bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–08–31
eighty-two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial homeostasis dysfunctions during the epithelial-mesenchymal transition process in lens epithelial cells.
  2. Rho kinase isoforms in neurodegeneration: from cellular functions to therapeutic targets.
  3. Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
  4. During Aspergillus nidulans nitrogen-limited biofilm formation, mitophagy is independent of mitochondrial fission.
  5. Mitophagy attenuates pyroptosis in human gingival fibroblasts through inhibition of NLRP3 inflammasome activation.
  6. Balancing act: Drp1 inhibition and mitochondrial homeostasis in cardiovascular diseases.
  7. MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy.
  8. SIRT3 attenuates sepsis-induced EndMT and cardiac remodeling by facilitating mitophagy process via PINK1/Parkin signaling.
  9. Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.
  10. Dapagliflozin sustains heart function in type 3 cardiorenal syndrome by restoring DUSP1-dependent mitochondrial quality control.
  11. Thrombopoietin Mitigates Neuronal Death by Enhancing Mitophagy and Suppressing NLRP3 Inflammasome Activation Under Oxygen-Glucose Deprivation Conditions.
  12. Mitophagy Regulators as Novel Targets in Sepsis-Induced Myocardial Dysfunction.
  13. Ginsenoside Rb1 attenuates coronary microvascular inflammatory injury via NDUFS4-SIRT5-DUSP1-mediated mitochondrial quality control in a murine ischemia-reperfusion model.
  14. Fucoxanthin protects retinal ganglion cells and regulates Parkin-mediated mitophagy in experimental glaucoma.
  15. Knockdown of MiD49 and MiD51 alleviates collagen-induced arthritis and suppresses mitophagy and fatty acid oxidation (FAO) in rheumatoid arthritis fibroblast-like synoviocytes.
  16. Asprosin Aggravates Tubular Epithelial Cell Injury and Phenotypic Transformation via Mitochondrial Dynamics Disorder Mediated by Excessive Drp1 SUMOylation in Diabetic Nephropathy Mice.
  17. Camellia japonica Flower Extract and the Active Constituent Hyperoside Repair DNA Damage Through FUNDC1-Mediated Mitophagy Pathway for Skin Anti-Aging.
  18. Impact of O-GlcNAcylation Elevation on Mitophagy and Glia in the Dentate Gyrus.
  19. PRMT1 (protein arginine methyltransferase 1) is essential for neuromuscular junction and mitochondrial homeostasis via mitophagy regulation.
  20. Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.
  21. Neurobiology of mitochondrial dynamics in sleep.
  22. The role of mitophagy in perioperative neurocognitive disorder: from mechanisms to implications.
  23. Targeting FAM111B attenuates mitophagy and increases the sensitivity to lenvatinib treatment by increasing MFN2 stability in hepatocellular carcinoma.
  24. Ketogenic diet ameliorates MASLD via balancing mitochondrial dynamics and improving mitochondrial dysfunction.
  25. Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.
  26. Porphyromonas gingivalis hijacks mitophagy and lysosomal function to persist in endothelial cells.
  27. Mitochondrial Extracellular Vesicles: A Novel Approach to Mitochondrial Quality Control.
  28. 3-n-butylphthalide improves cerebral ischemia/reperfusion injury by regulating neuronal mitochondrial biogenesis via AMPK/PGC-1α signaling pathway.
  29. Oxycodone attenuates endotoxin-induced acute lung injury by regulating mitophagy via the HO-1 pathway.
  30. Regulation of mitochondrial autophagy via the PINK1/Parkin pathway to improve cognitive function in vascular dementia using governor vessel acupuncture.
  31. Canagliflozin Alleviates Metabolic Dysfunction-Associated Steatotic Liver Disease via Mitochondrial Protection and Enhanced Mitophagy.
  32. Zuogui and Yougui pills extend lifespan and improve ageing biomarkers via kaempferol-mediated mitophagy in Caenorhabditis elegans.
  33. Jolkinolide B Activates Mitophagy to Exhibit Anti-pancreatic Cancer Activity and Alleviate Cognitive Deficits in Alzheimer's Disease.
  34. Dihydromikanolide Inhibits ROS-Mediated NLRP3 Inflammation via Antioxidant Nrf2 Activation and Mitophagy Induction in LPS/ATP-Stimulated Macrophages.
  35. CDK5 Inhibits Synphilin-1 Ubiquitination and Basal Mitophagy: Implications for Parkinson's Disease.
  36. Astragaloside IV Ameliorates Cerebral Ischemic-Reperfusion Injury via Improving Mitochondrial Function and Inhibiting Neuronal Apoptosis.
  37. Highly Oligomeric DRP1 Strategic Positioning at Mitochondria-Sarcoplasmic Reticulum Contacts in Adult Murine Heart Through ACTIN Anchoring.
  38. Traditional Chinese Medicine Monomers and Their Derivatives as a Promising Therapeutic Tool for Hepatocellular Carcinoma by Activation of Mitophagy.
  39. Correction: Novel mitophagy inducer TJ0113 alleviates pulmonary inflammation during acute lung injury.
  40. Mitochondrial Homeostasis in Cancer: Functions and Targeted Therapies.
  41. Mechanical Force Promotes Mitochondrial Transfer From Macrophages to BMSCs to Enhance Bone Formation.
  42. AIMP1 exerts hearing protection role in age related hearing loss mice by regulating SIRT1 expression.
  43. mGluR5 promotes oxidative stress and central sensitization in chronic migraine through ERK-mediated phosphorylation of Drp1 to activate mitochondrial fission.
  44. L-arginine alleviates intervertebral disc degeneration by suppressing TRIB3/AKAP1-mediated Drp1 phosphorylation dysregulation and mitochondrial fragmentation.
  45. PPP1R3G inhibition impairs OPCs differentiation and myelination in aged mice.
  46. Role of IRGM in acute lung injury: Inducing mitophagy and inactivating cGAS-STING signaling to improve lipopolysaccharide-induced alveolar epithelial barrier dysfunction.
  47. Integrating bulk and single-cell RNA data with machine learning to explore mitophagy in periodontitis.
  48. Possible Role of Novel Mitochondrial Subsets in Migraine.
  49. Drp1-mediated mitochondrial fission exacerbates inflammatory responses in intestinal epithelial cells: A potential therapeutic target for IBD.
  50. Mechanisms and therapeutic perspectives of mitochondrial dysfunction of macrophages in periodontitis.
  51. UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice.
  52. Estrogen receptor 1 (ESR1) promotes Di-butyl phthalate (DBP)-induced hypospadias by regulating mitophagy through PINK1-Parkin axis to inhibit ferroptosis.
  53. PGC-1α-mediated mitochondrial homeostasis imbalance aggravated gingival lesions of diabetic periodontitis by disrupting ECM remodeling of human gingival fibroblast.
  54. Dynorphin A Impairs Mitochondrial Biogenesis in Osteosarcoma Cells by Increasing SP-1.
  55. Isoliensinine inhibits mitophagy and sensitizes T cell malignancies for STING-mediated NK clearance.
  56. Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.
  57. Paternal BDE-209 exposure disrupts spermatogenesis in mouse offspring via cGAS-STING pathway activation and mitophagy inhibition.
  58. Effects of Dietary Terpinen-4-ol on Oxidative Stress and Mitochondrial Biogenesis in the Liver of Broilers with Pulmonary Hypertension Syndrome.
  59. Platycodin D attenuates diabetic renal ischemia/reperfusion injury by enhancing mitophagy and suppressing MAPK/NF-κB signaling activation.
  60. MARY1 Restores Mitochondrial Homeostasis and Accelerates Renal Recovery Following Acute Kidney Injury.
  61. Baicalin Improves Skeletal Muscle Atrophy by Attenuating DRP-1-Mediated Mitochondrial Fission in Aged Mice.
  62. Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways.
  63. EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat.
  64. RAS in lung transplantation - Renin-Angiotensin System and mitochondrial protection with Angiotensin-1-7 during pulmonary preservation at 10°C.
  65. Structurally diverse diterpenoids from cones of Taxodium ascendens inhibit colorectal cancer proliferation via regulating mitophagy.
  66. Potential Synergistic Effects of Caffeine and Naringin on Mitochondrial Biogenesis and Hepatic Steatosis in Adult Male Rats With NAFLD Induced by a High-Fat Diet.
  67. Cancer as a failed response to renegade mitochondria.
  68. ACR-16/α7-nicotinic receptor signaling mediates nicotine-induced mitochondrial dysfunction and suppression of host defense against gram-negative bacteria.
  69. Resveratrol: Great potential for alleviating di-2-ethylhexyl phthalate (DEHP)-induced testicular ferroptosis via the SIRT1-HIF-1α axis.
  70. Intracellular Interleukin-1α in Peritumoral Monocytes Induces IL8 Production and Inhibits Mitophagy to Promote Stemness and Metastasis of Hepatocellular Carcinoma.
  71. Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.
  72. Bioinformatic Analysis of the Value of Mitophagy and Immune Responses in Corneal Endothelial Dysfunction.
  73. Metoprolol exacerbates dementia in scopolamine-induced cognitive impairment in rats: A potential role of NADPH oxidase.
  74. Complex Conformational Interplay for Parkin Activation is Revealed by 19F NMR Spectroscopy.
  75. Hexafluoropropylene oxide dimer acid (GenX) induces apoptosis in primary cortical neurons via stimulating ROS production and NF-κB activation.
  76. 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces early hearing loss in guinea pigs via activating AhR to trigger mitochondrial and endoplasmic reticulum stress-regulated autophagy.
  77. From mitochondria to heart: the role and challenges of mitochondrial antiviral signaling protein in cardiovascular disease.
  78. Hydrogen promoted mitochondrial autophagy and alleviated CIH-induced vascular endothelial cell senescence by regulating oxidative stress.
  79. Neurodegenerative features of damage to Deiters neurons in the lateral vestibular nucleus of mice after vestibular stimulation.
  80. Alpha-Mangostin Alleviates Mitochondrial Damage and Autophagy Dysregulation in the MPP+ Cellular Model of Parkinson's Disease.
  81. The role of the mitochondrial dynamic distribution in oocyte development arrest induced by F-53B.
  82. Link between Parkinson's disease and melanoma: insights into the influence of the PARK gene family.
  1. Exp Eye Res. 2025 Aug 19. pii: S0014-4835(25)00354-9. [Epub ahead of print]260 110583
    Mitochondrial homeostasis dysfunctions during the epithelial-mesenchymal transition process in lens epithelial cells.
    Hang Xie, Rong Huang, Ke Xu, Lei Du, Xingyu Yang, Weichen Xu, Xiaoyu Guo, Guojing Lu, Tingting Fan, Changzheng Chen.
      Lens epithelial cells (LECs), the main mitochondria-containing cells in the lens, play a vital role in maintaining lens transparency. Mitochondrial homeostasis is essential for cellular function, yet its changes during epithelial-mesenchymal transition (EMT) in LECs remain unclear. In this study, EMT was induced in LECs using transforming growth factor-β2 (TGF-β2), and mitochondrial function was evaluated through ROS, ATP levels, membrane potential, Mitotracker staining, and electron microscopy. TGF-β2 treatment resulted in mitochondrial dysfunction, evidenced by increased ROS, decreased ATP production, and reduced membrane potential. Mitochondria changed from elongated tubular shapes to fragmented spherical forms. Mitochondrial dynamics were disrupted, with downregulation of fusion proteins (Mfn1, Mfn2, Opa1) and upregulation of fission protein Drp1. Mitophagy was impaired despite activation of the PINK1/Parkin pathway, and mitochondrial biogenesis was suppressed, as shown by decreased expression of PGC-1α and TFAM and reduced mtDNA copy number. These findings highlight a significant imbalance in mitochondrial homeostasis during TGF-β2-induced EMT in LECs, which may contribute to lens opacity and fibrotic cataract formation, offering potential targets for therapeutic intervention.
    Keywords:  EMT; Mitochondrial biogenesis; Mitochondrial fusion and fission; Mitochondrial homeostasis; Mitophagy
    DOI:  https://doi.org/10.1016/j.exer.2025.110583
  2. Mol Biol Rep. 2025 Aug 26. 52(1): 846
    Rho kinase isoforms in neurodegeneration: from cellular functions to therapeutic targets.
    Chesta Shandilya, Shalini Mani.
      Mitochondria serve as an important cellular organelle for maintaining neurotransmission and synaptic plasticity in neuronal cells by playing a key role in ATP generation, maintaining calcium homeostasis, and regulating the levels of reactive oxygen species (ROS), etc. The regulation of the dynamic nature of mitochondria, including their fission, fusion, and removal of damaged mitochondria by mitophagy, is also very important for neuronal health. Abnormalities in mitochondrial processes, including but not limited to fission, fusion, and mitophagy, are known to be associated with numerous neurodegenerative diseases (NDDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). In the recent past, the Rho kinase (ROCK) isoforms, particularly ROCK1 and ROCK2, have gained a lot of attention in NDDs, mainly for their role in regulating the dynamics of the mitochondria, mitophagy, and other cell signalling pathways. By adding phosphate groups to Drp1, ROCK1 is crucial in supporting excessive mitochondrial fission, causing the death of neuronal cells. On the other hand, ROCK2 inhibits Parkin-dependent mitophagy by inhibiting the PTEN protein, the activator of Parkin-dependent mitophagy. This impaired mitochondrial quality control via reduced mitophagic flux leads to oxidative stress and neuronal degeneration, the central pathological feature of NDDs. The inhibition of ROCK isoforms has shown great promise in neuroprotective effects, controlling the dynamics of mitochondria in neuronal cells, lowering inflammation, and improving motor and cognitive functions in preclinical models of different NDDs, indicating ROCK isoforms as an attractive therapeutic target in different NDDs. This review aims to highlight the therapeutic significance of targeting ROCK isoforms in different NDDs.
    Keywords:  Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; Neuroprotective; ROCK isoforms
    DOI:  https://doi.org/10.1007/s11033-025-10947-9
  3. Sci Adv. 2025 Aug 29. 11(35): eady0240
    Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
    William M Rosencrans, Ryan W Lee, Logan McGraw, Ian Horsburgh, Ting-Yu Wang, Baiyi Quan, Diana Huynh, Jennifer A Johnston, David C Chan, Tsui-Fen Chou.
      The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson's disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or "silent" mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson's disease.
    DOI:  https://doi.org/10.1126/sciadv.ady0240
  4. Autophagy Rep. 2025 ;4(1): 2547194
    During Aspergillus nidulans nitrogen-limited biofilm formation, mitophagy is independent of mitochondrial fission.
    Hari Krishnan Balasubramanian, Stephen A Osmani.
      During chronic infections, biofilms are resistant to both antimicrobial agents as well as the host immune system, often giving rise to recalcitrant persister cells with reduced mitochondrial function rendering biofilm infections difficult to cure. How mitochondrial dynamics and fate are regulated during fungal biofilm formation is poorly understood. In this study, we used live cell microscopy to track mitochondrial morphology during Aspergillus nidulans in vitro biofilm formation. We show that mitochondria undergo fragmentation during early biofilm development, and that externally induced oxidative stress similarly induces mitochondrial fragmentation, indicating a role for redox regulation in this process. Deletion of core components of the mitochondrial fission machinery resulted in a swollen mitochondrial phenotype. Mitochondria in the fission-mutant strains are known not to complete fragmentation in response to externally induced oxidative stress, and we show that this results in a "beads on a string" phenotype. We further show that mitochondria remain unfragmented during biofilm formation in the fission-mutant strains, although other biofilm cellular modifications, like disassembly of microtubules, are unaffected. We report that mitophagy is triggered during biofilm development in nitrogen-limiting conditions independently of mitochondrial fission. This indicates mitochondrial fission is dispensable for mitophagy during biofilm development with limiting nitrogen. We further note that general autophagy, but notably not mitophagy, is triggered during biofilm development in carbon-limiting conditions, demonstrating differential regulation of mitochondrial fate in response to specific nutritional limitations during fungal biofilm formation.
    Keywords:  Aspergillus nidulans; autophagy; biofilm formation; carbon; mitochondrial fission; mitophagy; nitrogen; redox regulation
    DOI:  https://doi.org/10.1080/27694127.2025.2547194
  5. Arch Oral Biol. 2025 Aug 15. pii: S0003-9969(25)00206-7. [Epub ahead of print]179 106378
    Mitophagy attenuates pyroptosis in human gingival fibroblasts through inhibition of NLRP3 inflammasome activation.
    Chun-Sheng Bi, Yi-Kuan Wu, Hao-Yu Li, Zi-Jian Cheng, Liaqat Hussain, Xiao-Jun Li.
       BACKGROUND: NLRP3 inflammasome-mediated pyroptosis in gingival fibroblasts (GFs) plays a pivotal role in periodontitis pathogenesis. Mitochondrial dysfunction serves as a critical upstream trigger for NLRP3 inflammasome activation, while mitophagy acts as a key homeostatic mechanism. The regulatory mechanisms of mitophagy in modulating GF pyroptosis remain poorly defined.
    METHODS: Human GFs were used in this study. An in-vitro inflammatory environment was created using 5 μg/mL lipopolysaccharide (LPS). Mitophagy was either activated using P62-mediated mitophagy inducer (PMI, 10 μM) or inhibited with Mdivi-1 (10 μM) in LPS-stimulated and healthy GFs, respectively. Mitophagy was visualized by immunofluorescence, alongside quantification by qRT-PCR/Western blot analysis of proteins associated with mitophagy (PINK1, Parkin, and Beclin-1). Mitochondrial integrity was comprehensively assessed by transmission electron microscopy (TEM), mitochondrial membrane potential (MMP) fluorescence assays, intracellular ROS/mtROS quantification via flow cytometry, and mitochondrial DNA (mtDNA) copy number analysis. NLRP3 inflammasome activation was analyzed by qRT-PCR and Western blot. Pyroptotic cell death was determined by propidium iodide (PI) staining, LDH release, and IL-1β/IL-18 secretion assays.
    RESULTS: LPS stimulation suppressed mitophagy in GFs, which was effectively rescued by PMI treatment. In contrast, the mitophagy inhibitor decreased basal mitophagy in healthy GFs. PMI-mediated mitophagy enhancement restored mitochondrial function in LPS-exposed GFs, as demonstrated by improved MMP, reduced ROS/mtROS levels, and normalized mtDNA/nDNA ratios. Mechanistically, mitophagy activation attenuated LPS-induced NLRP3 inflammasome assembly, thereby reducing pyroptotic cell death and IL-1β/IL-18 secretion.
    CONCLUSIONS: These findings revealed that mitophagy safeguarded against NLRP3 inflammasome-dependent pyroptosis in GFs by preserving mitochondrial homeostasis, highlighting its therapeutic potential for periodontitis management.
    Keywords:  Gingival fibroblasts; Mitophagy; NLRP3 inflammasome; Periodontitis; Pyroptosis
    DOI:  https://doi.org/10.1016/j.archoralbio.2025.106378
  6. Vascul Pharmacol. 2025 Aug 21. pii: S1537-1891(25)00070-9. [Epub ahead of print]160 107531
    Balancing act: Drp1 inhibition and mitochondrial homeostasis in cardiovascular diseases.
    Nandini Dubey, Ahsas Goyal, Neeraj Parakh, Rajiv Narang, Sudhir Kumar Arava, Arvind Kumar, Mayank Yadav, Harlokesh Narayan Yadav.
      The heart is an organ that depends significantly on mitochondria to operate, since it requires a lot of energy, which mitochondria create, making them essential for the efficient functioning of the heart. The term "mitochondrial dynamics" refers to extremely dynamic organelles known as mitochondria that undergo cycles of fusion and fission to modify their appearance, distribution, and function. Drp1 or Dynamin-related protein 1, a primary fission protein, strictly regulates the elimination of damaged mitochondria by mitophagy. This ensures that the complex processes of organ and cellular dynamics in the heart are strictly managed. Phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation are some of the posttranslational modifications (PTMs) of Drp1 that contribute to the regulation of mitochondrial dynamics. While abnormalities in mitochondrial dynamics are a crucial component of the pathophysiology of a number of cardiovascular diseases (CVDs), the heart requires an effective mitochondrial balance to sustain cardiomyocyte metabolism along with contractile activity. This review summarizes the current knowledge of the crucial function of Drp1 inhibitors in the pathophysiology of cardiovascular diseases, including myocardial ischemia-reperfusion, dysfunction of endothelial cells, smooth muscle remodelling, hypertrophy of the heart, high blood pressure, and myocardial infarction. We further highlighted the possible advantages of treating CVDs by specifically targeting Drp1.
    Keywords:  CVDs; Drp1; Heart; Mitochondrial dynamics; SUMOylation
    DOI:  https://doi.org/10.1016/j.vph.2025.107531
  7. J Genet Genomics. 2025 Aug 22. pii: S1673-8527(25)00229-2. [Epub ahead of print]
    MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy.
    Baige Cao, Lei Fang, Yinan Zhang, Chuwen Lin, Peng Liu, Huina Zhang, Orion Fan, Ming Xu, Zhao Qin, Congrong Wang.
