA1 Expression Increases Neuronal Vulnerability to Ischaemic Stroke during Ageing: Role of Timm8b as a Therapeutic Target.
    Hang Li, Xiang Li, Zhongmou Xu, Lianxin Li, Eryi Sun, Chang Cao, Jinxin Lu, Lei Bai, Gang Chen, Qing Sun, Haiying Li.
      Ischaemic stroke stands as a major global driver of mortality and disability, with advancing age significantly worsening patient outcomes. Mitochondrial impairment plays a pivotal role in both ischaemia-triggered neuronal damage and ageing, yet its precise role in age-related neuronal stroke susceptibility and regulatory mechanisms remains a key unresolved question. To address this, we applied weighted gene coexpression network analysis (WGCNA) to the GSE212336 dataset, identifying 65 mitochondrial genes downregulated with age-most notably OPA1. OPA1 gradually declined with age in murine models and humans, and decreased further post-stroke. Neuronal-specific OPA1 knockout in aged mice with distal middle cerebral artery occlusion (dMCAO) notably worsened mitochondrial cristae disruption, enlarged infarct volumes, and increased neuronal loss. Proteomic analyses showed OPA1 deficiency and ischaemia both reduce Timm8b expression. Timm8b overexpression effectively preserved mitochondrial ultrastructure, mitigated ischaemic damage in heterozygous OPA1-deficient mice while diminished in homozygotes, restored OPA1 dimerization, and alleviated neuronal apoptosis and infarct expansion in aged ischaemic brains. Collectively, this work uncovers a novel regulatory axis: ageing reduces OPA1 and exacerbates ischaemic damage, while Timm8b downregulated by OPA1 depletion protects mitochondria, restores OPA1 function, and reduces ischaemic harm, highlighting Timm8b as a promising therapeutic target for age-related stroke.
    Keywords:  Ageing; Ischaemic stroke; Mitochondria; Neuron; OPA1; Timm8b
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.005
  72. FASEB J. 2025 Dec 31. 39(24): e71340
    Disruption of Mitochondrial Dynamics and Integrity Drives Divergent Metabolic Flexibility and Resilience in Podocytes.
    Cem Özel, Katrin M Reitmeier, Emilia Kieckhöfer, Khawla Abualia, Duc Nguyen-Minh, Mahsa Matin, Henning Hagmann, Richard J M Coward, Sebastian Brähler, Philipp Antczak, Bernhard Schermer, Thomas Benzing, Patrick Giavalisco, Paul T Brinkkoetter.
      Mitochondrial dysfunction is central to the pathogenesis of podocytopathies, yet the determinants of metabolic resilience versus failure remain elusive. We investigated how distinct disruptions of mitochondrial architecture, specifically hyperfusion via OMA1 deletion versus compromised inner mitochondrial membrane (IMM) integrity via PHB2 knockdown, influence the metabolic fate and insulin responsiveness of podocytes. To this end, we analyzed conditionally immortalized mouse podocytes with genetic OMA1 deletion or inducible PHB2 knockdown and employed an integrated approach combining bioenergetic studies, quantitative proteomics, phosphoproteomics, metabolomics, and stable isotope tracing studies with 13C6-glucose and 13C5-glutamine. We characterized metabolic remodeling at baseline and after insulin treatment and uncovered profoundly divergent metabolic states. OMA1 deficiency conferred robust metabolic resilience, characterized by a compensatory glycolytic shift and remodeling of TCA cycle flux through glutamine-driven anaplerosis while maintaining oxidative phosphorylation. OMA1-deficient podocytes sustained bioenergetic homeostasis upon insulin challenge by flexibly rerouting carbon flux, including the GABA shunt. In contrast, PHB2 deficiency led to metabolic failure, impaired respiration, and anaplerotic insufficiency. While maintaining basal ATP levels at baseline, PHB2-deficient podocytes exhibited energetic collapse upon insulin treatment, revealing profound metabolic inflexibility. Taken together, the structural integrity of the inner mitochondrial membrane, rather than mitochondrial morphology per se, is a driving determinant of metabolic competence and resilience in podocytes.