      The mitochondrial 3243A>G mutation (m.3243A>G) is associated with diverse clinical phenotypes. To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients, urine-derived stem cells (USCs) and a mitochondrial leucyl-tRNA synthetase (lars-2) deficient Caenorhabditis elegans (C. elegans) model are used to assess mitochondrial homeostasis and neuromuscular dysfunction. Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function, disrupted mitochondrial dynamics, and inhibited mitophagy, which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase (OMA1)-induced mitochondrial phosphatase and tensin (PTEN) induced kinase 1 (PINK1) degradation. Furthermore, lars-2 knockdown in C. elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation. MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway. These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.
    Keywords:  C. elegans; MitoQ; Mitochondrial quality control; USCs; m.3243A>G
    DOI:  https://doi.org/10.1016/j.jgg.2025.08.007
  8. Int Immunopharmacol. 2025 Aug 20. pii: S1567-5769(25)01368-2. [Epub ahead of print]164 115377
    SIRT3 attenuates sepsis-induced EndMT and cardiac remodeling by facilitating mitophagy process via PINK1/Parkin signaling.
    Penghao Liu, Tianhua Xu, Yujun Luo, Jieqiong Meng, Derong Cui, Aizhong Wang.
       OBJECTIVE: Endothelial-mesenchymal transition (EndMT) is a key contributor to the progression of sepsis-induced myocardial injury (SIMI). Defective mitophagy can result in oxidative stress and mitochondrial dysfunction, both of which play a critical role in EndMT. Sirtuin 3 (SIRT3), a major deacetylase responsible for mitochondrial quality control, has the potential to regulate EndMT, although the exact mechanism remains unclear. Therefore, this study aims to investigate the role of SIRT3 in mediating EndMT and cardiac remodeling during SIMI.
    METHODS: Wild-type and SIRT3 knockout mice were induced with lipopolysaccharide (LPS) for 24-h to mimic SIMI. Human cardiac microvascular endothelial cells were treated with LPS for in vitro experiments. Cardiac function was measured by echocardiography. Cardiac fibrosis was determined by Sirus red and Masson's trichrome staining. The expression of endothelial biomarkers and mesenchymal biomarkers was detected using immunofluorescence and western blot to determine EndMT. Mitochondria function and mitophagy were determined by transmission electron microscopy (TEM) and protein biomarkers. The interaction of SIRT3 with PINK1/Parkin was detected by immunoprecipitation (IP) and co-IP.
    RESULTS: Following endotoxin exposure, SIRT3 knockout mice exhibited a more severe EndMT phenotype and increased collagen deposition in cardiac tissues, along with mitochondrial dysfunction and impaired mitophagy. Similarly, LPS treatment induced mitochondrial oxidative stress and disrupted mitophagy flux during EndMT in CMECs, effects that were partially rescued by either rapamycin treatment or SIRT3 upregulation. Furthermore, SIRT3 overexpression enhanced deacetylation of the PINK1/Parkin pathway, thereby promoting mitophagy.
    CONCLUSION: Our findings suggest that SIRT3 suppresses EndMT-mediated cardiac fibrosis by promoting PINK1/Parkin-dependent mitophagy, offering novel insights for the treatment of SIMI.
    Keywords:  Endothelial-mesenchymal transition; Mitophagy; Oxidative stress; SIRT3; sepsis-induced myocardial injury
    DOI:  https://doi.org/10.1016/j.intimp.2025.115377
  9. Biomolecules. 2025 Aug 13. pii: 1159. [Epub ahead of print]15(8):
    Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.
    Sakthijothi Muthu, Zinnia Tran, Ramasamy Saminathan, Pratikshya Shrestha, Sundararajan Venkatesh.
      Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether such defects can be mitigated through inter-organ crosstalk by modulating mPQC in extra-cardiac tissues, a potentially valuable strategy given the challenges of directly targeting the heart. To investigate this, we examined two mouse models of Lonp1 haploinsufficiency at young adulthood: a cardiomyocyte-specific heterozygous knockout (Lonp1CKO-HET) and a whole-body heterozygous knockout (Lonp1GKO-HET). Despite similar reductions in Lonp1 mRNA expression in the hearts, Lonp1GKO-HET mice exhibited no cardiac dysfunction, whereas Lonp1CKO-HET mice showed mild cardiac dysfunction accompanied by activation of the mitochondrial stress response, including induction of genes such as Clpx, Spg7, Hspa9, and Hspd1, increased mitochondrial dynamics (Pink1, Dnm1l), reduced mitochondrial biogenesis, and compensatory upregulation of the mtDNA transcriptional regulator Tfam, all occurring without overt structural remodeling. These alterations were absent in Lonp1GKO-HET hearts. Our findings reveal a novel adaptive mechanism in which systemic mPQC deficiency can buffer mitochondrial dysfunction in the heart through inter-organ communication that is lost with cardiomyocyte-specific mPQC disruption. This study identifies systemic modulation of Lonp1-mediated mitochondrial stress pathways as a promising strategy to promote cardiac resilience through protective inter-organ signaling.
    Keywords:  LONP1; cardiac dysfunction; heart; mitochondria; mitochondrial dysfunction; mitochondrial matrix; protein quality control
    DOI:  https://doi.org/10.3390/biom15081159
  10. Acta Diabetol. 2025 Aug 23.
    Dapagliflozin sustains heart function in type 3 cardiorenal syndrome by restoring DUSP1-dependent mitochondrial quality control.
    Zunyan Li, Ang Zhang, Huida Lu, Ying Jiang, Xiuling He, Hang Zhu, Hao Zhou.
       AIMS: This study tested the hypothesis that the anti-diabetes drug dapagliflozin (DAPA) alleviates heart dysfunction induced by type 3 cardiorenal syndrome (CRS-3) by normalizing mitochondrial quality control (MQC). MQC is a stress-activated mechanism, regulated by Dual specificity phosphatase 1 (DUSP1), that maintains mitochondrial homeostasis to support heart function. Due to its known renal and cardioprotective effects, DAPA was investigated as a potential treatment for CRS-3.
    METHODS: CRS-3 was induced in mice through renal ischemia/reperfusion. The effects of DAPA pre-treatment were assessed by measuring heart function, serum levels of myocardial injury biomarkers, oxidative stress, inflammation, and cardiomyocyte apoptosis. Assays in cardiomqyocytes from CRS-3 mice were used to analyze MQC, including mitochondrial dynamics, mitophagy, and biogenesis. The role of DUSP1 was investigated using DUSP1-knockout mice, and a docking analysis was performed to assess the DAPA-DUSP1 interaction.
    RESULTS: DAPA pre-treatment dose-dependently improved heart function and reduced serum markers of myocardial injury, oxidative stress, inflammation, and cardiomyocyte apoptosis in CRS-3 mice. DAPA treatment stabilized MQC in cardiomyocytes, shown by improved mitochondrial dynamics and restored mitophagy and biogenesis. Docking analysis suggested that DAPA directly interacts with DUSP1 and suppresses its nuclear translocation. Notably, in DUSP1-knockout mice, the stabilizing effect of DAPA on MQC was abolished. Furthermore, upon DUSP1 deletion, DAPA failed to prevent CRS-3-related oxidative stress, inflammation, apoptosis, and heart dysfunction.
    CONCLUSIONS: Defective MQC critically contributes to CRS-3-related myocardial dysfunction. The study proposes that DAPA therapy may normalize DUSP1-dependent MQC and consequently alleviate the cardiac depression associated with CRS-3.
    Keywords:  Cardiorenal syndrome type 3; DUSP1; Dapagliflozin; Mitochondrial quality control
    DOI:  https://doi.org/10.1007/s00592-025-02579-z
  11. Am J Physiol Cell Physiol. 2025 Aug 20.
    Thrombopoietin Mitigates Neuronal Death by Enhancing Mitophagy and Suppressing NLRP3 Inflammasome Activation Under Oxygen-Glucose Deprivation Conditions.
    Liang Li, Yu Zhang, Junyan Zhong, Huimin Kong, Yong Liu, Hui Chen, Xiaoyi Fang, Zhiyuan Zhong, Hongman Xue, Mo Yang, Chun Chen.
      Thrombopoietin (TPO), a principal hematopoietic cytokine, regulates the development and proliferation of megakaryocytes and platelets. Our previous research demonstrated TPO's neuroprotective role against hypoxic-ischemic brain injury in rats. Yet, the underlying mechanisms remain unclear. This study reveals that A20 (Tumor necrosis factor alpha-induced protein 3, Tnfaip3) significantly contributes to TPO's neuroprotective effect by enhancing mitophagy in neurons. TPO reduces cell death under oxygen-glucose deprivation (OGD) conditions. Mechanistically, TPO induces the TNF-α and NF-κB signaling pathways to increase A20 expression, thereby promoting mitophagy, diminishing ROS production, and stabilizing mitochondrial membrane potential (MMP). A20 maintains mitochondrial dynamics and mitigates OGD-induced excessive mitochondrial fission. Furthermore, A20 suppresses NLRP3 inflammasome activation by enhancing mitophagy. This study elucidates a novel mechanism of TPO's neuroprotection, distinct from its hematological effects, supporting its potential therapeutic application in treating neurological injuries.
    Keywords:  Mitophagy; NLR Family Pyrin Domain Containing 3; Neuroprotection; Thrombopoietin; Tumor Necrosis Factor Alpha-Induced Protein 3
    DOI:  https://doi.org/10.1152/ajpcell.00847.2024
  12. JACC Basic Transl Sci. 2025 Aug;pii: S2452-302X(25)00178-0. [Epub ahead of print]10(8): 101290
    Mitophagy Regulators as Novel Targets in Sepsis-Induced Myocardial Dysfunction.
    Katharina Friedrich, Kai Kappert.
      
    Keywords:  FUNDC1; c-FLIP; cardiac microcirculation; mitochondrial autophagy; sepsis-induced myocardial dysfunction (SIMD)
    DOI:  https://doi.org/10.1016/j.jacbts.2025.04.004
  13. J Ginseng Res. 2025 Sep;49(5): 509-522
    Ginsenoside Rb1 attenuates coronary microvascular inflammatory injury via NDUFS4-SIRT5-DUSP1-mediated mitochondrial quality control in a murine ischemia-reperfusion model.
    Xiangyi Pu, Jinfeng Liu, Yanli Wang, Xuanke Guan, Qiaomin Wu, Qin Zhang, Ruxiu Liu, Xing Chang.
       Background: Ginsenoside Rb1 is a prominent bioactive component in traditional Chinese medicine.
    Purpose: This study investigated the molecular mechanisms underlying the protective effects of Ginsenoside Rb1 on endothelium during ischemia-reperfusion (I/R) injury.
    Materials and methods: To enrich for marker genes and investigate the differential expression of DUSP1 and NDUFS4 in coronary artery disease, single-cell transcriptome sequencing was utilized. SIRT5CKO/TG and NDUFS4CKO/TG mouse models were established using gene modification techniques. Si-DUSP-1/ad-DUSP-1 and si-SIRT5/ad-SIRT5 cell models were constructed. Fluorescence detection, mitochondrial membrane potential assays, RT-PCR, and Western blotting were employed to detect the mitochondrial function.
    Results: NDUFS4 and DUSP1 regulate the mitochondrial unfolded protein response (mtUPR), energy metabolism, and dynamics, and may be crucial regulatory genes in the development of coronary artery disease. Ginsenoside Rb1 modulates the NDUFS4-SIRT5-DUSP1 axis, regulates the mitochondrial quality control network, and alleviates coronary microvascular inflammatory injury.
    Conclusions: Ginsenoside Rb1 regulates the NDUFS4-SIRT5-DUSP1 axis, modulating the mitochondrial quality control network, inhibiting the inflammatory cascade response, and improved myocardial function.
    Keywords:  DUSP-1; Inflammation; Mitochondrial quality control; NDUFS-4; SIRT5
    DOI:  https://doi.org/10.1016/j.jgr.2025.04.006
  14. BMJ Open Ophthalmol. 2025 Aug 21. pii: e002126. [Epub ahead of print]10(1):
    Fucoxanthin protects retinal ganglion cells and regulates Parkin-mediated mitophagy in experimental glaucoma.
    Haixia Ma, Xinxin Hu, Juntao Zhang, Wei Lian, Dandan Wang, Lifang Zhang, Qinkang Lu.
       OBJECTIVE: Glaucoma is a common neurodegenerative disease resulting in irreversible blindness. This study investigates whether fucoxanthin can safeguard retinal ganglion cells (RGCs) by modulating Parkin-mediated mitophagy in experimental glaucoma.
    METHODS: An experimental glaucomatous model was induced in Sprague-Dawley rats via translimbal laser photocoagulation. Intraocular pressure (IOP) was monitored using a Tonolab tonometer. RGC survival was evaluated through FluoroGold labelling. Retinal and optic nerve samples were analysed at 3 days and 2 weeks post-IOP elevation for mitochondrial morphology and gene/protein expression using immunohistochemistry and molecular assays.
    RESULTS: Results demonstrated that mitophagy was acutely overactivated in the short term and impaired over the long term in ocular hypertensive rats. Fucoxanthin intravitreal administration enhanced RGC survival and Bcl-2 expression while reducing Bax and glial fibrillar acidic protein levels. During acute IOP elevation, fucoxanthin curtailed Parkin expression and mitophagosome formation, mitigating excessive mitophagy. Under prolonged IOP elevation, it elevated mitophagy-related proteins and restored mitophagy function, contributing to damaged mitochondrial clearance.
    CONCLUSION: Fucoxanthin exerts neuroprotective effects in experimental glaucoma by modulating Parkin-mediated mitophagy. This highlights the therapeutic potential of maintaining mitophagy homeostasis for glaucoma treatment.
    Keywords:  Glaucoma
    DOI:  https://doi.org/10.1136/bmjophth-2024-002126
  15. Free Radic Biol Med. 2025 Aug 20. pii: S0891-5849(25)00921-9. [Epub ahead of print]240 514-531
    Knockdown of MiD49 and MiD51 alleviates collagen-induced arthritis and suppresses mitophagy and fatty acid oxidation (FAO) in rheumatoid arthritis fibroblast-like synoviocytes.
    Jiaqing Liu, Cheng Zhang, Ruicong Ma, Chunlai Yin, Jinyi Ren, Siwen Yang, Ying Zhao, Yawei Tang, Jing Wei, Xia Li.
      Increasing evidence confirms that imbalances in mitochondrial dynamics can impair mitochondrial function, thereby disrupting cellular homeostasis and potentially contributing to a variety of diseases. This study investigated whether mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, MiDs) contribute to the maintenance of the abnormal functions of fibroblast-like synoviocytes (FLS), thereby participating in the pathological process of rheumatoid arthritis (RA), and to elucidate the specific mechanisms. We found that MiDs were significantly upregulated in the FLS of synovial tissues from RA patients and collagen-induced arthritis (CIA) models, as well as in the serum of RA patients. The elevated expression of MiDs in RA serum exhibited a positive correlation with clinical markers. Moreover, knocking down MiD49 or MiD51 alleviated CIA symptoms and attenuated the aggressive behavior of RA-FLS. We found the potential interactions between MiDs and the PTEN-induced kinase 1 (PINK1)-PARK2 E3 ubiquitin-protein ligase (Parkin) pathway, as well as the correlation between the PINK1-Parkin pathway and lipid metabolism, were revealed through protein-protein interaction (PPI) analysis. The PINK1-Parkin-dependent mitophagy and carnitine palmitoyltransferase-1A (CPT-1A) mediated-fatty acid β oxidation (FAO) were impaired following siRNA-mediated knockdown of MiD49 or MiD51. We found that siRNA-mediated knockdown of PINK1 and Parkin effectively reversed the aggressive phenotype of RA-FLS. Finally, we further verified that shRNA targeting MiD49 or MiD51 inhibited Pink1-Parkin-dependent mitophagy and CPT-1A-regulated FAO in FLS derived from the synovial tissues of CIA models. Our study highlights the involvement of MiDs-mediated mitochondrial dynamics dysfunction helps maintain the invasiveness of FLS, and thereby participates in the pathogenesis of RA. These findings provide a theoretical basis for the development of potential therapies for RA in the future.
    Keywords:  Fatty acid oxidation; MiD49; MiD51; Mitophagy; Rheumatoid arthritis fibroblast-like synoviocytes
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.034
  16. Adv Sci (Weinh). 2025 Aug 27. e03259
    Asprosin Aggravates Tubular Epithelial Cell Injury and Phenotypic Transformation via Mitochondrial Dynamics Disorder Mediated by Excessive Drp1 SUMOylation in Diabetic Nephropathy Mice.
    Qianqian Huang, Xiaowei Xiong, Sheng Chen, Yuan Wang, Li Wang, Wentao Liu, Chen Liu, Guohua Zeng, Qiren Huang.
      Epidemiological studies show that some diabetic patients develop end-stage renal dysfunction without significant proteinuria or glomerulopathy, underscoring the role of renal tubular epithelial cell (TEC) impairment in diabetic kidney disease (DKD). However, the primary pathogenic determinants underlying TEC impairment and disease advancement in DKD progression remain unclear. This study reveals that asprosin (ASP) is up-regulated and positively correlated with kidney dysfunction in DKD mice. Moreover, elevated ASP is mainly located in the renal TEC, and negatively impacts TEC. In addition, supraphysiological ASP concentration impairs mitochondrial dynamics and function in both DKD mice and HK2 cells. Mechanistically, ASP promotes Drp1 over-SUMOylation, thus reducing Drp1 degradation and disrupting mitochondrial dynamics homeostasis. However, the mutation of Drp1-SUMOylation modification sites alleviates the mitochondrial dynamics disorder, TEC injury, and phenotypic transformation induced by ASP. Also, it is further elucidated that such a regulatory effect of ASP on the Drp1-SUMOylation modification is fulfilled by modulating PIAS1 or SENP1 (a de-SUMOylation protease). Importantly, either adipose tissue-specific ASP deficiency (ASP-/-) or ASP antibody (AASP) intervention significantly alleviates the kidney injury and mitochondrial dynamics disorder induced by STZ/HFD. These findings identify ASP as a novel predictor of DKD and offer new therapeutic strategies for DKD prevention and treatment.
    Keywords:  SUMOylation; asprosin; diabetic kidney disease; mitochondrial dynamics
    DOI:  https://doi.org/10.1002/advs.202503259
  17. Antioxidants (Basel). 2025 Aug 06. pii: 968. [Epub ahead of print]14(8):
    Camellia japonica Flower Extract and the Active Constituent Hyperoside Repair DNA Damage Through FUNDC1-Mediated Mitophagy Pathway for Skin Anti-Aging.
    Hongqi Gao, Jiahui Shi, Guangtao Li, Zhifang Lai, Yan Liu, Chanling Yuan, Wenjie Mei.
      Skin aging is closely related to mitochondrial dysfunction and cell cycle abnormalities, and developing intervention strategies targeting mitochondrial quality control is an important direction for anti-aging research. In this study, we investigated the anti-aging mechanism of Camellia japonica flower (CJF) extract and its active ingredient hyperoside based on a doxorubicin (DOX)-induced endogenous senescence model in human skin fibroblasts (HSFs). LC-MS proteomics analysis revealed that CJF extract and hyperoside specifically activated the FUNDC1-mediated mitochondrial autophagy pathway, significantly ameliorated the DOX-induced decrease in mitochondrial membrane potential and the accumulation of reactive oxygen species (ROS), and alleviated the cellular S-phase blockade and reversed the high expression of senescence-associated β-galactosidase (SA-β-gal). Further studies showed that the two cleared damaged mitochondria by enhancing mitochondrial autophagy and restoring cellular energy metabolism homeostasis while promoting type III collagen and elastin synthesis and repairing the expression of Claudin 1 related to skin barrier function. For the first time, the present study reveals the molecular mechanism of CJF extract in delaying skin aging by regulating the FUNDC1-dependent mitochondrial autophagy pathway, which provides a theoretical basis and a candidate strategy for developing novel anti-aging agents targeting mitochondrial quality control.
    Keywords:  Camellia japonica flower extract; DNA damage; FUNDC1-mediated mitophagy pathway; hyperoside; skin anti-aging
    DOI:  https://doi.org/10.3390/antiox14080968
  18. J Neurochem. 2025 Aug;169(8): e70205
    Impact of O-GlcNAcylation Elevation on Mitophagy and Glia in the Dentate Gyrus.
    Joshua Kramer, Sarah Fu, Xiaosen Ouyang, Eric Rohwer, John C Chatham, Martin E Young, Victor Darley-Usmar, Jianhua Zhang.
      O-GlcNAcylation is a dynamic and reversible protein posttranslational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O-GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative diseases. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of O-GlcNAcase (OGA) with thiamet G which leads to elevation of protein O-GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP-positive astrocytes and is significantly decreased in response to elevated O-GlcNAcylation. Furthermore, with increased O-GlcNAcylation, the levels of astrocyte markers GFAP and S100B, and the microglial cell marker IBA1, decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O-GlcNAc pathway.
    Keywords:  O‐GlcNAc; astrocyte; hippocampus; microglia; mitophagy
    DOI:  https://doi.org/10.1111/jnc.70205
  19. Autophagy. 2025 Sep 01. 1-18
    PRMT1 (protein arginine methyltransferase 1) is essential for neuromuscular junction and mitochondrial homeostasis via mitophagy regulation.
    Ju-Hyeon Bae, Chang-Lim You, Yideul Jeong, June Kim, Jinwoo Lee, Hyeon-Ju Jeong, Hyebeen Kim, Tuan Anh Vuong, Youngdae Gwon, Gyu-Un Bae, Jong-Sun Kang.
      The neuromuscular junction (NMJ) is essential for transmitting neural stimulus to muscles, triggering muscle contraction. Mitochondria are enriched in NMJ to support the energy needs required for neuromuscular function and stability. Thus, maintaining mitochondrial homeostasis through the clearance of damaged mitochondria, a process known as mitophagy, is vital for preserving neuromuscular health. Here, we highlight the crucial role of muscle PRMT1 in maintaining NMJ and mitochondrial homeostasis via mitophagy regulation. PRMT1 is distinctively expressed in myofibers, accumulating in the postsynaptic area, with its levels upregulated in denervated muscles. PRMT1-ablated muscles displayed disrupted NMJs and an accumulation of abnormal mitochondria, accompanied by increased mitochondrial oxidative stress. Additionally, prmt1 depletion in muscles specifically impaired TBK1 (TANK binding kinase 1)-OPTN (optineurin)-mediated mitophagy. Overall, our findings suggest that PRMT1 plays a critical role in maintaining NMJ and mitochondrial health by regulating selective mitophagy through TBK1-OPTN.Abbreviations: ADMA: asymmetric arginine dimethylation; BTX: α-bungarotoxin; EDL: extensor digitorum longus; FDB: flexor digitorum brevis; GAS: gastrocnemius; NMJ: Neuromuscular junction; Mko: mice with muscle-specific prmt1 ablation; MTOR: mechanistic target of rapamycin kinase; OPTN: optineurin; PRMT1: protein arginine methyltransferase 1; SA: sodium arsenate; SNI: sciatic nerve crush injury; Sol: soleus; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; TOMM20: translocase of outer mitochondrial membrane 20; TA: tibialis anterior; VDAC1: voltage dependent anion channel 1.
    Keywords:  Mitophagy; PRMT1; TBK1; neuromuscular junction; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2025.2551477
  20. Cell Death Dis. 2025 Aug 27. 16(1): 652
    Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.
    Yanling Chen, Xun Liu, Yixuan Liu, Yujia Li, Dingxiang Li, Zhigang Mei, Yihui Deng.
      Diabetes mellitus (DM), a metabolic disease of globally health concern, is pathologically attributed to mitochondrial dysfunction, an essential component in disease progression. Mitochondrial quality control (MQC) acts as a critical defense mechanism for metabolic homeostasis, yet its implications in DM and its complications remain incompletely understood. This study thoroughly summarizes emerging evidence that delineates the molecular processes of MQC, with an emphasis on effector protein post-translational regulation, upstream signaling hubs, and interactions with other metabolic processes including ferroptosis and lipid metabolism. We highlight newly discovered processes involving mitochondrial-derived vesicles, licensed mitophagy, and mitocytosis that broaden the regulatory landscape of MQC, going beyond the traditionally recognized process including biogenesis, dynamics and mitophagy. MQC imbalance exacerbates insulin resistance, while impaired insulin signaling reciprocally compromises mitochondrial function, creating a vicious cycle of metabolic deterioration. Despite tissue-specific pathophysiology, diabetic complications exhibit identical MQC impairment including suppressed biogenesis, fission-fusion imbalance, and deficient mitophagy. Emerging therapies including clinical hypoglycemic agents and bioactive phytochemicals demonstrate therapeutic potential by restoring MQC. However, current strategies remain anchored to classical pathways, neglecting novel MQC mechanisms such as mitocytosis. Addressing this gap demands integration of cutting-edge MQC insights into drug discovery, particularly for compounds modulating upstream regulators. Future studies must prioritize mechanistic dissection of MQC novel targets and their translational relevance in halting metabolic collapse of diabetes progression. Since mitochondrial function is a cornerstone of metabolic restoration, synergizing precision MQC modulation with multi-target interventions, holds transformative potential for refine diabetic complications therapeutics.
    DOI:  https://doi.org/10.1038/s41419-025-07936-y
  21. J Physiol. 2025 Aug 22.
    Neurobiology of mitochondrial dynamics in sleep.
    Raffaele Sarnataro.
      The cycling of sleep and wakefulness reshapes neuronal activity, gene expression, and cellular metabolism of the brain. Such reshuffling of brain metabolism implicates key mediation by mitochondria. Mitochondrial dynamics enable organelles to adapt their morphofunction to changing metabolic demands, and experimental evidence increasingly links these processes to sleep-wake regulation. Across species, sleep loss perturbs mitochondrial gene expression, increases oxidative stress, and disrupts organelle structure, particularly in energy-demanding brain regions. In Drosophila, sleep-control neurons projecting to the dorsal fan-shaped body (dFBNs) exhibit a homeostatic feedback mechanism coupling mitochondrial activity to behavioural state. As sleep pressure elevates, dopaminergic inhibition reduces dFBN excitability and ATP consumption, triggering mitochondrial fission and accumulation of reactive oxygen species (ROS) that biochemically prime the neurons for subsequent sleep induction. Upon relief of inhibition during recovery sleep, dFBNs elevate their activity, consume ATP, and undergo mitochondrial fusion to restore energy balance. Artificial modulation of mitochondrial morphology and ATP production in these neurons bidirectionally alters sleep. dFBNs' elevated OxPhos expression and mitochondrial turnover render them sensitive to metabolic shifts and capable of encoding internal states. While dFBNs remain the only known neurons where mitochondrial dynamics are coupled to sleep behaviour, other populations, like mammalian cortical neurons or fly Kenyon cells, also display mitochondrial changes after sleep loss. Sleep, like other state-dependent behaviours including hunger and memory, imposes shifting energetic demands on specific neuronal populations. Mitochondrial dynamics may thus provide a conserved, cell-autonomous mechanism for tuning neural excitability and sleep pressure, enabling brain-wide coordination of metabolic and behavioural homeostasis.
    Keywords:  ATP; energy; homeostasis; metabolism; mitochondria; neurobiology; neuron; sleep
    DOI:  https://doi.org/10.1113/JP288054
  22. Neuroscience. 2025 Aug 18. pii: S0306-4522(25)00868-1. [Epub ahead of print]584 160-165
    The role of mitophagy in perioperative neurocognitive disorder: from mechanisms to implications.
    Shuai Gao, Jiaqiang Wang, Jiawei Chen.
      Perioperative neurocognitive disorder (PND) is a significant neurological complication in aging perioperativepatients, seriously impacting their postoperative recovery and cognition as well as quality of life. The occurrence of PND is closely related to various factors, including neuroinflammation and oxidative stress, while the exact mechanism is still unknown. Mitophagy is a specialized form of autophagy and maintains cellular homeostasis by selectively degrading damaged and dysfunctional mitochondria, serving as a crucial quality control mechanism to ensure the mitochondrial network's integrity and functionality. Mitophagy has been proved to be involved in the onset and progression of major neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Recently, findings indicated that mitophagy may also play critical roles in the pathogenesis of PND, and the mechanisms may involve ubiquitin-dependent pathways (such as the PINK1/Parkin pathway) and non-ubiquitin-dependent pathways (such as the BNIP3/FUNDC1 pathway). Studies indicated that the PINK1/Parkin pathway is impaired in the animal PND models. In contrast, the BNIP3/ FUNDC1 pathway is neuroprotective by promoting mitophagy under stress conditions such as hypoxia. In addition, abnormal Tau protein aggregation and ferroptosis are correlated with mitophagy and PND in animal studies. In this review, we focused on the role and detailed mechanism of mitophagy in the occurrence and development of PND, as well as on possible potential targets involving mitophagy modulation.
    Keywords:  Cognitive function; Ferroptosis; Mitophagy; Perioperative neurocognitive disorder (PND); Signal pathway; Tau protein
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.08.028
  23. Cell Death Dis. 2025 Aug 25. 16(1): 645
    Targeting FAM111B attenuates mitophagy and increases the sensitivity to lenvatinib treatment by increasing MFN2 stability in hepatocellular carcinoma.
    Yu-Chuan Yan, Li-Juan Shao, Guang-Xiao Meng, Guo-Qiang Pan, Rui-Zhe Li, Chen Xiong, Shi-Jia Liu, Zi-Niu Ding, Xiao-Lu Zhang, Xiao-Feng Dong, Ying Qu, Zhao-Ru Dong, Tao Li.
      Lenvatinib resistance significantly limits its clinical efficacy and application in the treatment of hepatocellular carcinoma (HCC). Mitofusin 2 (MFN2) is an important GTPase involved in mitochondrial fusion, energy balance and mitophagy. The role and regulatory mechanism of MFN2 in HCC progression and lenvatinib resistance remain unclear. Herein, we demonstrated that the family with sequence similarity 111 member B (FAM111B) regulated the stability of MFN2 and the sensitivity to lenvatinib in HCC. Mechanistically, FAM111B promoted MFN2 ubiquitination by recruiting RAN-binding protein 9 (RANBP9), a core subunit of the C-terminal to LisH (CTLH) E3 ligase complex. Targeting FAM111B generated hyperfused mitochondria, driving a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and antagonising cytoprotective mitophagy. Clinically, FAM111B protein levels were inversely correlated with MFN2 expression in HCC samples, with patients who exhibited high FAM111B levels having a worse prognosis and reduced sensitivity to lenvatinib treatment. More importantly, we developed glypican-3 (GPC3)-targeted lipid nanoparticles for efficient delivery of siFAM111B, which demonstrated strong efficacy in combination with lenvatinib. Together, our findings uncover a novel regulatory mechanism for MFN2 posttranscriptional regulation and highlight the therapeutic potential of targeting FAM111B in HCC treatment.
    DOI:  https://doi.org/10.1038/s41419-025-07941-1
  24. Nutr Diabetes. 2025 Aug 25. 15(1): 37
    Ketogenic diet ameliorates MASLD via balancing mitochondrial dynamics and improving mitochondrial dysfunction.
    Yuehua You, Hongbin Ni, Qin Ma, Lincheng Jiang, Jingshu Cai, Wenjun He, Xiaojing Lin, Kemeng Li, Zhuyun Wang, Weiyan Yan, Xiaoqiu Xiao, Li Ma.
       BACKGROUND & AIMS: Ketogenic diet (KD) is recognized as an effective lifestyle intervention for managing metabolic dysfunction-associated steatotic liver disease (MASLD). This research aimed to assess the impact of KD on metabolic parameters in MASLD mice and elucidate the underlying mechanism.
    METHODS: High-fat diet (HFD)-induced MASLD mice were subjected to KD for 2 weeks. Researchers measured hepatic fat, plasma Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) levels to assess metabolic changes. Hepatic mitochondrial dynamics were examined using transmission electron microscopy and Western blot. Mitochondrial functions were evaluated through Quantitative Polymerase Chain Reaction (qPCR) and measurement of ATP content. In vitro, HepG2 cells were treated with palmitate (PA), β-hydroxybutyric acid (β-OHB), and/or the mitochondrial fusion inhibitor MFI8 to study mitochondrial morphology, function, and lipid deposition.
    RESULTS: KD feeding partially improved the MASLD phenotype and reduced Fission 1 protein (Fis1) and Dynamin-related protein 1 (Drp1) levels in the livers of MASLD mice. Additionally, KD ameliorated HFD-stimulated mitochondrial dysfunctions, as evidenced by elevated ATP levels and upregulation of key genes responsible for fatty-acid-oxidation. β-OHB mitigated PA-stimulated mitochondrial dysfunction and fission in HepG2 cells. Furthermore, β-OHB attenuated PA-stimulated lipid deposition, with this effect being counteracted by MFI8.
    CONCLUSIONS: Our study suggests that a 2-week KD partially alleviates lipid deposition, restores mitochondrial dynamics balance, and improves mitochondrial dysfunctions in the livers of MASLD mice.
    DOI:  https://doi.org/10.1038/s41387-025-00391-w
  25. Inflammopharmacology. 2025 Aug 27.
    Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.
    Rufaida Wasim.
      The pathophysiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, is greatly impacted by mitochondrial dysfunction. Recent research suggests that a number of interconnected processes, such as elevated oxidative stress, disturbed energy metabolism, compromised calcium homeostasis, and malformed mitochondrial dynamics, all lead to neuronal injury. The mitochondria in AD brains have structural defects and the function of important oxidative phosphorylation-related enzymes is lowered, which results in less ATP being produced. Further exacerbated by mitochondrial dysfunction is the build-up of amyloid-beta (Aβ) peptides and hyperphosphorylated tau proteins, which interact directly with mitochondrial membranes and proteins to cause mitochondrial fragmentation and hinder mitochondrial transport along neuronal axons. These occurrences cause an increase in reactive oxygen species (ROS) generation, which exacerbates oxidative damage and feeds a vicious cycle. In AD, mutations in mitochondrial DNA (mtDNA) and changes in mitochondrial biogenesis have also been documented, indicating a key involvement in the development of the illness. Preclinical models show promise for therapeutic approaches that attempt to maintain mitochondrial function, including antioxidants, drugs that target the mitochondria. It is crucial to comprehend the intricate relationship between mitochondrial dysfunction and other pathological aspects of AD to find new treatment targets and enhance patient outcomes. In addition to underlining its role in the development of AD, this review examines the complex interaction between mitochondrial dysfunction and AD pathogenesis, taking into account its potential as a biomarker and a target for intervention.
    Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Oxidative stress; Pathology
    DOI:  https://doi.org/10.1007/s10787-025-01916-6
  26. Front Cell Infect Microbiol. 2025 ;15 1613366
    Porphyromonas gingivalis hijacks mitophagy and lysosomal function to persist in endothelial cells.
    Cheng Zheng, Jianmin Huang, Shengming Xu, Bin Lu, Hanxin Que, Tianhao Chen, Yubo Hou, Linlin He, Xia Fan, Fa-Ming Chen, Yi Wang, Hui Deng.
       Introduction: The direct infection of endothelial cells by Porphyromonas gingivalis (P. gingivalis), a keystone periodontal pathogen, has been implicated in the development of atherosclerosis. While non-selective autophagy facilitates its intracellular persistence in endothelial cells, the role of selective autophagy in this process remains unclear. This study investigated whether P. gingivalis hijacks mitophagy and lysosomes to persist in endothelial cells.
    Methods: Human aortic endothelial cells (HAECs) were infected with P. gingivalis for 24 h. Mitophagy was detected by Western Blotting (WB), immunofluorescence, and transmission electron microscopy. Lysosomal function was assessed by acridine orange staining, lysosensor staining, and WB. The effects of mitophagy and lysosomes on P. gingivalis intracellular survival were evaluated by antibiotic protection assays and SYTO-9 staining.
    Results: Our data demonstrated that P. gingivalis initiates PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy in HAECs, leading to increased formation of autophagosomes and mitophagosomes, but disrupted autophagy/mitophagy flux. This blockage of autophagy/mitophagy flux was linked to lysosomal dysfunction, characterized by increased lysosome number, lysosomal membrane permeabilization, disruption of the lysosomal acidic environment, and decreased enzymatic activity. Additionally, antibiotic protection assays and SYTO-9 staining further revealed that P. gingivalis promotes its intracellular survival in endothelial cells by initiating mitophagy and impairing lysosomal function. Furthermore, the mitophagy activator decreased the co-localization of P. gingivalis with microtubule-associated protein 1 light chain 3 (LC3)-p62, LC3-NDP52, and lysosomal-associated membrane protein 1 (LAMP1), suggesting that P. gingivalis-initiated mitophagy inhibited xenophagosome formation and autophagosome/xenophagosome-lysosome fusion.
    Conclusion: Our findings reveal that P. gingivalis may promote its intracellular survival in endothelial cells by initiating PINK1-Parkin-mediated mitophagy and impairing lysosomal function, thereby suppressing xenophagosome formation and xenophagic degradation. This study provides new insights into the mechanisms by which P. gingivalis persists in endothelial cells and its potential role in atherosclerosis progression.
    Keywords:  Porphyromonas gingivalis; endothelial cells; lysosomal function; mitophagy; xenophagy
    DOI:  https://doi.org/10.3389/fcimb.2025.1613366
  27. Biomolecules. 2025 Aug 08. pii: 1145. [Epub ahead of print]15(8):
    Mitochondrial Extracellular Vesicles: A Novel Approach to Mitochondrial Quality Control.
    Jie Kong, Rui Sun, Chengying Du, Yiyang Tang, Chengzhi Xie, Qian Li, Li Lin, Hongyan Wang.
      Mitochondria are central to cellular energy metabolism and play a key role in regulating important physiological processes, including apoptosis and oxidative stress. Mitochondrial quality control has recently garnered significant attention, with the underlying mechanisms traditionally considered to be mitophagy and its dynamics. Various studies have demonstrated that extracellular vesicles are crucial for the transmission of mitochondria and their components. These vesicles effectively transport mitochondria to target cells, facilitating intercellular material exchange and signal transmission, thereby enhancing cellular function and viability. This review explores the mechanisms of mitochondrial transfer through mitochondrial extracellular vesicles (MitoEVs), analyzes the novel roles of MitoEVs in mitochondrial quality control, and discusses their applications in disease treatment. We aim to provide new perspectives for future research and support the development of relevant therapeutic strategies.
    Keywords:  MitoEVs; extracellular vesicle; intercellular material exchange; mitochondria; mitochondrial quality control; signal transmission
    DOI:  https://doi.org/10.3390/biom15081145
  28. Int Immunopharmacol. 2025 Aug 19. pii: S1567-5769(25)01334-7. [Epub ahead of print]164 115343
    3-n-butylphthalide improves cerebral ischemia/reperfusion injury by regulating neuronal mitochondrial biogenesis via AMPK/PGC-1α signaling pathway.
    Jing Li, Xiaochen Zhu.
      Reperfusion therapy can lead to ischemia/reperfusion (I/R) injury in patients with ischemic stroke. The underlying mechanism of I/R injury is still unclear. At present, it is believed that mitochondrial quality control is the key to cerebral I/R injury. This study aimed to explore the protective effects of Race-3-n-Butylphthalide (NBP) on I/R injury and its underlying mechanism through the activation of the AMPK/PGC-1α pathway. The middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation/reoxygenation (OGD/R) model were used to evaluate NBP's effect on neuronal damage, oxidative stress, mitochondrial dysfunction, and mitochondrial biogenesis. Behavioral testing, including the rotarod and grip strength tests, was also performed to assess neurological function. Using both middle cerebral artery occlusion (MCAO) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary neurons, we demonstrated that NBP enhances mitochondrial biogenesis via AMPK/PGC-1α activation, thereby mitigating neuronal I/R injury.
    Keywords:  3-n-butylphthalide; AMPK/PGC-1α signaling pathway; Cerebral ischemia/reperfusion injury; Neuronal mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115343
  29. Clinics (Sao Paulo). 2025 Aug 23. pii: S1807-5932(25)00172-3. [Epub ahead of print]80 100753
    Oxycodone attenuates endotoxin-induced acute lung injury by regulating mitophagy via the HO-1 pathway.
    Cuicui Liu, Yanting Wang, Shaona Li, Jia Shi, Pei Wang, Yang Ma, Xiangkun Li, Jianbo Yu.
       BACKGROUND: Endotoxin-induced Acute Lung Injury (ALI) is a severe clinical syndrome with limited treatment. Oxycodone can alleviate the endotoxin-induced ALI, but the exact mechanism remains unclear. The previous study showed that Heme Oxygenase-1 (HO-1) plays a protective role against endotoxin-induced ALI by regulating mitophagy. Thus, the authors aimed to elucidate whether oxycodone attenuates lung injury by regulating mitophagy via the HO-1 pathway.
    METHODS: Lipopolysaccharide (LPS) ‒ stimulated mice and Mouse Lung Epithelial (MLE12) cells were used to create the model of ALI. After pre-treatment with Oxycodone for the LPS-induced model in vivo and in vitro, markers of cell and tissue damage, oxidative stress, inflammation, and mitophagy were detected. HO-1 knockout mice and HO-1 siRNA in vitro were used to further clarify the role of Oxycodone.
    RESULTS: Pre-treatment with oxycodone could alleviate lung pathological damage, reduce oxidative stress and inflammatory cytokines, increase the expression of HO-1 while down-regulate the mitophagy-related proteins (PINK1, Parkin, LC3 II/I). Furthermore, treatment with oxycodone in HO-1-knockout mice or HO-1 siRNA-transfected MLE12 cells revealed the protective role of the HO-1 pathway on oxycodone-mediated mitophagy in LPS-induced ALI.