    Keywords:  OMA1; PHB2; anaplerosis; glycolysis; insulin signaling; metabolism; mitochondria; podocytes
    DOI:  https://doi.org/10.1096/fj.202502934R
  73. Nutrients. 2025 Nov 26. pii: 3712. [Epub ahead of print]17(23):
    Microbial Metabolite, Macro Impact: Urolithin A in the Nexus of Insulin Resistance and Colorectal Tumorigenesis.
    Vennila Joseph, Slavomir Hornak, Peter Kubatka, Dietrich Büsselberg.
      Urolithin A (UA), a metabolite of dietary ellagitannins produced by the gut microbiome, is a potential dual-purpose bioactive compound that may interfere with the shared pathogenic pathways linking colorectal cancer (CRC) and type 2 diabetes mellitus (T2DM). This review summarizes recent preclinical and clinical data on UA's mechanisms, therapeutic potential, and translational challenges. In CRC models, UA promotes G2/M cell cycle arrest, triggers both intrinsic and extrinsic caspase-mediated apoptosis, enhances CD8+ T-cell mitophagy and memory functions, suppresses Wnt/β-catenin signaling, and reduces chemoresistance, especially to 5-FU. For T2DM, UA enhances autophagic flux, mitophagy, insulin signaling, and GLUT4-mediated glucose uptake through the AMPK and PI3K/AKT pathways, reduces fasting glucose and insulin resistance in animal studies, and promotes adipose tissue browning and mitochondrial beta-oxidation. Human biomarker research is limited but indicates positive changes following interventions that increase UA. Future priorities include biomarker-driven, dose-finding trials stratified by metabotype, developing colon-targeted vs. systemic formulations, and testing combinations with chemotherapy and immunotherapy to determine safety and effectiveness.
    Keywords:  Urolithin A; apoptosis; autophagy; colorectal cancer; mitophagy; type 2 diabetes
    DOI:  https://doi.org/10.3390/nu17233712
  74. Cells. 2025 Nov 27. pii: 1877. [Epub ahead of print]14(23):
    Imbalance in MICOS Proteins in Rat Liver Mitochondria in an Induced Hyperthyroidism Model.
    Natalya Venediktova, Ilya Solomadin, Anna Nikiforova, Tatiana Bessonova.
      This study investigated rearrangements in the cristae structure and the possible relationship between these changes and the MICOS levels in the liver mitochondria of rats with experimentally induced hyperthyroidism. In hyperthyroid rats (HRs), the number, area, and perimeter of mitochondria were increased, and organelles of a worm-shaped, branched, highly elongated, or spherical shape appeared. A structural change in the mitochondria of HR liver was detected, consisting of a decrease in the number of cristae relative to the cross-section of the organelle. In some mitochondria, multilamellar bodies were detected. Hyperthyroidism caused an increase in the expression of genes and the level of proteins of the MIC60 subcomplex, with an unchanged level of the MIC10 subcomplex. Moreover, the levels of Sam50 and OPA1 in HRs were reduced. A functional assessment of HR mitochondria revealed changes in oxygen consumption, a decrease in membrane potential, and disruption of Ca2+ homeostasis. These data indicate that excess thyroid hormones cause partial changes in liver mitochondrial structure and an imbalance in the levels of Mic60 and Mic10 subcomplex proteins. The decreased levels of Sam50 and OPA1 proteins suggest their potential as targets for correcting mitochondrial dysfunction in metabolic disorders.
    Keywords:  MICOS; OPA1; calcium retention capacity; cardiolipin; cristae membranes; hyperthyroidism; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/cells14231877
  75. Mol Neurobiol. 2025 Dec 08. 63(1): 270
    The Potential of Ectoine as a Brain Anti-Aging Agent in Rat Model of D-Galactose-Accelerated Aging May Be Mediated Through Crosstalk Between Redox/Mitochondrial Homeostasis/Autophagic/Apoptotic Pathways.