    CONCLUSION: HO-1 deficiency partially counteracts the beneficial effects of oxycodone on pulmonary protection and inhibition of mitophagy both in vivo and in vitro. Oxycodone pretreatment attenuated LPS-induced systemic inflammation and subsequent lung injury by regulating mitophagy via the HO-1 pathway.
    Keywords:  Acute lung injury; Endotoxin; Heme oxygenase-1 (HO-1); Mitophagy; Oxycodone
    DOI:  https://doi.org/10.1016/j.clinsp.2025.100753
  30. Int Immunopharmacol. 2025 Aug 22. pii: S1567-5769(25)01389-X. [Epub ahead of print]164 115398
    Regulation of mitochondrial autophagy via the PINK1/Parkin pathway to improve cognitive function in vascular dementia using governor vessel acupuncture.
    Yuanhua Wu, Yanna Ren, Liping Cao, Jianghu Zhao, Jing Cai, Azhen Wang, Maoping Tian, Yueli Li, Yijia Zheng, Jingyu Shi, Tong Lei.
       BACKGROUND: As a common cognitive impairment disease, vascular dementia (VD) belongs to the category of "dementia" in Chinese medicine, and should be treated with the principle "Governor Vessel" as the primary focus. The occurrence of VD is closely related to cerebral ischemia, hippocampal neuron damage, and excessive mitochondrial autophagy activation, which has been considered as is a key mechanism of PINK1/Parkin signaling pathway regulation. Our study aims to investigate molecular mechanisms of the Governor Vessel acupuncture method in improving VD cognitive dysfunction by regulating mitochondrial autophagy.
    METHODS: The study utilized 310 healthy adult male Sprague-Dawley (SD) rats (SPF-grade, aged 18 months, weighing 500-700 g). Vascular dementia (VD) model was established using permanent bilateral common carotid artery ligation (2VO). Additionally, adenoviral vector intervention and drug intervention groups were set up to explore the mechanistic pathways. Morris water maze and shuttle box tests were used to assess cognitive function. Hippocampal tissue changes were analyzed through Nissl staining, HE staining, TUNEL (cell apoptosis), JC-1 (mitochondrial membrane potential), qPCR, and Western blot (to detect PINK1/Parkin pathway proteins). Data are presented as mean ± SEM, analyzed by one-way ANOVA (for normal distribution) or Friedman test (for non-normal distribution), with Tukey's post-hoc test. p < 0.05 was considered statistically significant.
    RESULTS: Rats in the VD model group showed significant cognitive decline in behavioral evaluations, while neurons in the hippocampal CA1 region exhibited varying degrees of damage and apoptosis. Besides, the expressions of autophagy-related proteins, Beclin-1, p-Parkin/Parkin, PINK1, and LC3 II/I was notably up-regulated, whereas the expression of p62 and Mfn2 proteins was significantly decreased. After governor vessel acupuncture, the cognitive ability of VD rats was improved significantly, and neuronal damage in hippocampal CA1 region was effectively alleviated, indicating that governor vessel acupuncture inhibited autophagy by down-regulating the PINK1/Parkin signaling pathway, thereby alleviating VD. Further, PINK1 viral vector and drug intervention experiments further confirmed that inhibiting autophagy could effectively protect neurons by down-regulating the PINK1/Parkin signaling pathway.
    CONCLUSION: Governor vessel acupuncture can effectively protect hippocampal neurons and enhance cognitive functions in VD models by down-regulating PINK1/Parkin signaling pathway to inhibit mitochondrial autophagy, providing a theoretical basis for its clinical application.
    Keywords:  Chronic cerebral hypoperfusion; Governor vessel acupuncture; Mitochondrial autophagy; PINK1/Parkin signaling pathway; Vascular dementia
    DOI:  https://doi.org/10.1016/j.intimp.2025.115398
  31. Hepatol Res. 2025 Aug 23.
    Canagliflozin Alleviates Metabolic Dysfunction-Associated Steatotic Liver Disease via Mitochondrial Protection and Enhanced Mitophagy.
    Ming Lu, Yixin Zhao, Zhihong Liu, Yanrong Zhang, Jing Liu.
       BACKGROUND: Canagliflozin shows anti-inflammatory and antioxidant properties. However, whether canagliflozin can mitigate metabolic dysfunction-associated steatotic liver disease (MASLD) by modulating mitochondrial dysfunction remains to be explored.
    METHODS: Canagliflozin was administered daily for MASLD mice at 10 mg/kg from Week 5 to Week 15. Biochemical assays were performed to assess serum triglyceride, total cholesterol, and liver damage markers. RT-qPCR was used to quantify the genes' expression involved in lipid synthesis and metabolism, whereas oil red O staining was utilized to visualize hepatic lipid accumulation. Western blot analysis was conducted to evaluate the expression of key proteins involved in mitochondrial damage and mitophagy.
    RESULTS: Canagliflozin treatment reduced liver hypertrophy, as shown by a lower liver weight/body weight ratio, and alleviated hepatic lipid accumulation with decreased triglyceride and total cholesterol levels. It improved the serum lipid profile by lowering low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol through inhibiting lipid metabolism genes, including Srebf1, Fasn, and Cd36. Canagliflozin also reduced oxidative stress, as shown by lower malondialdehyde levels, and restored superoxide dismutase and catalase activity. Mitochondrial function was improved with increased ATP production and mitochondrial DNA content. Additionally, canagliflozin activated Parkin/PINK1-mediated mitophagy, as evidenced by upregulation of key mitophagy-related proteins such as PINK1, Parkin, and Atg7, as well as enhanced colocalization of LC3 and TOM20.
    CONCLUSION: Our results demonstrate that canagliflozin may effectively treat MASLD by reducing liver fat and oxidative stress and improving mitochondrial function. It could be a promising treatment option for MASLD, particularly in diabetic patients.
    Keywords:  Canagliflozin; MASLD; diabetes; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1111/hepr.70021
  32. Biogerontology. 2025 Aug 27. 26(5): 172
    Zuogui and Yougui pills extend lifespan and improve ageing biomarkers via kaempferol-mediated mitophagy in Caenorhabditis elegans.
    Wendi Chen, Shuang Liu, Guoqiang Xu, Xin Liu, Yuxuan Shi, Guolong Wang, Yunna Ning, Zhiming Lu, Yongzhi Cao, Yueran Zhao.
      Zuogui pill (ZGP) and Yougui pill (YGP) are classical kidney-tonifying formulas in Traditional Chinese Medicine, widely used clinically but with their potential to delay ageing and improve ageing biomarkers remaining unclear. This study combined network pharmacology and Caenorhabditis elegans models to investigate the anti-ageing effects and mechanisms of ZGP and YGP. Both formulas significantly extended lifespan (ZGP dose-dependently at 5-20 mg/mL; YGP at 20 mg/mL) and improved ageing biomarkers, as evidenced by enhanced motility, reduced lipofuscin accumulation and endogenous ROS levels, and increased resistance to heat and oxidative stress. Network analysis identified quercetin and kaempferol as the top-ranked shared active components. Subsequent experimental validation demonstrated that kaempferol (0.05-0.2 mM) replicated these pro-longevity effects and was shown to act by inducing mitophagy: it triggered an initial decrease followed by a long-term increase in mitochondrial content, concomitant with upregulated expression of mitophagy genes. Crucially, the lifespan-extending effects of kaempferol, ZGP, and YGP were completely abolished in bec-1 and pink-1 null mutants. This study establishes that ZGP and YGP delay ageing and improve ageing biomarkers in C. elegans by activating BEC-1/PINK-1-dependent mitophagy. Kaempferol was identified as a major active component mediating this effect, highlighting a key mechanism for the pro-longevity properties of these traditional formulas.
    Keywords:   C. elegans ; Kaempferol; Lifespan; Mitophagy; Yougui pill; Zuogui pill
    DOI:  https://doi.org/10.1007/s10522-025-10317-9
  33. Mol Cell Proteomics. 2025 Aug 25. pii: S1535-9476(25)00159-8. [Epub ahead of print] 101060
    Jolkinolide B Activates Mitophagy to Exhibit Anti-pancreatic Cancer Activity and Alleviate Cognitive Deficits in Alzheimer's Disease.
    Mingjie Gao, Weiyi Hu, Delan Meng, Pengju Yao, Siqi Yang, Yuanpeng Tong, Lei Wang, Ya Zhang, Qingsong Wang, Jianguo Ji, Wenyuan Zhu.
      Dysfunctional mitophagy leads to the pathological accumulation of damaged mitochondria, which is closely associated with the development of human diseases such as cancer and Alzheimer's disease. The identification of safer and more effective mitophagy regulators may provide a novel approach for treating mitochondrial diseases. Covalent-binding drugs have attracted substantial attention due to their high specificity, selectivity, and low resistance potential. In this study, we demonstrated that the natural epoxide compound jolkinolide B (JB) specifically induces mitophagy both in vitro and in vivo. Mass spectrometry analysis confirmed that JB directly binds to the outer mitochondrial membrane translocase protein TOM40, leading to autophagic cell death in pancreatic cancer. As a mitophagy enhancer, JB also ameliorates mitochondrial dysfunction and mitigates cognitive deficits in the 5×FAD mouse model of Alzheimer's disease. The findings indicate that JB selectively targets mitochondria to enhance mitophagy while exhibiting minimal toxicity in pancreatic cancer and Alzheimer's disease mouse models, highlighting its potential as a therapeutic agent for mitochondrial diseases.
    Keywords:  Alzheimer's disease; Jolkinolide B; Mitochondrial protein TOM40; Mitophagy enhancer; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.mcpro.2025.101060
  34. J Cell Mol Med. 2025 Aug;29(16): e70803
    Dihydromikanolide Inhibits ROS-Mediated NLRP3 Inflammation via Antioxidant Nrf2 Activation and Mitophagy Induction in LPS/ATP-Stimulated Macrophages.
    You-Cheng Hseu, Yu-Fang Tseng, Jhih Ke-Hseu, Sudhir Pandey, Siang-Jyun Chen, Kai-Yuan Lin, Hsueh-Wei Chang, Tzong-Der Way, Chuan-Chen Lee, Jhih-Hsuan Hseu, Hsin-Ling Yang.
      Dihydromikanolide (DHK) is a natural product in Mikania species. We examined the anti-inflammatory molecular mechanisms of DHK employing in vitro RAW264.7 macrophages and in vivo BALB/c mice under LPS/ATP stimulation. We found that DHK suppressed NLRP3 inflammasome, procaspase-1 activation and then pro-inflammatory IL1β expression in LPS/ATP-stimulated RAW264.7 cells. Notably, DHK-triggered autophagy in RAW264.7 cells was demonstrated by increased LC3-II accumulation, p62/SQSTM1 expression, Beclin-1/Bcl-2 ratio and PI3K/AKT/mTOR phosphorylation. Besides, DHK increased Parkin and Pink-1 protein expressions implying mitophagy induction in RAW264.7 cells. Interestingly, DHK enhanced Nrf2 nuclear translocation and provoked antioxidant HO-1, NQO-1 and γ-GCLC expressions in RAW264.7 cells. Nrf2 knockdown reversed DHK-inhibited LPS/ATP-stimulated IL1β expression in RAW264.7 cells. Interestingly, LPS/ATP-stimulated NLRP3 inflammasome and IL1β expression were inhibited by DHK, Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (a ROS inhibitor). In vivo study revealed that DHK attenuated wet/dry weight ratio of lung tissue, lung neutrophil intrusions and pulmonary oedema, and reduced the increased total cells, neutrophils, TNFα and IL1β expression in bronchoalveolar lavage fluid (BALF) in LPS-stimulated BALB/c mice. DHK alleviated LPS-induced pathological alterations of lung through inhibiting NLRP3 inflammation, enhancing antioxidant Nrf2 pathway and inducing mitophagy in LPS-stimulated BALB/c mice. Dihydromikanolide may be a potential therapeutic agent for inflammatory diseases.
    Keywords:  NLRP3; Nrf2; dihydromikanolide; macrophages; mitophagy
    DOI:  https://doi.org/10.1111/jcmm.70803
  35. Int J Mol Sci. 2025 Aug 20. pii: 8048. [Epub ahead of print]26(16):
    CDK5 Inhibits Synphilin-1 Ubiquitination and Basal Mitophagy: Implications for Parkinson's Disease.
    Mor Savyon, Eyal Avraham, Ankit Kumar Shah, Haya Hamza, Raymonde Szargel, Fatimah Abd Elghani, Malik Farhoud, Michal Toren-Hershkoviz, Nicole Pavoncello, Sofia Zaer, Rina Bandopadhyay, Hazem Safory, Simone Engelender.
      Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of α-synuclein-positive inclusions known as Lewy bodies. Synphilin-1 is a protein of unknown function that interacts with α-synuclein and has been shown to exhibit cytoprotective effects in both in vitro and in vivo models. In this study, we investigated whether synphilin-1 is phosphorylated by pathological CDK5 and explored the consequences of this modification. Pathological activation of CDK5 occurs mainly through its association with the calpain-cleaved protein p25. Although CDK5 inhibition protects against neurodegeneration in pharmacological PD models, we now show that p25 levels are increased in PD brains. Furthermore, we demonstrate that CDK5, in conjunction with p25, directly phosphorylates synphilin-1, mainly at serine 566. This phosphorylation reduces synphilin-1's interaction with SIAH1, leading to reduced ubiquitination and subsequent accumulation. We also observed that CDK5-phosphorylated synphilin-1 exhibits a reduced ability to interact with PINK1 and to promote basal levels of mitophagy. Consistent with these findings, the phosphorylation-mimicking synphilin-1 S566E shows decreased translocation to mitochondria, and synphilin-1 levels are reduced in the mitochondria of PD brains compared to age-matched controls. Finally, synphilin-1 S566E promotes retraction of neuronal processes. Taken together, our results suggest that phosphorylation by CDK5 disrupts synphilin-1's interactions with its protein partners, rendering it more toxic and impairing its ability to support mitophagy and maintain neuronal process homeostasis. We hypothesize that phosphorylation of synphilin-1 by CDK5 may contribute to the pathogenesis of PD.
    Keywords:  CDK5; Parkinson’s disease; mitophagy; neurodegeneration; neuronal processes; synphilin-1; ubiquitination
    DOI:  https://doi.org/10.3390/ijms26168048
  36. Curr Issues Mol Biol. 2025 Jul 29. pii: 597. [Epub ahead of print]47(8):
    Astragaloside IV Ameliorates Cerebral Ischemic-Reperfusion Injury via Improving Mitochondrial Function and Inhibiting Neuronal Apoptosis.
    Tongtong He, Xiaohong Zhou, Xiaorong Wang, Yanmeng Zhao, Zhenyi Liu, Ping Gao, Weijuan Gao, Xiaofei Jin.
      Cerebral ischemic-reperfusion injury (CIRI) involves mitochondrial dysfunction, with mitophagy playing a key role. Astragaloside IV (AS-IV) shows neuroprotective potential; however, its mechanisms related to mitochondrial function and apoptosis remain unclear.
    METHODS: Using a rat MCAO/R model, we evaluated the AS-IV's effects via neurological scores, TTC staining, and histopathology. Molecular assays and docking were used to analyze mitophagy (PINK1, Parkin, p62, ROS, Bcl-2, and BAX) and apoptosis markers.
    RESULTS: AS-IV improved neurological function, reduced infarct volume, and alleviated neuronal/mitochondrial damage. It upregulated PINK1/Parkin, decreased p62, and modulated Bcl-2/Bax. Docking confirmed AS-IV binds PINK1/Parkin with high affinity.
    CONCLUSIONS: AS-IV protects against CIRI by regulating the PINK1/Parkin pathway, improving mitochondrial function, and inhibiting neuronal apoptosis, providing an experimental basis for the clinical use.
    Keywords:  PINK1/Parkin pathway; astragaloside IV; cerebral ischemic reperfusion injury; reactive oxygen species
    DOI:  https://doi.org/10.3390/cimb47080597
  37. Cells. 2025 Aug 14. pii: 1259. [Epub ahead of print]14(16):
    Highly Oligomeric DRP1 Strategic Positioning at Mitochondria-Sarcoplasmic Reticulum Contacts in Adult Murine Heart Through ACTIN Anchoring.
    Celia Fernandez-Sanz, Sergio De la Fuente, Zuzana Nichtova, Marilen Federico, Stephane Duvezin-Caubet, Sebastian Lanvermann, Hui-Ying Tsai, Yanguo Xin, Gyorgy Csordas, Wang Wang, Arnaud Mourier, Shey-Shing Sheu.
      Mitochondrial fission and fusion appear to be relatively infrequent in cardiac cells compared to other cell types; however, the proteins involved in these events are highly expressed in adult cardiomyocytes (ACM). Therefore, these proteins likely have additional non-canonical roles. We have previously shown that DRP1 not only participates in mitochondrial fission processes but also regulates mitochondrial bioenergetics in cardiac tissue. However, it is still unknown where the DRP1 that does not participate in mitochondrial fission is located and what its role is at those non-fission spots. Therefore, this manuscript will clarify whether oligomeric DRP1 is located at the SR-mitochondria interface, a specific region that harbors the Ca2+ microdomains created by Ca2+ release from the SR through the RyR2. The high Ca2+ microdomains and the subsequent Ca2+ uptake by mitochondria through the mitochondrial Ca2+ uniporter complex (MCUC) are essential to regulate mitochondrial bioenergetics during excitation-contraction (EC) coupling. Herein, we aimed to test the hypothesis that mitochondria-bound DRP1 preferentially accumulates at the mitochondria-SR contacts to deploy its function on regulating mitochondrial bioenergetics and that this strategic position is modulated by calcium in a beat-to-beat manner. In addition, the mechanism responsible for such a biased distribution and its functional implications was investigated. High-resolution imaging approaches, cell fractionation, Western blot, 2D blue native gel electrophoresis, and immunoprecipitations were applied to both electrically paced ACM and Langendorff-perfused beating hearts to elucidate the mechanisms of the strategic DRP1 localization. Our data show that in ACM, mitochondria-bound DRP1 clusters in high molecular weight protein complexes at mitochondria-associated membrane (MAM). This clustering requires DRP1 interaction with β-ACTIN and is fortified by EC coupling-mediated Ca2+ transients. In ACM, DRP1 is anchored at the mitochondria-SR contacts through interactions with β-ACTIN and Ca2+ transients, playing a fundamental role in regulating mitochondrial physiology.
    Keywords:  DRP1 oligomers; adult cardiomyocytes (ACM); dynamin-related protein 1 (DRP1); high Ca2+ microdomains; mitochondria-associated membranes (MAM); sarcoplasmic reticulum (SR); β-ACTIN
    DOI:  https://doi.org/10.3390/cells14161259
  38. Drug Des Devel Ther. 2025 ;19 7069-7087
    Traditional Chinese Medicine Monomers and Their Derivatives as a Promising Therapeutic Tool for Hepatocellular Carcinoma by Activation of Mitophagy.
    Jiayu Zhu, Sihan Yin, Shengping Luo, Fei Yu, Kewei Sun.
      Hepatocellular carcinoma (HCC) is a malignant tumor of the liver. Treatment programs according to its physiological and pathological characteristics have reduced the number of new cases and deaths of HCC, but the morbidity and mortality are still high, posing a significant threat to human health. In recent years, the importance of mitophagy in the treatment of HCC has gradually been recognized. The activation of mitophagy inhibits the survival, proliferation and migration of HCC cells through a variety of pathways, promotes cell apoptosis, and can also reduce drug resistance, providing a new direction for the treatment of HCC. Studies have shown that Traditional Chinese medicine (TCM) monomers and their derivatives can improve the therapeutic efficacy of HCC and slow down disease progression by regulating mitophagy. This article summarizes the potential mechanism of mitophagy in the progression of HCC and comprehensively explores the potential of TCM monomers and their derivatives in the treatment of HCC, providing new perspectives and strategies for clinical treatment.
    Keywords:  derivatives; hepatocellular carcinoma; mitophagy; traditional Chinese medicine monomers
    DOI:  https://doi.org/10.2147/DDDT.S535244
  39. Front Pharmacol. 2025 ;16 1667879
    Correction: Novel mitophagy inducer TJ0113 alleviates pulmonary inflammation during acute lung injury.
    Zhengyuan Liu, Danruo Fang, Kaijun Chen, Lingling Dong, Huaqiong Huang, Zhihua Chen.
      [This corrects the article DOI: 10.3389/fphar.2025.1590458.].
    Keywords:  NF-κB; NLRP3 inflammasome; TJ0113; acute lung injury; mitophagy inducer
    DOI:  https://doi.org/10.3389/fphar.2025.1667879
  40. Crit Rev Oncol Hematol. 2025 Aug 21. pii: S1040-8428(25)00287-2. [Epub ahead of print] 104899
    Mitochondrial Homeostasis in Cancer: Functions and Targeted Therapies.