    Aisha H A Alsenousy, Marwa B Bakir, Mohammed S Zommara, Hanan A Edres, Wael S Darwish, Rania M H M Eid, Maher A Kamel.
      Aging has emerged as a prominent area of academic inquiry. Brain aging is a complex physiological process characterized by features such as enhanced apoptosis, oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy. Currently, effective preventative or therapeutic approaches for age-related neurodegenerative disorders remain elusive. Ectoine, a naturally occurring compatible solute, possesses diverse applications in biological engineering, cosmetics, medicine, and the food industry. Ectoine is reported to exhibit anti-inflammatory, antioxidant, and anti-apoptotic properties, making it a potential anti-aging agent. Consequently, the present study investigated the potential neuroprotective effects of Ectoine against D-galactose (D-gal)-induced brain aging. Accelerated aging was induced by subcutaneous injection of D-gal. Rats were subsequently divided into a control group, an aged group, and Ectoine-supplemented groups, receiving daily doses of 10, 20, and 40 mg/kg, respectively. Our findings revealed that Ectoine effectively and dose-dependently protected against D-gal-induced brain aging by inhibiting oxidative stress, enhancing the antioxidant system, decreasing neuroinflammation, restoring autophagy and mitochondrial homeostasis, and inhibiting apoptosis. Furthermore, Ectoine significantly restored the expression of miR-124 and its target genes; however, this effect is correlative and warrants further mechanistic validation. Additionally, while Ectoine's neuroprotective effects were observed at the tissue level, its cell-type specificity remains to be determined. These findings suggest that Ectoine may exert multi-pathway neuroprotective effects in brain aging. However, the current data are exploratory and warrant further validation to define causality and translational applicability.
    Keywords:  Aging; Apoptosis; Autophagy; D-galactose; Ectoine; MiR-124; Mitochondrial homeostasis; Neuroinflammation; Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-025-05451-x
  76. J Transl Med. 2025 Dec 06.
    A mitochondria-related gene-based signature predicts pancreatic ductal adenocarcinoma clinical outcome and revealed CAMK2A/THEM4 regulates progression phenotypes and mitophagy in vivo and in vitro.
    Gang Nie, Zhongfei Zhu, Jing Huang, Xiaohan Shi, Xiaoyi Yin, Gang Li, Gang Jin.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited available prognostic tools. There is a need to develop robust molecular signatures to improve risk stratification and identify potential therapeutic targets.
    METHODS: A 12-gene mitochondrial-related prognostic signature was developed using machine learning. The performance was compared with signatures developed using other algorithms and published signatures. The detailed synergistic role and molecular mechanism of signature gene CAMK2A and THEM4 was investigated. Additionally, an immunohistochemical (IHC) microarray and in vivo xenograft model was performed to evaluate the prognostic utility of candidate genes.
    RESULTS: The prognostic signature effectively stratified patients into high- and low-risk groups with significantly different survival outcomes (median OS: 15.4 vs. 24.1 months, p < 0.0001). It demonstrated robust predictive accuracy across datasets and outperformed 101 other machine learning-based signatures as well as previously reported models. High-risk samples showed enrichment in cancer-related pathways and unique adaptive drug profiles. Single-cell sequencing data indicated that the signature reflects immune cell infiltration and cell-cell interaction heterogeneity. Functional experiments revealed that CAMK2A suppresses PDAC progression by impairing mitochondrial function-reducing membrane potential, ATP production, and ROS levels-and facilitating THEM4 release from mitochondria. THEM4, which is downregulated in PDAC, inhibited tumor growth by suppressing AKT phosphorylation (p < 0.01). THEM4 knockdown accelerated in vivo tumor growth. Clinically, combining THEM4 and CAMK2A expression improved prognostic performance compared to either biomarker alone.
    CONCLUSIONS: This study establishes a mitochondria-driven prognostic model for PDAC and identifies the CAMK2A-THEM4-AKT axis as a novel therapeutic target. To our knowledge, this is the first pancreatic cancer signature that investigates the synergistic effect of candidate genes, offering both prognostic and mechanistic insights into PDAC progression.