    Lihan Wei, Boxiang Hong, Xiawei Zhang, Ruoying Cao, Liyuan Huang, Chenyang Xu, Lihua Wang, Tongke Chen.
      The dysregulation of mitochondrial homeostasis in tumor cells plays a significant role in tumorigenesis and progression. Mitochondria within tumor cells exhibit extensive mutations, proliferation, and fragmentation to accommodate heightened metabolic and energy requirements. This disruption of mitochondrial homeostasis is intricately linked to tumor cell proliferation, invasion, metastasis, energy metabolism, and redox balance. Disrupting the homeostasis of mitochondria in tumor cells has emerged as a novel approach in the clinical management of tumors, with mitochondria-targeted pharmaceuticals showing promise as a potential breakthrough in tumor therapy. This review outlines recent advancements in the understanding of mitochondrial homeostatic dysregulation in oncology and discusses the potential of targeting oncogenic mitochondria as a novel therapeutic avenue for the treatment of tumors.
    Keywords:  Mitochondria; Mitochondrial dynamics; Mitostasis; Targeted therapies; Tumor
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104899
  41. Cell Prolif. 2025 Aug 27. e70121
    Mechanical Force Promotes Mitochondrial Transfer From Macrophages to BMSCs to Enhance Bone Formation.
    Yingyi Li, Ziwei Yan, Yueming Dai, Hanjia Cai, Yue Chen, Yuyi Chen, Ruofan Jin, Wen Sun, Hua Wang.
      Macrophages and bone marrow mesenchymal stem cells (BMSCs) share a close relationship within the osteoimmune microenvironment. During mechanically induced bone formation, macrophages respond to stimuli and regulate this microenvironment, influencing BMSCs' proliferation and differentiation. However, the underlying mechanisms remain incompletely understood. In our study, we employed a cellular tension system and found that mechanical tension altered mitochondrial dynamics in macrophages, leading to increased mitochondrial fission. Using a macrophage-BMSC direct co-culture system, we demonstrated that macrophages transferred mitochondria to BMSCs, a process enhanced by tension. This enhancement was associated with Drp1-mediated mitochondrial fission, as Drp1 knockdown in macrophages abolished the effect. Additionally, using in vitro co-culture and in vivo tibial injection models, we found that mitochondria-rich extracellular vesicles (Mito-EVs) secreted by mechanically stretched macrophages promoted BMSCs' osteogenesis and enhanced bone formation via the CD200 receptor (CD200R)-CD200 interaction. Our findings reveal a pivotal role for mitochondrial transfer in promoting osteogenesis during mechanotransduction, highlighting a novel mechanism of intercellular communication in bone biology.
    Keywords:  bone marrow mesenchymal stem cell; macrophage; mechanical tension; mitochondria transfer; osteogenesis
    DOI:  https://doi.org/10.1111/cpr.70121
  42. BMC Geriatr. 2025 Aug 20. 25(1): 645
    AIMP1 exerts hearing protection role in age related hearing loss mice by regulating SIRT1 expression.
    Haisen Peng, Jiali Liu, Yuehui Liu, Chunhua Li, Zhilin Zhang, Shuihua Hu, Wen Xie.
       BACKGROUND: Age related hearing loss (ARHL) is a sensorineural hearing disease caused by multiple factors and its pathogenesis is still unclear. This work aims to investigate the precise role of AIMP1 in ARHL.
    METHODS: HEI-OC1 cells were treated with 1 mM H2O2 for 2 h to induce cell damage. CCK-8, flow cytometry and TUNEL staining examined cell viability and apoptosis. DCFH-DA fluorescence probe assessed ROS. The levels of MDA, SOD and copper were detected by kits. The expression of proteins related to mitophagy, cuproptosis were examined by western blotting and immunofluorescence. Finally, D-galactose was administered to mice to establish an ARHL model for verifying the functional role of AIMP1 in ARHL.
    RESULTS: AIMP1 and SIRT1 were down-regulated in H2O2-treated HEI-OC1 cells. AIMP1 overexpression promoted cell viability, reduced ROS and MDA levels, and increased SOD levels in H2O2-treated HEI-OC1 cells. Moreover, the levels of copper and apoptosis were decreased in H2O2-treated HEI-OC1 cells in the presence of AIMP1 overexpression. AIMP1 overexpression caused a down-regulation of cuproptosis-related proteins FDX1, DLAT, DLST, and an up-regulation of mitophagy-related proteins PINK1, Parkin, Mfn2 and Drp1 in H2O2-treated HEI-OC1 cells. Knockdown PINK1 or SIRT1 reversed the influence of AIMP1 overexpression on H2O2 induced HEI-OC1 cell damage. In vivo, AIMP1 overexpression reduced damage of cochlear tissues and partially restored hearing in ARHL mice.
    CONCLUSION: AIMP1 up-regulated SIRT1 to promote PINK1/Parkin-mediated mitophagy and inhibit cuproptosis of cochlear hair cells in ARHL mice. Thus, AIMP1 may be a potential target for ARHL treatment.
    Keywords:  AIMP1; Age related hearing loss; Cuproptosis; Mitophagy; Oxidative stress; SIRT1
    DOI:  https://doi.org/10.1186/s12877-025-06237-5
  43. Neuroscience. 2025 Aug 18. pii: S0306-4522(25)00869-3. [Epub ahead of print]584 166-179
    mGluR5 promotes oxidative stress and central sensitization in chronic migraine through ERK-mediated phosphorylation of Drp1 to activate mitochondrial fission.
    Haifeng Wen, Han Wang, Juan Zhong, Xiaojian Liu, Yaying Yang, Wei Zhang, Dunke Zhang, Guangcheng Qin, Lixue Chen.
      Chronic migraine (CM) imposes a significant social burden due to its frequent attacks and high disability rate. However, the pathological mechanism remains unclear, and central sensitization was proven to play a crucial role. Various studies have shown that oxidative stress also contributes significantly to chronic migraine. Metabotropic glutamate receptor 5 (mGluR5), a GPCR, is vital in pain modulation. Additional research is required to fully clarify mGluR5's involvement in chronic migraine and its underlying mechanisms. In this work, a chronic migraine model was developed through daily Inflammatory soup (IS) injections into the dura mater for seven consecutive days. Hyperalgesia was quantified via mechanical and thermal pain sensitivity, while central sensitization was evaluated using CGRP and c-Fos expression levels. To ascertain mitochondrial fission, the expression level of phosphorylated dynamin-related protein 1 (Drp1) at Serine 616 (S616) and mitochondrial ultrastructure were examined. Oxidative stress was assessed using malondialdehyde (MDA) content and superoxide dismutase (SOD) activity. Our results indicated that blocking mGluR5 lowered oxidative stress by preventing mitochondrial fission driven by phosphorylated Drp1. Furthermore, blocking the action of phosphorylated Drp1 in mitochondrial fission has the potential to reduce hyperalgesia and central sensitization. ERK may mediate mGluR5's influence on mitochondrial fission. The findings suggest that mGluR5 regulates mitochondrial fission through ERK-mediated Drp1 phosphorylation, driving oxidative stress and central sensitization in chronic migraine. Consequently, mGluR5 may serve as a promising treatment target for chronic migraines.
    Keywords:  Central sensitization; Chronic migraine; Mitochondrial fission; Oxidative stress; mGluR5
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.08.029
  44. Osteoarthritis Cartilage. 2025 Aug 21. pii: S1063-4584(25)01115-X. [Epub ahead of print]
    L-arginine alleviates intervertebral disc degeneration by suppressing TRIB3/AKAP1-mediated Drp1 phosphorylation dysregulation and mitochondrial fragmentation.
    Chao Zhang, Songbo Gao, Weitao Han, Jiajun Wu, Zhengqi Huang, Xiaohe Zhang, Yuliang Wu, Shuangxing Li, Ming Shi, Bo Gao, Bo Sun, Mingxi Zhu, Yan Peng, Kang Xu, Wei Ye.
       OBJECTIVE: To clarify therapeutic potential and underlying mechanism of L-arginine (L-arg) in intervertebral disc degeneration (IDD).
    DESIGN: Human nucleus pulposus (NP) samples (n=36) underwent metabolomics, L-arg quantification, and immunohistochemistry to characterize the relationship between L-arg metabolism and IDD severity. In vitro NP cell experiments integrated RNA-sequencing, Western blot, co-immunoprecipitation, and immunofluorescence colocalization to clarify the therapeutic effects and mechanism of L-arg. In vivo validation using rat models (n=30) was performed with magnetic resonance imaging (MRI) and immunohistochemistry to assess the efficacy of L-arg in alleviating IDD.
    RESULTS: Metabolomics revealed a depletion of L-arg in severely degenerated NP tissues. L-arg supplementation mitigated TNFα-induced cellular senescence (β-galactosidase positive rate reduced by 37.4%, 95% CI: 29.5-45.3), extracellular matrix dysfunction (ACAN increased 1.59-fold, 95% CI: 1.19-2.11), and mitochondrial dysfunction (ATP content increased 1.43-fold, 95% CI: 1.29-1.57) in NP cells by inhibiting mitochondrial fragmentation. In rat IDD models, L-arg attenuated disc degeneration (MRI intensity: 3.245-fold vs. degeneration, 95% CI: 2.05-5.13). Mechanistically, L-arg suppressed inflammation-driven Tribbles homolog 3 (TRIB3) expression (0.49-fold vs. TNFα, 95% CI: 0.29-0.84). Elevated TRIB3 disrupted the interaction between A-kinase anchoring protein 1 (AKAP1) and protein kinase A regulatory subunit IIα (PKA RIIα)-an interaction critical for Drp1-S656 phosphorylation that inhibits mitochondrial fission. By preserving the AKAP1-PKA RIIα interaction, L-arg sustained Drp1 phosphorylation at S656 and blocked pathological mitochondrial fission.
    CONCLUSION: L-arg may alleviate IDD in vitro and vivo by modulating TRIB3-AKAP1-PKA/Drp1(S656) axis, highlighting its promising therapeutic potential in IDD.
    Keywords:  AKAP1; Arginine; Cellular senescence; Intervertebral disc degeneration; Mitochondrial dynamics; TRIB3
    DOI:  https://doi.org/10.1016/j.joca.2025.08.005
  45. Int Immunopharmacol. 2025 Aug 19. pii: S1567-5769(25)01356-6. [Epub ahead of print]164 115365
    PPP1R3G inhibition impairs OPCs differentiation and myelination in aged mice.
    Zhao-Wei Feng, Xu Miao, Hao Shi, Chu Zhang, Gui Wang, Yu-Ning Ding, Ke-Xin Shi, Zhi-Ming Tang, Rui-Qin Yao, Hai-Yan Liu.
      Age-related cognitive decline is closely linked to white matter integrity, yet the molecular regulators of myelination during aging remain poorly defined. Protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is implicated in cellular metabolism, but its role in brain aging is unknown. We assessed PPP1R3G expression in the corpus callosum of aging mice (1-18 months) and stratified aged mice into High/Low-PPP1R3G groups. Cognitive function was evaluated using Morris water maze (MWM) and touchscreen tests. Ppp1r3g knockout (KO) mice and primary oligodendrocyte precursor cells (OPCs) were used to investigate mechanisms via immunohistochemistry, TEM, RNA-seq, and mitochondrial functional assays. Brain PPP1R3G levels peaked at 4 months and declined with aging. Low-PPP1R3G aged mice exhibited significant cognitive impairment in spatial learning and memory tasks. Ppp1r3g KO aged mice showed severe myelin loss, reduced MBP/MOG expression, increased g-ratio, and impaired OPC differentiation. KO disrupted mitochondrial dynamics characterized with reduced length/number, fission activation, and impaired membrane potential/ATP production. In vitro, KO inhibited OPC differentiation, reversed by Ppp1r3g overexpression. RNA-seq revealed dysregulated mitochondrial fission/fusion and myelin pathways. PPP1R3G deletion inhibited AMPK. As AMPK negatively regulates Drp-1 phosphorylation, which drives Drp1-mediated fission, AMPK activation rescued the fission defects. Taken together, PPP1R3G is essential for maintaining myelination and cognitive function in aging by promoting OPC differentiation through AMPK-Drp1-dependent mitochondrial homeostasis. Its decline represents a novel mechanism underlying age-related cognitive impairment and a potential therapeutic target.
    Keywords:  AMPK-Drp1 signaling; Cognitive decline; Mitochondrial dynamics; Myelination; Oligodendrocyte precursor cells; PPP1R3G
    DOI:  https://doi.org/10.1016/j.intimp.2025.115365
  46. Prostaglandins Other Lipid Mediat. 2025 Aug 22. pii: S1098-8823(25)00079-6. [Epub ahead of print]180 107026
    Role of IRGM in acute lung injury: Inducing mitophagy and inactivating cGAS-STING signaling to improve lipopolysaccharide-induced alveolar epithelial barrier dysfunction.
    Yanqiong Shi, Yang Liang, Yang Chen, Zhenghuan Li.
      Acute lung injury (ALI) is a common disorder of the respiratory system with high mortality. Inducing mitophagy is generally considered to be an effective target for alleviating ALI. We aimed to elucidate the role of immunity related GTPase M (IRGM) in ALI by using a lipopolysaccharide (LPS)-induced alveolar epithelial cell model. Firstly, IRGM expression in A549 cells under LPS conditions was evaluated. Then, IRGM was upregulated and oxidative stress was evaluated by measuring intracellular reactive oxygen species (ROS) using 2', 7'-Dichlorofluorescin diacetate (DCFH-DA) staining. The permeability of A549 cells was determined by detecting transepithelial electrical resistance (TEER) value and fluorescein isothiocyanate-dextran 4 (FITC-FD4) fluorescence. Proteins related to epithelial barrier, mitophagy and mitochondrial function were assessed. Further Mdivi-1 (an inhibitor of mitophagy) addition or cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signaling overexpression was conducted to investigate the potential mechanism. Results suggested that IRGM was downregulated in LPS-treated A549 cells and IRGM upregulation alleviated LPS-induced oxidative stress, inflammation and barrier dysfunction in A549 cells. IRGM upregulation induced mitophagy and maintains mitochondrial function in LPS-treated A549 cells. Particularly, Mdivi-1 treatment or cGAS overexpression abrogated the impacts of IRGM upregulation on oxidative stress, inflammation and barrier dysfunction in LPS-treated A549 cells. Collectively, IRGM attenuates LPS-triggered alveolar epithelial cell damage by enhancing mitophagy to inactivate cGAS/STING signaling.
    Keywords:  Acute lung injury; Alveolar epithelial barrier dysfunction; CGAS-STING; IRGM; Mitophagy
    DOI:  https://doi.org/10.1016/j.prostaglandins.2025.107026
  47. Medicine (Baltimore). 2025 Aug 22. 104(34): e44002
    Integrating bulk and single-cell RNA data with machine learning to explore mitophagy in periodontitis.
    Qisheng Hu, Yongheng Zhang, Huawei Ming, Zongyi Yuan, Fangyuan Chen, Wenjie Hao, Xiaoyao Tan, Xingan Zhang.
      Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; however, its specific regulatory mechanisms in PD remain unclear. This study utilized single-cell and bulk RNA sequencing data to identify core genes and investigate their potential roles. We utilized single-cell RNA sequencing data and applied 4 algorithms - area under the curve cell level enrichment, U-statistics-based single-cell signature scoring, single-sample gene set scoring, and AddModuleScore - to assess mitophagy activity and identify candidate genes. Subsequently, based on bulk RNA-seq data, 5 machine learning algorithms, including Least Absolute Shrinkage and Selection Operator Regression, random forest, Boruta, gradient boosting machine, and eXtreme Gradient Boosting, were employed to further screen core genes from the candidate gene set. Finally, immune infiltration analysis, cell communication analysis, and gene interaction network construction were integrated to systematically elucidate the regulatory mechanisms of core genes in the progression of PD. Single-cell RNA sequencing combined with multiple algorithms revealed significantly elevated mitophagy activity in PD tissues, particularly in monocytes/macrophages and endothelial cells. Additionally, we identified 4 core genes: BNIP3L, VPS13C, CTTN, and MAP1LC3B. BNIP3L and CTTN were downregulated in periodontitis, correlating negatively with disease prevalence, immune infiltration, and inflammatory pathways, whereas VPS13C and MAP1LC3B were upregulated, showing positive correlations. CellChat analysis highlighted monocytes/macrophages and endothelial cells with high core gene expression as key mediators of intercellular communication. This study identified BNIP3L, VPS13C, CTTN, and MAP1LC3B as core mitophagy-related genes associated with PD, and highlighted the pivotal roles of monocytes/macrophages and endothelial cells in disease progression. These findings provide new insights into the pathogenesis of PD and offer a theoretical foundation for mitophagy-targeted diagnosis, biomarker identification, and precision therapy.
    Keywords:  BNIP3L; CTTN; MAP1LC3B; VPS13C; mitophagy; periodontitis; single-cell RNA sequencing
    DOI:  https://doi.org/10.1097/MD.0000000000044002
  48. Life (Basel). 2025 Aug 11. pii: 1273. [Epub ahead of print]15(8):
    Possible Role of Novel Mitochondrial Subsets in Migraine.
    Ozgur Yildirim Savran, Meltem Tuncer.
      Migraine is a complex neurological disorder characterized by recurrent headaches and sensory disturbances. Emerging evidence highlights a critical role for mitochondrial dysfunction in migraine pathophysiology, including impairments in oxidative phosphorylation, disruptions in mitochondrial dynamics, and altered biogenesis. Experimental migraine models-ranging from nitroglycerin-induced attacks to inflammatory stimuli-consistently demonstrate mitochondrial swelling, cristae disruption, decreased ATP production, and increased oxidative stress. These findings are accompanied by the altered expression of key mitochondrial regulators such as PGC-1α, Drp1, and Mfn1. Recent studies have further identified distinct metabolic subtypes of mitochondria, including P5CS-containing subsets, which exhibit unique structural and functional profiles, including cristae loss and reduced ATP synthase expression. Notably, the mitochondrial alterations observed in migraine models show remarkable parallels to those described in P5CS-related mitochondrial subsets. These similarities suggest a potential mechanistic link between metabolic reprogramming within mitochondria and migraine pathogenesis. Understanding the contribution of these newly defined mitochondrial populations could offer novel insights into migraine biology and open new avenues for targeted therapeutic strategies.
    Keywords:  migraine; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial subtypes
    DOI:  https://doi.org/10.3390/life15081273
  49. Biochem Biophys Res Commun. 2025 Aug 16. pii: S0006-291X(25)01223-9. [Epub ahead of print]781 152508
    Drp1-mediated mitochondrial fission exacerbates inflammatory responses in intestinal epithelial cells: A potential therapeutic target for IBD.
    Youra Kang, Ben Kang.
      Inflammatory bowel disease (IBD) is a chronic inflammatory condition characterized by immune-mediated damage to the intestinal barrier. Mitochondrial fission, a crucial regulator of cellular homeostasis, has been increasingly implicated in IBD pathogenesis, although its precise role remains to be fully elucidated. This study investigated how mitochondrial fission contributes to intestinal inflammation and whether its inhibition can mitigate inflammatory responses. Human colorectal adenocarcinoma cells (HT-29) were treated with lipopolysaccharide and TNF-α (tumor necrosis factor-alpha) to induce inflammation. To assess the role of mitochondrial fission, we used pharmacological inhibition (Mdivi-1 and P110) as well as genetic suppression (Drp1 knockdown via siDrp1). Mitochondrial function was evaluated via oxygen consumption rate, assessments of ATP production, and analyses of mitochondrial membrane potential (ΔΨm). Inflammatory responses were assessed using Western blotting and qRT-PCR. Intestinal barrier integrity was evaluated by measuring trans-epithelial electrical resistance (TEER). Lipopolysaccharide stimulation promoted Drp1 translocation to mitochondria, enhancing mitochondrial fission and dysfunction. Drp1 inhibition significantly reduced pro-inflammatory cytokine expression (TNF-α, IL-1β, IL-6), suppressed NF-κB and MAPK activation, and restored mitochondrial function by reducing mitochondrial reactive oxygen species. Additionally, Drp1 inhibition downregulated inducible nitric oxide synthase and cyclooxygenase-2, key inflammatory enzymes, and effectively preserved epithelial barrier integrity, as demonstrated by significantly improved TEER values. These findings provide evidence that excessive mitochondrial fission contributes to intestinal inflammation and barrier dysfunction, and that targeting Drp1 can restore mitochondrial and epithelial homeostasis. By demonstrating that Drp1 inhibition suppresses inflammatory signaling, preserves mitochondrial integrity, and maintains epithelial barrier function, this study highlights mitochondrial fission as a potential therapeutic target for IBD treatment. Further validation using in vivo models and patient-derived tissues is warranted to confirm the clinical applicability of these findings.
    Keywords:  Inflammation; Inflammatory bowel disease; Mitochondria; drp1
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152508
  50. Front Cell Infect Microbiol. 2025 ;15 1634909
    Mechanisms and therapeutic perspectives of mitochondrial dysfunction of macrophages in periodontitis.
    Yibing Jia, Zili Li, Pengjie Huang, Yan Wang, Bo Yang.
      Periodontitis is a global inflammatory oral disease, and plaque-induced host excessive immune response is recognized as a major cause of its pathogenesis. In recent years, the relevance of mitochondrial dysfunction to periodontitis has been increasingly investigated, particularly with respect to macrophages, the key immune cells in the periodontal immune microenvironment. Mitochondrial dysfunction drives macrophage M1 polarization and osteoclast differentiation through mechanisms such as metabolic reprogramming, reactive oxygen species release, abnormal mitophagy, abnormal mitochondrial biogenesis and damaged mitochondrial dynamic. In addition, mitochondrial transfer in the periodontitis setting has been reported in several researches. In this review, we highlight the impact of mitochondrial dysfunction on macrophages in the periodontitis setting and summarize emerging therapeutic strategies for targeting mitochondria in periodontitis, including antioxidants, modulators of metabolic reprogramming, nanomaterials and photodynamic therapy.
    Keywords:  macrophage polarization; mitochondrial dysfunction; osteoclast differentiation; periodontitis mechanism; periodontitis treatment
    DOI:  https://doi.org/10.3389/fcimb.2025.1634909
  51. Immunobiology. 2025 Aug 16. pii: S0171-2985(25)00242-6. [Epub ahead of print]230(5): 153108
    UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice.
    Dalei Sun, Shu Ouyang, Xiaoxuan Xu, Jingjing Yan, Heqian Wang, Chenkai Lan, Wubin Ouyang, Liangjun Zhong, Jun Lin.
       OBJECTIVE: To investigate the therapeutic and ameliorative effects of the Myeloid Cell Leukemia 1 protein (MCL-1) inhibitor UMI-77 on experimental murine periodontitis via mitophagy activation, with a focus on comparing administration routes (local/intraperitoneal) and doses (high/low/combined).
    METHODS: A ligature-induced periodontitis model was established in 54 male C57BL/6 J mice, randomized into 9 groups (n = 6 per group): normal control (Group Aa), periodontitis model (Group Ab), positive control (Group Ac, local minocycline), local PBS control (Group Ad), intraperitoneal PBS control (Group Ae), local high-dose UMI-77 (Group Ba, 2 mg/kg), local low-dose UMI-77 (Group Bb, 1 mg/kg), intraperitoneal UMI-77 (Group Ca, 2 mg/kg), and combined intraperitoneal UMI-77 + local minocycline (Group Cb, 2 mg/kg + standard minocycline regimen). Outcomes included periodontal bleeding on probing (BOP), alveolar bone resorption via micro-CT, histopathological analysis (HE/methylene blue staining), MCL-1 expression (Western blot), autolysosome detection (transmission electron microscopy, TEM), and systemic organ safety (HE staining).
    RESULTS: All UMI-77 treatment groups exhibited significant amelioration of periodontal inflammation and bone resorption compared to the model group (Ab, p < 0.0001). Local high-dose UMI-77 (Group Ba) demonstrated the most potent efficacy, reducing BOP by 76 % (0.67 ± 0.5 vs. Ab: 2.8 ± 0.4, p < 0.001) and cementoenamel junction-alveolar bone crest distance by 48.7 % (0.20 ± 0.04 mm vs. Ab: 0.41 ± 0.05 mm, p < 0.0001), outperforming the positive control (Group Ac, BOP: 2.17 ± 0.4, p < 0.001). Histological analysis showed reduced inflammatory cell infiltration and organized periodontal fibers in Group Ba. Western blot confirmed downregulation of MCL-1 expression to near-normal levels in Group Ba, while TEM detected autolysosomes in both Group Ba and Group Ca, indicating mitophagy activation. Systemic safety assessments revealed only mild grade 1 cardiac septal thickening in Group Ba and transient splenic lymphocyte elevation in Group Ca, with no severe organ toxicity.
    CONCLUSION: UMI-77 exerts significant therapeutic and ameliorative effects against periodontitis in mice, with local high-dose administration (Group Ba) demonstrating optimal efficacy. Intraperitoneal UMI-77 combined with local minocycline (Group Cb) achieved comparable outcomes to high-dose local UMI-77, highlighting potential combinatorial strategies. These findings establish UMI-77 as a promising agent for periodontitis treatment via MCL-1-targeted mitophagy activation.
    CLINICAL SIGNIFICANCE: UMI-77, especially with local high-dose administration, offers a new, potentially effective and safe approach for periodontitis treatment, holding great promise for clinical translation.
    Keywords:  MCL-1; Mitophagy; Periodontitis; Targeted therapy; UMI-77
    DOI:  https://doi.org/10.1016/j.imbio.2025.153108
  52. Reprod Toxicol. 2025 Aug 22. pii: S0890-6238(25)00207-2. [Epub ahead of print]137 109036
    Estrogen receptor 1 (ESR1) promotes Di-butyl phthalate (DBP)-induced hypospadias by regulating mitophagy through PINK1-Parkin axis to inhibit ferroptosis.
    Jinping Liu, Yi Cheng, Enfu Huang, Zhixiang Liu, Yun Zhou.
      This study reveals how Di-butyl phthalate (DBP), an estrogen-mimicking environmental pollutant, induces hypospadias by inhibiting ferroptosis through ESR1 activation and PINK1-Parkin-dependent mitophagy. Utilizing a prenatal DBP-exposed fetal rat hypospadias model, we observed significant downregulation of pro-ferroptotic ACSL4 and upregulation of anti-ferroptotic GPX4/SLC7A11 in urethral tissues, alongside elevated oxidative stress markers (MDA, Fe²⁺) and reduced glutathione (GSH). In vitro experiments using rat urethral plate fibroblasts (RUPFs) demonstrated that DBP enhanced ferroptosis resistance and promoted proliferation at concentrations below 200 μM. Mechanistically, DBP activated ESR1, which triggered mitophagy via the PINK1-Parkin pathway, reducing mitochondrial damage and reactive oxygen species (ROS) accumulation, thereby suppressing ferroptosis. Inhibition or silencing of ESR1 reversed these effects, restoring ferroptosis sensitivity and oxidative stress. These findings unveil a novel ESR1-mitophagy-ferroptosis regulatory axis, linking DBP exposure to hypospadias pathogenesis. The study not only elucidates a previously unrecognized molecular pathway underlying phthalate-induced congenital malformations but also identifies ESR1 and mitophagy as potential therapeutic targets. By integrating in vivo and in vitro approaches, this work advances the understanding of environmental endocrine disruptors' role in developmental toxicity and provides actionable insights for mitigating their health impacts, aligning with current priorities in reproductive and environmental health research.
    Keywords:  Di-n-butylphthalate; ESR1; Ferroptosis; Hypospadias; Mitophagy
    DOI:  https://doi.org/10.1016/j.reprotox.2025.109036
  53. Redox Biol. 2025 Aug 22. pii: S2213-2317(25)00342-8. [Epub ahead of print]86 103829
    PGC-1α-mediated mitochondrial homeostasis imbalance aggravated gingival lesions of diabetic periodontitis by disrupting ECM remodeling of human gingival fibroblast.
    Junling Huang, Yi Li, Qingyuan Ye, Rui Li, Yazheng Wang, Qintao Wang, Jinjin Wang.
      Diabetic periodontitis (DP) usually has more severe clinical symptoms compared with chronic periodontitis (CP), especially the worsened gingival lesions. Mitochondrial homeostasis plays an important role in both diabetes and periodontitis, and some studies have already confirmed its role in DP. However, there are few reports on whether mitochondrial homeostasis is involved in regulating DP gingival lesions. In this study, we focused on the pathological changes of the gingival connective tissues from DP and identified the extracellular matrix (ECM) pathway as the key regulatory pathway. Additionally, we found that the pathological changes in DP gingiva were accompanied by significant alterations in the morphology and structure of cellular mitochondria. We discovered that the regulatory molecule PGC-1α related to mitochondrial quality control (MQC) was significantly downregulated in DP group through RNA sequencing. Furthermore, by using high glucose and LPS co-stimulation to simulate DP environment in vitro, we confirmed the changes in ECM synthesis and remodeling of human gingival fibroblasts (HGFs), accompanied with the abnormal mitochondrial morphology, structure and function, including the presence of internal vacuolation, the increased area and perimeter, the loss of cristae, as well as the increased mtROS, the decreased ATP, mitochondrial membrane potential, and the mtDNA copy number, and even the reduced number of mitochondria in HGFs, which suggesting the changes of mitochondrial homeostasis. Moreover, we verified that upregulating PGC-1α could reverse the above phenomena in HGFs. Finally, periodontal injection of PGC-1α agonists (ZLN005) was found to ameliorate the abnormal ECM synthesis and remodeling by improving mitochondrial homeostasis in DP rats, demonstrating a significant therapeutic effect on DP gingival lesions and moderating the progression of DP. In conclusion, our study proposed the possible therapeutic effect of PGC-1α-mediated mitochondrial homeostasis in the aggravated gingival lesions of DP, providing new ideas for the clinical treatment of DP.
    Keywords:  Diabetic periodontitis; Extracellular matrix; Human gingival fibroblasts; Mitochondrial homeostasis; PGC-1α
    DOI:  https://doi.org/10.1016/j.redox.2025.103829
  54. J Biochem Mol Toxicol. 2025 Sep;39(9): e70451
    Dynorphin A Impairs Mitochondrial Biogenesis in Osteosarcoma Cells by Increasing SP-1.
    Yaxiong Dai, Jian Zhang, Yingzhen Peng, Lingyan Hu.
      Mitochondria are vital for energy generation, apoptosis control, and cellular metabolism. As a result, they represent an attractive therapeutic target in cancer treatment, particularly osteosarcoma (OS). Despite evidence indicating that Dynorphin A exhibits anti-tumor characteristics via multiple mechanisms, its influence on the physiology of osteosarcoma (OS) has not been thoroughly investigated. In this study, we explore the impacts of Dynorphin A on mitochondrial function and biogenesis within human OS U2OS cells. Human osteosarcoma (U2OS) cells were treated with Dynorphin A at varying concentrations for 48 h. Cell viability and cytotoxicity were assessed using the Cell Counting Kit-8 (CCK-8) and LDH assay, respectively. Mitochondrial function was evaluated by measuring complex IV activity, oxygen consumption rate (OCR), and ATP production, while mitochondrial biogenesis was analyzed by determining the mtDNA/nDNA ratio, mitochondrial protein expression (NDUFB8 and MTCO2), and mitochondrial mass (MitoTracker Red staining). The expression of key mitochondrial regulators (PGC-1α, Nrf1, TFAM) and SP-1 was quantified using real-time RT-PCR and Western blot analysis. Our findings reveal that Dynorphin A notably decreases cell viability and enhances the release of lactate dehydrogenase (LDH)., indicating cytotoxicity. It also impaired mitochondrial function, as evidenced by a decrease in complex IV activity, oxygen consumption, and ATP production. Additionally, Dynorphin A suppressed mitochondrial biogenesis, shown by a reduced mtDNA/nDNA ratio, lower expression of mitochondrial proteins (NDUFB8 and MTCO2), and decreased mitochondrial mass. Furthermore, Dynorphin A downregulated key mitochondrial regulators, including PGC-1α, Nrf1, and TFAM. Notably, Dynorphin A also upregulated SP-1 expression, and silencing SP-1 reversed its effects on mitochondrial function and biogenesis. These findings suggest that Dynorphin A exerts antitumor effects by disrupting mitochondrial function and biogenesis in OS cells.
    Keywords:  Dynorphin A; PGC‐1α; SP‐1; mitochondrial biogenesis; osteosarcoma
    DOI:  https://doi.org/10.1002/jbt.70451
  55. Acta Pharmacol Sin. 2025 Aug 21.
    Isoliensinine inhibits mitophagy and sensitizes T cell malignancies for STING-mediated NK clearance.
    Xiao Ge, Guang-Ming Yang, Xiao-Long Zhang, Jing Cao, Ying-Jie Qing, San-Bing Shen, Yang Pan, Po Hu.
      Mitochondrial DNA (mtDNA) damage and accumulation activate the cGAS-STING DNA-sensing pathway, which promotes immune clearance of tumor cells. Maintenance of the cytosolic level of mtDNA is key to sustain immune activation. T cell malignancies (T-CMs) are a general name of diseases with abnormal clonal proliferation of T lymphocytes at various stages. Immunotherapy of T-CMs is challenged by the lack of specific antigens to discriminate T-CMs from normal T cells. As intrinsic STING activation can promote the clearance of T-CMs by immune cells, we herein explored whether isoliensinine (IsoL), a natural compound from Nelumbinis Plumula could enhance NK clearance by mtDNA-mediated immune responses in tumor cells. To investigate whether IsoL modulated immune recognition and clearance of T-CMs, we pre-treated three T-CM cell lines (Jurkat, Molt4 and Hut102) with IsoL then co-cultured with NK-92MI cells. We showed that IsoL pre-treatment promoted cytosolic mtDNA accumulation by inducing ROS-dependent mitochondrial damage and inhibiting mitophagy via peroxiredoxin 1 (PRDX1), an antioxidant enzyme. Loss of PRDX1 in T-CMs also induced ROS-dependent mitochondrial DNA damage, and blocked mitophagy by preventing accumulation of mature PINK1, which was required to initiate mitophagy via recruiting Parkin to the damaged mitochondria. Remarkably, IsoL could induce expression of activating ligands in vitro, enhance NK cell infiltrations, and increase apoptosis of T-CMs. Moreover, we demonstrated that IsoL could sensitize T-CMs for NK clearance in vitro and in vivo. These results suggest that IsoL could be a potential therapeutic agent to enhance immune therapy of T-CMs.
    Keywords:  NK cells; T cell malignancies; immune clearance; isoliensinine; mitophagy; peroxiredoxin 1
    DOI:  https://doi.org/10.1038/s41401-025-01636-1
  56. Nat Commun. 2025 Aug 25. 16(1): 7671
    Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.
    Kayleigh M Voos, Joyce Tzeng, Priya Patel, Sophie Rubinsky, Ha E Choi, Trevor Pharr, Sebastian Sookram, Joseph A Baur, Erik J Soderblom, Damaris N Lorenzo.
      Mitochondrial dynamics enable cellular adaptation to fluctuations in energy demand, such as those imposed on skeletal muscle by exercise, metabolic disorders, or aging. Here, we report a novel pathway that modulates mitochondria dynamics in skeletal muscle involving the scaffolding protein ankyrin-B. Rare variants in ankyrin-B, encoded by ANK2, increase risk for cardio-metabolic syndrome in humans and mice. We show that mice selectively lacking skeletal muscle ankyrin-B have reduced endurance exercise capacity without alterations in muscle strength or systemic glucose regulation. Muscle fibers in these mice have increased oxidative stress, reduced fatty acid oxidation, and enlarged and hyperconnected mitochondria. We found that ankyrin-B interacts with and is required for efficient mitochondria recruitment of fission modulators and sarcoplasmic reticulum-mitochondria coupling. Thus, we conclude that ankyrin-B enables substrate adaptability and bioenergetic homeostasis under energetic stress, and exercise capacity by promoting efficient mitochondrial fission in skeletal muscle.
    DOI:  https://doi.org/10.1038/s41467-025-62977-3
  57. J Environ Sci (China). 2025 Dec;pii: S1001-0742(25)00088-9. [Epub ahead of print]158 137-150
    Paternal BDE-209 exposure disrupts spermatogenesis in mouse offspring via cGAS-STING pathway activation and mitophagy inhibition.
    Jinglong Xue, Junhong Xie, Xiangyang Li, Leqiang Gao, Yue Zhang, Ruxuan Zhang, Moxuan Zhao, Ruiyang Zhang, Hongou Wang, Zhixiong Shi, Jialiu Wei, Xianqing Zhou.
      Decabromodiphenyl ether (BDE-209) has been recognized for its adverse effects on the male reproductive system. The specific negative effects and underlying mechanisms through which BDE-209 impacts the reproductive function of offspring are not yet fully understood. The present study classified institute of cancer research (ICR) mice into control and BDE-209 treatment groups, administering doses of 0 and 75 mg/(kg·day), respectively. After 50 days of exposure, normal female mice were co-housed with the male mice, and their male offspring were sacrificed at 2 and 12 months of age. Paternal BDE-209 exposure reduced both sperm quantity and quality in offspring. Furthermore, exposure to BDE-209 resulted in DNA damage and the upregulation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) DNA-sensing and inflammatory signaling pathways. The activation resulted in Z-DNA binding protein 1 (ZBP1) binding to the mitochondrial antiviral signaling protein (MAVS), subsequently activating mitochondrial apoptosis in the testes. The activation of the cGAS-STING pathway inhibited mitophagy, leading to senescence in the testes of male offspring. In vitro studies indicated that the cGAS inhibitor RU320521 (RU.521) effectively reversed the cGAS-STING pathway activation, alleviated the mitophagy inhibition, and decreased apoptosis and senescence in mouse spermatocyte line GC-2spd cells treated with BDE-209. The results showed that paternal BDE-209 exposure might disrupt spermatogenesis in mouse offspring by activating the cGAS-STING pathway and inhibiting mitophagy. This study provides essential data on the toxicity of BDE-209 to male reproduction and have important scientific and practical implications for maintaining biodiversity and population health in general.
    Keywords:  BDE-209; Inflammatory signaling pathway; Mitophagy; Senescence; cGAS-STING
    DOI:  https://doi.org/10.1016/j.jes.2025.02.039
  58. Int J Mol Sci. 2025 Aug 09. pii: 7702. [Epub ahead of print]26(16):
    Effects of Dietary Terpinen-4-ol on Oxidative Stress and Mitochondrial Biogenesis in the Liver of Broilers with Pulmonary Hypertension Syndrome.
    Xinyue Jiang, Liang Fei, Yayun Yang, Jiao Han, Zhaoxin Tang, Jianzhao Liao, Lianmei Hu, Ying Li, Jiaqiang Pan.
      Pulmonary hypertension syndrome (PHS), a metabolic disorder causing economic losses in broilers, arises from hypoxia-induced portal hypertension and liver cirrhosis, triggering mitochondrial oxidative damage, excessive ROS production, and altered mitochondrial biogenesis. This study explored terpinen-4-ol (T4O), known for antimicrobial and anti-inflammatory properties, in mitigating PHS. Broilers were divided into four groups, including PHS-affected birds with/without T4O supplementation. Analyses revealed that PHS birds exhibited reduced antioxidant capacity, elevated MDA and ROS levels, increased mitochondrial numbers, and upregulated expression of oxidative stress markers (Keap1, HO-1, Nrf-2) and mitochondrial biogenesis regulators (PGC-1α, Nrf-1, Tfam). T4O administration enhanced antioxidant activity, reduced ROS and MDA, suppressed compensatory mitochondrial proliferation, and downregulated Keap1/Nrf-2 and mitochondrial biogenesis pathways. These effects suggest that T4O alleviates hypoxia-driven oxidative stress and mitochondrial dysfunction in broilers. Findings highlight T4O's potential as a therapeutic agent to mitigate PHS-related losses in poultry production.
    Keywords:  broiler; liver; mitochondrial biogenesis; oxidative stress; pulmonary hypertension syndrome
    DOI:  https://doi.org/10.3390/ijms26167702
  59. Biochim Biophys Acta Mol Basis Dis. 2025 Aug 21. pii: S0925-4439(25)00374-6. [Epub ahead of print]1871(8): 168026
    Platycodin D attenuates diabetic renal ischemia/reperfusion injury by enhancing mitophagy and suppressing MAPK/NF-κB signaling activation.
    Xuke Qin, Jin Liu, Xiaojie Zhao, Lei Wang, Xiuheng Liu, Zhiyuan Chen.
      The global incidence of diabetes mellitus (DM) is rapidly rising, and DM worsens renal ischemia/reperfusion (I/R) injury, a major cause of high-mortality acute kidney injury (AKI). Therefore, preventing renal I/R injury in DM is crucial. Platycodin D (PD), a compound from Platycodon grandiflorum roots, is known to activate AMP-activated protein kinase (AMPK). Numerous studies have demonstrated that AMPK activation has protective effects in diabetes mellitus (DM) and ischemia/reperfusion (I/R) injury. However, the impact of PD on renal I/R injury in DM and its underlying mechanisms remain unclear. Our experiments revealed that PD treatment via gavage significantly alleviated kidney tissue damage and cell apoptosis in diabetic renal I/R injury. Additionally, PD reduced reactive oxygen species (ROS) levels, and transmission electron microscopy (TEM) indicated a notable discovery in mitophagosome formation. The expression levels of P-AMPK, light chain 3B (LC3B)-II, PTEN-induced putative protein kinase 1 (PINK1) and Parkin all increased under PD treatment, while sequestosome 1 (P62) level decreased. Importantly, AMPK antagonist Compound C (CC) abolished these effects. Additionally, our transcriptomic profiling revealed that PD treatment significantly suppressed MAPK/NF-κB signaling activation. Through functional rescue experiments, we mechanistically demonstrated that PD-mediated AMPK phosphorylation governs this regulatory axis. AMPK inhibition abolished PD's effects on both MAPK/NF-κB suppression, establishing AMPK activation as the upstream modulator. Overall, PD may reduce renal I/R injury in DM through AMPK/PINK1/Parkin-mediated mitophagy and inhibiting MAPK/NF-κB pathway.