    Keywords:  Mitochondrion; Pancreatic ductal carcinoma; Prognosis; Signature; THEM4
    DOI:  https://doi.org/10.1186/s12967-025-07456-5
  77. Transl Neurodegener. 2025 Dec 08. 14(1): 64
    LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner.
    Mei Ding, Fen Wang, Lan-Lan Jiang, Chao Ma, Yu-Wan Qi, Jun-Yi Liu, Juan Li, Mei-Xia Wang, Hong Jin, Jin-Ru Zhang, Cheng-Jie Mao, Xiao-Kang Li, Chun-Feng Liu, Xiao-Yu Cheng.
       BACKGROUND: Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation.
    METHODS: DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S.
    RESULTS: Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival.
    CONCLUSIONS: The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.
    Keywords:   LRRK2 G2019S mutation; Astrocyte; Dopaminergic neuron; Induced pluripotent stem cell; Membrane fusion-related protein STX17; Mitochondrial transfer; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40035-025-00525-1
  78. Int J Mol Sci. 2025 Nov 30. pii: 11615. [Epub ahead of print]26(23):
    Cell-Free DNA and Mitochondria in Parkinson's Disease.
    Małgorzata Wojtkowska, Franciszek Ambrosius.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the gradual and irreversible loss of neurons, especially within the substantia nigra region of the midbrain. Early and accurate diagnosis remains a significant challenge in both research and clinical practice. This difficulty is further compounded by the substantial clinical and molecular heterogeneity of PD, emphasizing the urgent need for reliable biomarkers to enhance diagnostic precision and guide therapeutic strategies. One promising candidate biomarker is cell-free DNA (cfDNA), comprising short DNA fragments composed of mitochondrial (cf-mtDNA) and nucleus-derived (cf-ntDNA) DNA. cfDNA is released into body fluids through physiological or pathological processes such as apoptosis, necrosis, NETosis, or active secretion. The presence of cfDNA in human biological fluids has been utilized for years in oncology and prenatal medicine and, more recently, it has gained attention as a non-invasive diagnostic tool in the context of neurodegenerative diseases such as PD. This review article aims to provide a comprehensive overview of the current knowledge on the origin of cfDNA, highlighting the roles of the mitochondria and cf-mtDNA in PD, mitochondria quality control, and neuroinflammation in cfDNA biogenesis. The review collates available research on cfDNA types in human serum, plasma, and CSF, sequence analysis, and its potential application as a biomarker in the diagnosis and monitoring of PD, contributing to the ongoing search for non-invasive biomarkers of neurodegenerative diseases.
    Keywords:  Parkinson’s disease; cell-free DNA (cfDNA); cell-free mitochondrial DNA (cf-mtDNA); cell-free nuclear DNA (cf-ntDNA); cerebrospinal fluid; mitochondria; mitophagy; neuroinflammation; plasma; serum
    DOI:  https://doi.org/10.3390/ijms262311615
  79. Chin Med. 2025 Dec 10. 20(1): 215
    Fat-targeted small molecule alleviates abnormal adipose tissue remodeling in obesity via SIRT3-driven mitophagy and inflammasome inhibition.
    Kegang Linghu, Longkun Hu, Yu-E Wang, Yuxia Zhou, Yuanyuan Wang, Mingjun Shi, Lirong Liu, Hua Yu, Lei Tang, Ligen Lin, Bing Guo, Ai Tian, Tian Zhang.
       BACKGROUND: In obesity, excessive energy intake and the expansion of adipose tissue increase ROS generation, contributing to adipocyte dysfunction and inflammation, which leads to abnormal adipose tissue remodeling (ATR). Alpha lipoamide (ALM) is the neutral amide form of lipoic acid, a natural antioxidant extracted from plant-based foods such as asparagus, spinach, and broccoli. This work focuses on ALM's beneficial effects and mechanism in adipose tissue inflammation (ATI) and abnormal ATR in obesity.