    Keywords:  Diabetes mellitus; Inflammation; Mitophagy; Platycodin D; Renal ischemia/reperfusion injury
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168026
  60. Am J Physiol Renal Physiol. 2025 Aug 26.
    MARY1 Restores Mitochondrial Homeostasis and Accelerates Renal Recovery Following Acute Kidney Injury.
    Paul Victor Santiago Raj, Jaroslav Janda, Natalie E Scholpa, Kevin A Hurtado, Rick G Schnellmann.
      Acute kidney injury (AKI) is a major clinical concern with limited therapeutic strategies, often leading to chronic kidney disease (CKD) and long-term morbidity. Mitochondrial dysfunction is a major causative factor for AKI onset and progression to CKD. Interventions that restore mitochondrial integrity and cellular energy represent promising therapeutic strategies. This study investigated the potential therapeutic role of MARY1, a novel, potent, and subtype-selective serotonin-2B receptor (5-HT2BR) antagonist, following ischemia/reperfusion (I/R)-induced AKI in mice and rats. We previously demonstrated that MARY1 induces renal mitochondrial biogenesis (MB), the generation of new functional mitochondria, in vivo. MARY1 (0.3 mg/kg, daily) administration for 6 days following AKI improves renal function, restores mitochondrial homeostasis and renal vascular integrity, upregulates β-oxidation, and restores genes associated with proximal tubule repair. Moreover, daily treatment with MARY1 (0.3 mg/kg) for 12 days following AKI restores mitochondrial homeostasis and increases autophagic activity in the renal cortex of mice. These findings establish MARY1-mediated 5-HT2BR antagonism as a mitochondria-targeted therapeutic strategy that addresses multiple hallmarks of AKI, and as a potential intervention for mitochondrial dysfunction-associated renal diseases.
    Keywords:  5-hydroxytryptamine receptor 2B; acute kidney injury; mitochondrial dysfunction; renal function
    DOI:  https://doi.org/10.1152/ajprenal.00232.2025
  61. Muscles. 2025 Aug 19. pii: 35. [Epub ahead of print]4(3):
    Baicalin Improves Skeletal Muscle Atrophy by Attenuating DRP-1-Mediated Mitochondrial Fission in Aged Mice.
    Hla Myat Mo Mo, Jong Han Lee.
      Baicalin is a natural flavonoid that has anti-apoptotic and anti-inflammatory effects. It shows some beneficial effects on muscle atrophy. However, its effects on age-related muscle atrophy are poorly understood. In this paper, we investigated whether baicalin exerts protective effect against skeletal muscle atrophy and its underlying mechanisms in aged mice using the grip strength test, histological analysis, and Western blots. Baicalin increased total muscle mass and strength in aged mice. Consistently, the cross-sectional area of quadriceps (QD) muscle significantly increased in both baicalin-administrated groups. Moreover, baicalin induced a shift in muscle fiber size distribution toward large fibers in both groups of mice. Expression levels of muscle atrophic factors, such as myostatin (MSTN) and atrogin-1, as well as pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were elevated in aged mice, but these increases were reduced by baicalin. While mitochondrial fission regulator, dynamin-related protein 1 (DRP-1), and apoptosis-related protein (apoptotic protease activating factor 1 (Apaf-1)) expressions were higher in aged mice than young mice, and their expression were downregulated following baicalin administration. The comprehensive results of this study suggest that baicalin provides beneficial effects on the treatment of sarcopenia not only by suppressing muscle atrophic factor expression and inflammation but also attenuating DRP-1-mediated mitochondrial fission and apoptosis.
    Keywords:  apoptosis; baicalin; inflammation; mitochondria fission; muscle atrophy; sarcopenia
    DOI:  https://doi.org/10.3390/muscles4030035
  62. Theranostics. 2025 ;15(16): 7973-7989
    Reduction-responsive RNAi nanoplatform for enhanced cancer sonoimmunotherapy via dual inhibition of mitophagy and Nrf2 pathways.
    Junyue Fang, Rui Xu, Yuan Cao, Zixuan Zhao, Weifan Li, Li Lin, Jingyi Hou, Xiaoding Xu, Phei Er Saw.
      Rationale: Sonodynamic therapy (SDT) has emerged as a promising non-invasive modality with deeper tissue penetration than photodynamic or chemodynamic therapies. However, its therapeutic efficacy remains limited due to inadequate reactive oxygen species (ROS) generation, largely attributed to tumor-intrinsic antioxidant systems and mitophagy. Existing combinations of SDT with immunotherapy are primarily additive and fail to address the mechanistic interplay between ROS suppression and immune evasion. Methods: To overcome these limitations, we developed a redox-responsive RNA interference (RNAi) nanoplatform (NP) for the co-delivery of Nrf2 siRNA, the mitophagy inhibitor 3-Methyladenine (3-MA), and the sonosensitizer purpurin-18 (P-18). This NP enables tumor-specific release in high-glutathione environments and facilitates dual-pathway inhibition upon ultrasound activation. Results: This synergistic platform simultaneously disrupted Nrf2-mediated antioxidant defenses and mitophagy-dependent mitochondrial clearance, resulting in enhanced intracellular ROS accumulation. Elevated ROS levels triggered immunogenic cell death (ICD), promoting dendritic cells maturation and antigen presentation. Concurrently, 3-MA inhibited NF-κB signaling, downregulating PD-L1 expression and mitigating T cell exhaustion. In murine breast cancer models, this dual-action approach elicited robust CD8⁺ T cell responses and significantly suppressed tumor growth and metastasis. Conclusions: This study introduces a mechanistically integrated sonoimmunotherapeutic strategy that concurrently overcomes ROS suppression and immune checkpoint resistance. By orchestrating redox disruption and immune reprogramming, our nanoplatform provides a compelling framework for next-generation SDT-based immunotherapy.
    Keywords:  immune checkpoint blockade; mitophagy inhibition; reactive oxygen species; redox-responsive nanoplatform; sonoimmunotherapy
    DOI:  https://doi.org/10.7150/thno.112649
  63. J Lipid Res. 2025 Aug 25. pii: S0022-2275(25)00150-6. [Epub ahead of print] 100888
    EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat.
    Sona Rajakumari, Soumya Jaya Divakaran.
      Mitochondria are fundamental in energy homeostasis and undergo dynamic changes in brown and beige fat. Mitochondrial dysfunctions impair thermogenic capacity and cause obesity-associated metabolic diseases. The phospholipid composition is crucial for maintaining mitochondrial function and fission-fusion processes. Here, we described EBF2, a transcription factor pivotal for brown fat development and function that regulates the integrity of mitochondrial membrane composition, function and dynamics in brown adipocytes. Strikingly, Myf5Cre-driven targeted deletion of Ebf2 in brown adipose tissue (BAT) drastically reduces cardiolipin and phosphatidylethanolamine abundance and alters acyl chain remodeling of major phospholipids. BAT mitochondria of Ebf2-KO neonates exhibit a severe reduction of DRP1 and OPA1, key regulators of mitochondrial fission-fusion dynamics; further, Ebf2 deletion impairs fragmentation-fusion events in brown adipose tissue. Mechanistically, EBF2 directly binds to key genes, including Srebf1, which are involved in membrane lipid metabolism and differentially regulate their expression. Also, the deletion of Ebf2 downregulates CL and PE-synthesizing genes and accumulates phosphatidylserine and sphingomyelin levels in mitochondria. Thus, the deletion of Ebf2 perturbs the acyl chain remodeling of mitochondrial lipids and affects the fission-fusion cycle in neonatal brown adipocytes. To conclude, Ebf2 is crucial for regulating the levels and remodeling of bilayer and non-bilayer-forming lipids to conserve mitochondrial metabolism.
    Keywords:  Brown adipocytes; Cardiolipin; Ebf2-BKO; Lipid metabolism; Membrane lipids; Mitochondria; Mitochondrial lipidome; OXPHOS; Reactive oxygen species; Thermogenesis
    DOI:  https://doi.org/10.1016/j.jlr.2025.100888
  64. J Heart Lung Transplant. 2025 Aug 19. pii: S1053-2498(25)02208-9. [Epub ahead of print]
    RAS in lung transplantation - Renin-Angiotensin System and mitochondrial protection with Angiotensin-1-7 during pulmonary preservation at 10°C.
    Ilker Iskender, Clemens Aigner.
      
    Keywords:  Angiotensin-1-7; Lung preservation; controlled 10°C storage; ischemia-reperfusion injury; mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.healun.2025.08.009
  65. Bioorg Chem. 2025 Aug 19. pii: S0045-2068(25)00772-2. [Epub ahead of print]164 108892
    Structurally diverse diterpenoids from cones of Taxodium ascendens inhibit colorectal cancer proliferation via regulating mitophagy.
    Jia Su, Meng-Xia Shen, Ya Chen, Ya-Xuan Ma, Zi-Yi Sun, Ruo-Han Li, Zhi-Ping Zhou, Wen-Chao Tu, Xing-De Wu.
      Taxascendins A - D (1-4), four unprecedented hetero-oligomeric terpenoids, and taxascendins E - K (5-11), seven new diterpenoids with five distinct and highly modified abietane-types frameworks, along with sixteen known analogues (10-27) were obtained from Taxodium ascendens. Their structures were determined by extensive spectroscopy, single-crystal X-ray diffraction, and quantum chemical calculations. Bioactivity screening indicated that the isolated compounds exhibited inhibitory activity in colorectal cancer cells. Compounds 11-14, 22, and 23 exhibited inhibitory activities against the HCT116, SW480, and RKO human colorectal cancer cell lines with IC50 values ranging from 3.46 to 34.46 μM. Among all the tested isolates, compound 12 possessed the most potent cytotoxicity. Evidence proved that 12 inhibited autophagy in HCT116 cells via regulating the AMPK/Akt signaling pathway, subsequently downregulating mitophagy, thereby suppressing colorectal cancer cell growth.
    Keywords:  AMPK; Akt; Diterpenoid; Mitophagy; Oligomeric terpenoid; Taxodium ascendens
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108892
  66. Biomed Res Int. 2025 ;2025 1565994
    Potential Synergistic Effects of Caffeine and Naringin on Mitochondrial Biogenesis and Hepatic Steatosis in Adult Male Rats With NAFLD Induced by a High-Fat Diet.
    Mehrasa Azizollahi, Zahra Nasehi, Maryam Derakhshan, Fouzieh Zadhoush.
      Introduction: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide, and disturbances in lipid metabolism and mitochondrial function play a significant role in its progression. In this study, to improve the effects of caffeine (CAF) treatment, we evaluated the effects of CAF and naringin (NAR) alone and in combination on gene expression involved in mitochondrial biogenesis, plasma nonesterified fatty acid (NEFA) levels, hepatic TG levels, and pathological changes in the liver tissue in adult male rats with NAFLD induced by a high-fat diet (HFD). Materials and Methods: Then, 35 male Wistar rats were randomly assigned to five groups: control, HFD, HFD + CAF, HFD + NAR, and HFD + CAF + NAR (seven rats per group). They were fed a HFD containing 51% fat for 10 weeks, followed by a 6-week gavage treatment with CAF (50 mg/kg/day) and NAR (12.5 mg/kg/day), either individually or in combination. Gene expression related to mitochondrial biogenesis (SIRT1, PGC1α, and TFAM), serum NEFA levels, hepatic triglyceride (TG) levels, and liver histological changes were assessed. Findings: The combination of CAF and NAR in the HFD + CAF + NAR group significantly increased the expression of SIRT1 (p < 0.01), PGC1-α (p < 0.01), and TFAM (p < 0.05) compared to the HFD group, while single treatments did not show such effects. Serum NEFA levels did not change significantly in any of the groups (HFD and treatment groups), but liver TG levels were significantly reduced in both single and combination treatments (p < 0.001). Pathological changes, including improvements in steatosis, inflammation, and ballooning, were observed in the treatment groups, particularly in the HFD + CAF + NAR group. Conclusion: Based on current findings, the combined use of CAF and NAR as an adjunct therapy may exert its protective effects by enhancing the expression of genes involved in mitochondrial biogenesis, improving liver lipid levels, and ameliorating liver pathology. Therefore, it can be considered an innovative strategy for improving liver metabolic status in the context of NAFLD.
    Keywords:  caffeine; high-fat diet; mitochondrial biogenesis; naringin; non-alcoholic fatty liver disease; non-esterified fatty acids
    DOI:  https://doi.org/10.1155/bmri/1565994
  67. Exp Cell Res. 2025 Aug 20. pii: S0014-4827(25)00321-0. [Epub ahead of print]451(2): 114721
    Cancer as a failed response to renegade mitochondria.
    John Hartung.
      In 1948, before the word 'mitochondrion' gained common parlance in the lexicon of cell biologists, Cyril Darlington published The Plasmagene Theory of the Origin of Cancer without referring to mitochondria per se. Reconsideration of Darlington's theory is warranted today because discoveries about the extraordinary capacities of mitochondria - the organelles that house Darlington's "plasmagenes" - have grown exponentially. If Darlington was right, if intracellular competition between mutant and wild-type mitochondria is the first cause of cancer, it may be the case that a general cure for cancer will include injection of: (A) nanoparticles carrying wild-type mitochondrial genes, and (B) copious amounts of wild-type mitochondria.
    Keywords:  Apoptosis; Cancer; Evolution; Experiment; Heteroplasmic; Homoplasmic; Mitochondria; Mitochondrial transfer; Mitophagy; Reproductive competition; Reversible reaction
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114721
  68. Environ Pollut. 2025 Aug 20. pii: S0269-7491(25)01380-6. [Epub ahead of print]384 127007
    ACR-16/α7-nicotinic receptor signaling mediates nicotine-induced mitochondrial dysfunction and suppression of host defense against gram-negative bacteria.
    Pablo Scharf, Romina Deza-Ponzio, Stephanie Stransky, Simone Sidoli, Michael Aschner, Sandra Helena Poliselli Farsky.
      Smoking, alongside e-cigarette and heated tobacco use, impairs immune function and increases susceptibility to infections, primarily due to nicotine's disruption of cellular processes. While mitochondria are traditionally associated with bioenergetics, they also serve as critical regulators of immunity, with mitochondrial dysfunction linked to compromised host defenses. To investigate nicotine's effects on mitochondrial function and immunity, we utilized Caenorhabditis elegans infected with Pseudomonas aeruginosa or Staphylococcus aureus. Acute nicotine exposure elicited pathogen-specific effects. Specifically, it enhanced immune responses and survival against S. aureus, but suppressed host defense mechanisms and mitochondrial responses against P. aeruginosa. These impairments were characterized by reduced bacterial clearance, impaired avoidance behavior, abnormal ROS production, and disrupted mitochondrial activity. Mechanistically, nicotine exerted its immunomodulatory effects through ACR-16/α7-nicotinic receptor signaling, as its absence abrogated both the beneficial and detrimental outcomes. Proteomic analysis revealed nicotine-induced mitochondrial dysfunction, disrupting the TCA cycle, and ATP synthesis. Upon P. aeruginosa infection, nicotine suppressed the mitochondrial unfolded protein response (mtUPR) and its associated immune functions. Pharmacological or genetic activation of mtUPR restored immune function and improved survival during P. aeruginosa infection. These novel findings highlight the essential role of mitochondrial health in regulating immune responses and propose mtUPR activation as a potential strategy to mitigate nicotine-induced immunotoxicity.
    Keywords:  Host defenses; Immunotoxicity; Mitochondrial unfolded protein response; Nicotine; Oxidative stress
    DOI:  https://doi.org/10.1016/j.envpol.2025.127007
  69. Ecotoxicol Environ Saf. 2025 Aug 26. pii: S0147-6513(25)01278-3. [Epub ahead of print]303 118933
    Resveratrol: Great potential for alleviating di-2-ethylhexyl phthalate (DEHP)-induced testicular ferroptosis via the SIRT1-HIF-1α axis.
    Xu Zhang, Yun Liu, Ruhan Yi, Xiance Sun, Jing Li, Ningning Wang, Xiaofeng Yao, Cong Zhang, Haoyuan Deng, Shaopeng Wang, Guang Yang.
       BACKGROUND/OBJECTIVES: Di-2-ethylhexyl phthalate (DEHP) is a universally used plasticizer and EDCs. Our previous studies verified that prolonged contact with DEHP induced detrimental impacts on reproductive physiology. Resveratrol (RES), a polyphenolic compound predominantly concentrated in Vitis vinifera epidermis, exhibits multifaceted pharmacological properties. The purpose of this study was to investigate whether RES can alleviate testicular injury caused by DEHP, and to investigate its possible mechanism.
    METHODS: The experimental design comprised 4 randomized groups of male SD rats: Control group: each animal was given corn oil and saline. DEHP group: the animals received DEHP (500 mg/kg/day) and saline. DEHP and RES group: the animals received DEHP (500 mg/kg/day) and RES (60 mg/kg/day). RES group: the animals received corn oil and RES (60 mg/kg/day).
    RESULTS: In vivo, RES alleviated DEHP-induced testicular ferroptosis by upregulating SIRT1 and enhancing its interaction with HIF-1α. This mechanism suppressed mitophagy, decreased Fe²⁺and ROS release, and inhibited lipid peroxidation. TM4 cell experiments confirmed these findings. Notably, SIRT1 knockdown inhibited the remission effect of RES on ferroptosis.
    CONCLUSIONS: In summary, we demonstrated that RES mitigated testicular damage caused by DEHP by inhibiting ferroptosis through the SIRT1-HIF-1α axis. This investigation delineates novel molecular targets and mechanistic frameworks for developing therapeutic interventions against DEHP toxicity.
    Keywords:  DEHP; Ferroptosis; Mitophagy; Resveratrol; Testes
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118933
  70. Cancer Res. 2025 Aug 26.
    Intracellular Interleukin-1α in Peritumoral Monocytes Induces IL8 Production and Inhibits Mitophagy to Promote Stemness and Metastasis of Hepatocellular Carcinoma.
    Yong-Hao Ruan, Wan-Ru Ning, Ai-Qi Huang, Da Jiang, Bai-Xi Zhu, Xing-Chen Liu, Jiang-Ling Gong, Kun Huang, Dong-Ming Kuang, Yan Wu, Limin Zheng.
      IL-1α is a potent inflammatory cytokine that is released by cell necrosis and activates IL-1R. More recently, IL-1α has been shown to have intracellular functions. In the current study, we investigated the expression and distinctive role of IL-1α in tumor progression. In hepatocellular carcinoma (HCC) patients, IL-1α levels were significantly upregulated in monocytes in peritumoral regions compared with nontumoral and intratumoral areas. A glycolytic switch mediated the upregulation of IL-1α via NF-κB signaling. The upregulated IL-1α was neither secreted by nor displayed on the cell surface of monocytes; instead, IL-1α translocated into the nucleus to induce the production of IL-8, which effectively enhanced cancer cell stemness and tumor metastasis. Additionally, IL-1α bound to mitochondria to inhibit mitophagy, inducing CA12 expression and macrophage accumulation via the mitochondrial reactive oxygen species-HIF-1α pathway. In accordance, IL-1α expression in peritumoral monocytes was negatively correlated with survival and positively associated with tumor metastasis in HCC patients. Targeting IL-1α+ monocytes or IL-8 effectively inhibited tumor progression and enhanced responsiveness to immune checkpoint blockade therapy in mouse HCC models. Overall, these results revealed an intracellular regulatory role of IL-1α in modifying the pro-tumor functions of monocytes within specific tumor microenvironments and pointed to both IL-1α and its downstream IL-8 as potential diagnostic and therapeutic targets for HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3355
  71. Biochem Soc Trans. 2025 Aug 26. pii: BST20253044. [Epub ahead of print]
    Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.
    Megan J Baker, Kai Qi Yek, Diana Stojanovski.
      Intrinsic protein quality control (QC) mechanisms are essential in maintaining mitochondrial health and function. These sophisticated molecular machineries govern protein trafficking and import, processing, folding, maturation and degradation, ensuring the organelle's health. Disruption in mitochondrial protein QC can lead to severe, multisystem disorders with variable age of onset and progression. In this review, we provide a snapshot of the intrinsic molecular protein QC machineries in mitochondria detailing their function, localisation and substrate specificity. We also highlight how dysfunction of these molecular machines contributes to mitochondrial disease. Ultimately, elucidating the consequences of proteostatic failure offers critical insights into the pathogenesis of complex mitochondrial disorders.