    METHODS: The anti-inflammatory effect of ALM was evaluated by ELISA, flow cytometry, Western blots, and immunofluorescence assays. The binding affinity of ALM to SIRT3 deacetylase was evaluated through cellular thermal shift assay (CETSA) and molecular docking. The adipose tissue-targeting alpha lipoamide nanoemulsion (ALM-NE) was validated using small animal live imaging. Adipose tissue inflammation was evaluated by histological analysis and immunohistochemical staining in both high-fat diet (HFD) and LPS plus ATP-induced inflammation models in mice.
    RESULTS: ALM suppressed the activation of NLRP3 inflammasome via enhancing SIRT3-mediated autophagy. Co-immunoprecipitation revealed that ALM blunted mitochondrial damage through SIRT3-mediated SOD2 deacetylation and FUNDC1-mediated mitophagy activation, resulting in ROS reduction and NLRP3 inflammasome inactivation. Moreover, ALM mitigates inflammatory crosstalk between macrophages and adipocytes in an in vitro co-culture model. Finally, we established an adipose tissue-targeting ALM-NE, which alleviated ATI in LPS and ATP-induced acute inflammation in mice and inhibited abnormal ATR in high-fat diet-induced obese mice.
    CONCLUSION: In summary, ALM attenuates inflammatory crosstalk between M1 macrophages and adipocytes by enhancing SIRT3-mediated mitophagy and suppressing NLRP3 inflammasome activation, thereby alleviating adipose tissue inflammation and pathological remodeling in obesity. Thus, ALM has the capacity to become a therapeutic candidate for treating obesity and its associated metabolic disorders.
    Keywords:  Abnormal adipose tissue remodeling; Alpha lipoamide; Autophagy; NLRP3 inflammasome; Nano-emulsion; Obesity
    DOI:  https://doi.org/10.1186/s13020-025-01253-4
  80. BMC Cardiovasc Disord. 2025 Dec 09.
    Integrated bioinformatic and in vivo analysis confirms the cardioprotective role of OPA1.
    Claire Fong-McMaster, Serena M Pulente, Luke S Kennedy, Tyler K T Smith, Stephanie Myers, Michel N Kanaan, Charbel Y Karam, Matthew Cope, Michelle M Levesque, Ella McIlroy, Ilka Lorenzen-Schmidt, Craig J Goergen, Morgan D Fullerton, Miroslava Cuperlovic-Culf, Erin E Mulvihill, Mary-Ellen Harper.
       BACKGROUND: OPA1 is an inner mitochondrial membrane protein that mediates diverse signaling processes. OPA1 is important for cardiac function and protects against cardiac insults such as ischemia/reperfusion injury. We sought to further assess OPA1 in cardiac pathologies, hypothesizing that OPA1 will function in a protective manner in chronic heart failure.
    METHODS: Integrated analyses of publicly available histological and transcriptomic data were used to identify functional associations between OPA1 and other genes of interest. To experimentally assess these associations, mice with a 1.5-fold whole body OPA1 overexpression (OPA1-OE) were subjected to a modified transverse aortic constriction surgery and underwent 2-dimensional and 4-dimensional echocardiography along with molecular analyses including high-resolution respirometry, enzymatic activities, flow cytometry and transcript level analyses.
    RESULTS: Bioinformatic analyses of histological and transcript data from the GTEx database indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were associated with fatty acid, branch chain amino acid and cardiac contractile gene signatures. These functional associations were further supported by in vivo findings showing that OPA1-OE mice displayed improved 2D ejection fraction, end systolic volume, end diastolic volume and 4D cardiac functional parameters including global peak circumferential and surface area strain compared to WT mice. As well, OPA1-OE mice displayed sustained transcript levels of fatty acid, branch chain amino acid and contractile markers and no induction of fibrotic transcript markers.
    CONCLUSION: These results further demonstrate the important role of OPA1 in supporting optimal cardiac function and highlight potentially protective contractile and metabolic signaling pathways.
    Keywords:  4-dimensional echocardiography; Heart failure; Mitochondria; Mitochondrial fusion; Optic atrophy protein-1
    DOI:  https://doi.org/10.1186/s12872-025-05413-0
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