    Keywords:  AAA+; chaperone; disaggregase; extractase; mitochondria; mitochondrial disease; protease; protein quality control
    DOI:  https://doi.org/10.1042/BST20253044
  72. Curr Issues Mol Biol. 2025 Aug 19. pii: 670. [Epub ahead of print]47(8):
    Bioinformatic Analysis of the Value of Mitophagy and Immune Responses in Corneal Endothelial Dysfunction.
    Ruilin Guo, Chenjia Xu, Yi Yu, Minglu Ma, Xiaojuan Dong, Jing Wu, Chen Ouyang, Jie Ling, Ting Huang.
      This study was conducted to elucidate the mitophagy-related differentially expressed genes (MRDEGs) in corneal endothelial dysfunction (CED) and to identify key hub genes that could provide insights into the disease pathogenesis and potential targeted therapies. To achieve this, CED models were established in female SD rats, and RNA sequencing of coronal endothelium samples was conducted to generate a self-testing dataset. Comprehensive bioinformatics analyses were executed, which included the identification of differentially expressed genes (DEGs), GO and KEGG enrichment analyses, GSEA, and GSVA. A protein-protein interaction (PPI) network was constructed to identify highly interconnected hub genes, followed by the construction of ROC curves to validate MRDEGs within the dataset, alongside qRT-PCR assays. Our findings revealed a total of 18,511 DEGs, among which 20 genes were characterized as MRDEGs. Enrichment analyses indicated significant associations with monocyte differentiation and lymphocyte proliferation. Importantly, eight hub genes emerged from the PPI network as promising therapeutic targets. In conclusion, this study underscores the important role of MRDEGs and immune infiltration in CED, laying the groundwork for future investigations into targeted therapies for this disease.
    Keywords:  biomarker; corneal endothelial dysfunction; differentially expressed genes; immune infiltration; mitophagy
    DOI:  https://doi.org/10.3390/cimb47080670
  73. Neuropharmacology. 2025 Aug 24. pii: S0028-3908(25)00365-X. [Epub ahead of print]280 110657
    Metoprolol exacerbates dementia in scopolamine-induced cognitive impairment in rats: A potential role of NADPH oxidase.
    Amal M Sharaf, Radwa N Muhammad, Hazim O Khalifa, Esraa A Kandil, Lamiaa A Ahmed.
      β-blockers have been implicated in cognitive impairment, with some studies suggesting their role in increasing the risk of vascular dementia (VD). While previous clinical and preclinical research has linked β-blockers, including metoprolol, to cognitive decline, the molecular mechanisms remain unclear. This study aims to elucidate the impact of metoprolol on scopolamine-induced cognitive impairment in rats, focusing on the role of NADPH oxidase-mediated oxidative stress. Adult male Wistar rats were administered metoprolol (30 mg/kg/day; p.o) alone or in combination with scopolamine (1 mg/kg/day; i.p). To assess the involvement of NADPH oxidase, a subset of rats also received apocynin (10 mg/kg/day; i.p), a specific NADPH oxidase inhibitor. Behavioral tests were performed to evaluate cognitive function, while biochemical analyses were conducted to measure oxidative stress markers, neuroinflammatory mediators, and mitochondrial biogenesis-related proteins. Metoprolol exacerbated scopolamine-induced cognitive decline, which was unvieled through the impaired learning and memory performance. This effect was accompanied by increased hippocampal NADPH oxidase activity, oxidative stress biomarkers, and p38 MAPK/NF-κB-mediated neuroinflammation. Subsequently, metoprolol disrupted mitochondrial biogenesis machinery through the negative regulation of the SIRT1/PGC-1α/NRF1/TFAM signaling axis, which was followed by apoptotic cell death. Co-administration of apocynin reversed most of these alterations, where attenuation of oxidative stress, neuroinflammation, and mitochondrial dysfunction were identified. In conclusion, metoprolol significantly worsens cognitive impairment, likely through oxidative stress amplification, neuroinflammation, and mitochondrial biogenesis impairment. These findings suggest that caution is needed when prescribing metoprolol to elderly patients, especially those at risk of cognitive decline. Targeting NADPH oxidase may offer a potential therapeutic approach to counteract metoprolol's adverse effects on cognitive function.
    Keywords:  Metoprolol; Mitochondrial biogenesis; NADPH oxidase; Vascular dementia; β-blockers
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110657
  74. J Mol Biol. 2025 Aug 19. pii: S0022-2836(25)00463-2. [Epub ahead of print] 169397
    Complex Conformational Interplay for Parkin Activation is Revealed by 19F NMR Spectroscopy.
    Elizabeth M Connelly, Gary S Shaw.
      Parkin is a 52 kDa RING-Between-RING E3 ligase that ubiquitinates proteins at the outer mitochondrial membrane in response to oxidative stress. Part of a neuroprotective pathway, over 100 mutations in the PRKN gene have been associated with Early Onset Parkinson's Disease. To be fully active parkin requires interaction with phosphorylated ubiquitin and phosphorylation of its N-terminal Ubl domain, both dependent on the PINK1 kinase. Along with recruitment of an E2 ∼ Ubiquitin conjugate these events form a ∼90 kDa complex, undergoing a series of conformational changes that regulate transthiolation of ubiquitin from the E2 enzyme to the catalytic domain in parkin (Rcat) prior to substrate labeling. Numerous crystal and NMR structures have captured snapshots of parkin activation and its catalytic mechanism, yet questions surrounding the relative abundance, timing and interplay of parkin conformations remain. Further, most studies use truncated versions of the E3 ligase that may hide details of conformational dependencies. To examine parkin through its activation cycle from inactive (autoinhibited) to E2 ∼ Ubiquitin binding states we incorporated 5-19F-tryptophan into the full-length enzyme and used 19F NMR spectroscopy to identify structural and dynamics changes. Using chemical shift perturbation and T2 analysis, we show that phosphorylation of parkin leads to a population of unbound and bound forms of the phosphorylated Ubl domain and that release of the catalytic Rcat domain is dependent upon E2 ∼ Ub conjugate binding. This study shows the unique abilities of 19F NMR spectroscopy to provide details of the structural rearrangements required for catalysis for the large E3 ligase parkin.
    Keywords:  NMR spectroscopy; conformational change; dynamics; protein structure; ubiquitination
    DOI:  https://doi.org/10.1016/j.jmb.2025.169397
  75. Ecotoxicol Environ Saf. 2025 Aug 19. pii: S0147-6513(25)01218-7. [Epub ahead of print]303 118873
    Hexafluoropropylene oxide dimer acid (GenX) induces apoptosis in primary cortical neurons via stimulating ROS production and NF-κB activation.
    Cimei Li, Jiahui Yang, Lingfei Cao, Aiwei Yan, Xinyi Zhang, Jiaruo Duan, Xinxin Yu, Dandan Wang, Xianwei Wang, Cixia Li.
      Hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, is a replacement for perfluorooctanoic acid (PFOA) which readily accumulates in the brain and exhibits neurotoxic effects. However, the adverse impacts of GenX on neurons and its underlying mechanisms remain poorly understood. In this study, primary cortical neurons isolated from neonatal mice were exposed to varying concentrations of GenX to assess cell viability, intracellular reactive oxygen species (ROS) levels, and morphological alterations. Additionally, the expression of apoptosis-related proteins Bcl-2, Bax, Caspase-3, NF-κB, and Tomm20 was examined. The results showed that increasing concentrations of GenX significantly elevated intracellular ROS levels and markedly reduced cell viability and the number of cells. Neuronal morphology was severely disrupted, characterized by decreased neurite branching, shortened neurite length, and reduced soma size. At 200 μM and 400 μM GenX, apoptosis rates were dramatically increased (p < 0.0001), accompanied by a pronounced increase in NF-κB fluorescence intensity and nuclear translocation. Western blot analysis further revealed a progressive downregulation of Bcl-2 and Tomm20, while levels of Bax, Cleaved Caspase-3/Caspase-3 increased in a dose-dependent manner. Notably, pretreatment with N-Acetylcysteine (NAC) effectively reversed GenX-induced ROS accumulation (p = 0.0001), NF-κB activation, and neuronal apoptosis. Collectively, these findings demonstrate that GenX exposure induces ROS accumulation in primary cortical neurons, leading to apoptosis through mitochondrial dysfunction mediated by Tomm20 downregulation and the activation of Caspase-3 and NF-κB. This study provides novel mechanistic insights into the neurotoxicity of the emerging environmental contaminant GenX and offers a theoretical basis for developing neuroprotective targets against such exposures.
    Keywords:  Apoptosis; GenX/HFPO-DA; Mitophagy; Primary cortical neurons; ROS
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118873
  76. Arch Toxicol. 2025 Aug 20.
    2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces early hearing loss in guinea pigs via activating AhR to trigger mitochondrial and endoplasmic reticulum stress-regulated autophagy.
    Jie Tang, Li Zhang, Yujia Yang, Chunji Wang, Fang Zhang, Muxin Yu, Nenghua Zhang, Guangtao Xu, Bo Hu, Meiling Shi, Long Xu.
      2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is a ubiquitous environmental pollutant linked to early neurotoxicity, but its effects on hearing loss during early development remain unclear. We exposed weanling guinea pigs to BDE-47 (1, 10, 50 mg/kg/day) via gavage for 28 days, finding increased hearing thresholds at 0.5 and 4 kHz, hair cell damage, and elevated AhR, LC3B, and P-SQSTM1 levels. In vitro, BDE-47 reduced HEI-OC1 cell viability dose dependently, increasing AhR, oxidative stress (MitoTracker, MitoSOX, ROS), and activating the Keap1-Nrf2 antioxidant pathway. Elevated autophagosomes, P-SQSTM1 and LC3B-II, were observed, indicating autophagic flux inhibition. The AhR inhibitor CH223191 mitigated these effects, while Mdivi-1 (mitochondrial division inhibitor) reduced ROS and autophagy, suggesting AhR promotes mitochondrial oxidative stress, impairing autophagy. BDE-47 also increased ER-Tracker fluorescence, reduced lysosomes, and altered UPR markers (Calnexin, PDI, IRE1-α, Bip, Erol-α, PERK, and Chop), most of which were attenuated by CH223191. The ER stress inhibitor TUDCA further alleviated ROS, Keap1-Nrf2 dysregulation, and autophagy disruption. Our findings demonstrate that early BDE-47 exposure induces hearing impairment via AhR-mediated mitochondrial oxidative stress and ER stress, suppressing autophagy. These findings enhance our understanding of environmental chemical-induced ototoxicity and provide valuable insights for both auditory disorder risk assessment and therapeutic strategies for hearing preservation.
    Keywords:  Aryl hydrocarbon receptor; Autophagy; BDE-47; ER stress; Hearing loss; Oxidative stress
    DOI:  https://doi.org/10.1007/s00204-025-04154-5
  77. Front Cardiovasc Med. 2025 ;12 1572559
    From mitochondria to heart: the role and challenges of mitochondrial antiviral signaling protein in cardiovascular disease.
    Mengting Jiang, Runze Huang, Wei Li.
      Mitochondrial Antiviral Signaling Protein (MAVS) is a pivotal adaptor protein in the innate immune response, mediating the activation of NF-κB and type I interferon signaling pathways during viral infections. As an integral component of the mitochondrial outer membrane, MAVS also plays critical roles in the regulation of apoptosis, cellular metabolism, and the activation of inflammasomes, including NLRP3 and caspase family members. Emerging evidence indicates that MAVS is not only essential in antiviral defense but also contributes significantly to the pathogenesis of various diseases, notably cardiovascular diseases. In this review, we provide a comprehensive overview of the molecular structure of MAVS and the regulatory mechanisms modulating its activity. We further highlight the involvement of MAVS in the development of cardiovascular diseases through its participation in innate immune signaling and mitochondrial dynamics. Particular attention is given to the regulation of MAVS by post-translational modifications-such as ubiquitination, methylation, and acetylation-as well as by microRNAs and other mitochondria-associated proteins. These insights aim to deepen the understanding of MAVS as a potential biomarker and therapeutic target, offering novel perspectives for the prevention, diagnosis, and immunotherapeutic intervention of cardiovascular diseases.
    Keywords:  cardiovascular diseases; inflammation; innate immunity; mitochondrial antiviral signaling protein (MAVS); mitochondrial homeostasis
    DOI:  https://doi.org/10.3389/fcvm.2025.1572559
  78. Eur J Pharmacol. 2025 Aug 20. pii: S0014-2999(25)00832-5. [Epub ahead of print]1005 178078
    Hydrogen promoted mitochondrial autophagy and alleviated CIH-induced vascular endothelial cell senescence by regulating oxidative stress.
    Dongli Li, Qingqing Liu, Xintong Fan, Kerong Qi, Mengfan Sun, Jixian Song, Yajing Guo, Ensheng Ji.
      Obstructive sleep apnea (OSA), characterized by recurrent upper airway collapse during sleep, has been linked to systemic physiological impairment and accelerated vascular senescence through chronic intermittent hypoxia (CIH). Currently, there is no approved medication to treat the complications of OSA. Molecular hydrogen (H2), an anti-oxidative therapeutic agent, plays an important role in regulating cardiovascular and anti-aging. In this study, we aimed to investigate the therapeutic effect of H2 on OSA-associated vascular endothelial aging by establishing a mouse model induced by CIH and explore the mechanism of H2 from the perspective of oxidative stress and autophagy. Echocardiography and aortic ring vasodilatory response were employed to assess the impact of H2 on the aortic function in CIH mice. Haematoxylin and eosin staining, transmission electron microscopy, SA-β-gal staining, DHE staining, and immunofluorescence staining were utilized to observe the changes in histopathology and protein expression. The results demonstrated that H2 alleviated CIH-induced vascular endothelial aging by improving the pathological injury of the aorta, alleviating vasodilation dysfunction, decreasing the expression of oxidative stress and aging markers, and increasing the expression of autophagy-related proteins. Mechanism investigations revealed that H2 could inhibit oxidative stress and activate autophagy pathways, but silencing Nuclear factor-erythroid 2 related factor 2 (Nrf2) impaired the ability of H2 to ameliorate endothelial senescence in the CIH cell model. These suggest that H2 can activate mitochondrial autophagy, reduce oxidative stress, and improve the senescence of endothelial cells induced by CIH, providing evidence for the clinical application of H2 in OSA-related vascular endothelial senescence diseases.
    Keywords:  Autophagy; Chronic intermittent hypoxia; Molecular hydrogen; Oxidative stress; Vascular endothelial senescence
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178078
  79. Neurosci Lett. 2025 Aug 22. pii: S0304-3940(25)00252-6. [Epub ahead of print]865 138363
    Neurodegenerative features of damage to Deiters neurons in the lateral vestibular nucleus of mice after vestibular stimulation.
    Irina B Mikheeva, Natalya S Zhuikova, Irina Yu Chernomorets, Lyubov L Pavlik, Vladimir I Arkhipov.
      The structure and function of the lateral vestibular nucleus (LVN), also called Deiters' nucleus, was studied in mice after 8 h of vestibular stimulation. This stimulation resulted in postural instability and movement disturbances in the open field, which recovered to control levels after 48 h. The behavioral disorder was accompanied by changes in the structure of the lateral vestibular nucleus: the number of neurons decreased, their size decreased, and the number of dark neurons increased. In addition, microglial density increased 48 h after stimulation. At the ultrastructural level, significant changes occurred in Deiters neurons: a large number of lysosomes and lipofuscin granules were identified, and dramatic changes in the morphology of mitochondria were revealed. We identified two phases of increased mitophagy: one hour after vestibular stimulation and 5 days after it. If the first phase of mitophagy activation is caused by severe stress and the death of some neurons, then the second phase, in our opinion, can be caused by delayed neuroinflammation. Notably, micromitophagosomes containing fragments of cristae surrounded by a double membrane were observed within and adjacent to mitochondria. The obtained data indicate that damage to Deiters neurons after long-term vestibular stimulation has signs of neurodegeneration. The results of our work can contribute to understanding the mechanisms of movement disorders in neurodegenerative diseases.
    Keywords:  Deiters neurons; Lateral vestibular nucleus; Micromitophagy; Mitochondria; Neurodegeneration; Vestibular stimulation
    DOI:  https://doi.org/10.1016/j.neulet.2025.138363
  80. Adv Pharmacol Pharm Sci. 2025 ;2025 5567858
    Alpha-Mangostin Alleviates Mitochondrial Damage and Autophagy Dysregulation in the MPP+ Cellular Model of Parkinson's Disease.
    Korede Jacob Abraham, Permphan Dharmasaroja.
      Alpha-mangostin (α-M), a xanthone derivative with known antioxidative properties, has demonstrated a protective effect on neurons under oxidative stress, a key factor in the pathogenesis of Parkinson's disease (PD). However, its impact on mitochondrial integrity and autophagy in PD remains insufficiently understood. Therefore, the present study aimed to investigate the role of α-M in regulating defective mitochondrial proteins and its influence on the mTOR pathway, both of which are critical in the regulation of autophagy. This study investigated the effects of α-M pretreatment on 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in SH-SY5Y dopaminergic neurons. MPP+, a mitochondrial complex I inhibitor, significantly reduced the expression of mitochondrial proteins NDUFS3 and TIMM23, induced mitochondrial damage, and triggered excessive autophagy, as evidenced by elevated LC3-II/LC3-I ratio and phospho-Beclin-1 expression. These changes were accompanied by dysregulation of the mTOR signaling pathway, including increased phosphorylation of mTOR and suppression of its downstream effector p70S6K. α-M pretreatment restored NDUFS3 and TIMM23 levels, preserved mitochondrial morphology and membrane potential, and reduced autophagy activation by mitigating MPP+-induced LC3B accumulation and Beclin-1 activation. Additionally, α-M restored balance in the mTOR signaling pathway by reducing mTOR phosphorylation and restoring p70S6K activity, counteracting the autophagic dysregulation caused by MPP+. Importantly, α-M exhibited no toxicity under normal conditions, indicating its protective effects are context-dependent and activated only during cellular stress. These findings highlight the potential of α-M as a therapeutic agent for PD, providing neuroprotection through its targeted modulation of mitochondrial proteins and mTOR signaling that regulates autophagy.
    Keywords:  MPP+; alpha-mangostin; autophagy; mTOR; mitochondria; p70S6K
    DOI:  https://doi.org/10.1155/adpp/5567858
  81. Ecotoxicol Environ Saf. 2025 Aug 22. pii: S0147-6513(25)01250-3. [Epub ahead of print]303 118905
    The role of the mitochondrial dynamic distribution in oocyte development arrest induced by F-53B.
    Chu Chu, Kun Zhao, Yuan-Yuan Fan, Marjut Roponen, Pasi Jalava, Mo Yang, Yong-Qi Luo, Li-Zi Lin, Yun-Ting Zhang, Jun-Heng Ma, Shu-Li Xu, Wen-Wen Bao, Wei-Hong Tan, Lin-Tao Xue, Guang-Hui Dong, Xiao-Miao Zhao.
      Chlorinated polyfluoroalkyl ether sulfonates (F-53B), an alternative to perfluorooctane sulfonate (PFOS), has gained attention for reproductive toxicity, but data on its specific effects on oocyte remain limited. We conducted in vitro maturation (IVM) experiments on ICR mouse oocytes exposed to F-53B at its medium inhibition of maturation concentration (IM50). PFOS and 0.5 % dimethyl sulfoxide (DMSO) served as positive and negative control, respectively, during 16-hour treatments. For each sample, 50 GV oocytes were tested, with six replicates. Phenotypic assessments included oocyte maturation status, spindle architecture, and mitochondrial function, and single-cell transcriptomic analysis was conducted to investigate molecular mechanism. Mitochondrial ultrastructure was evaluated by transmission electron microscopy, and distribution patterns were tracked by live-cell imaging. In vitro, F-53B exposure led to meiotic arrest, spindle defects, chromosome misalignment, and mitochondrial dysfunction. Single-cell transcriptomic analysis revealed mitochondria as the primary organelle affected by F-53B exposure. Disrupted mitochondrial organization caused by F-53B contributed to spindle assembly abnormalities, with significant alterations observed in key genes related to mitochondrial distribution. Our findings provide new insights into the reproductive toxicity of F-53B, identifying disrupted mitochondrial distribution and function as key factors in oocyte maturation impairment caused by F-53B.
    Keywords:  F-53B; Mitochondrial distribution; Oocyte development; Single-cell transcriptome; Spindle assembly
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118905
  82. Front Oncol. 2025 ;15 1506744
    Link between Parkinson's disease and melanoma: insights into the influence of the PARK gene family.
    Jinghua Wu, Haojun Xiong, Jinhua Chen, Dengrong Yang, Yujing Li, Jinglai Wang, Jiaoyu Chen, Ruixia Zhang, Ruiqi Zhang, Xiwei Li, Feng Li, Runnan Zhang, Zhi Yang.
      Parkinson's disease (PD) is a common neurodegenerative disorder characterized by damage to dopaminergic neurons within the substantia nigra region of the midbrain. Melanoma, on the other hand, is a malignant skin tumor formed by the abnormal proliferation of melanocytes, often linked to genetic predisposition and ultraviolet exposure. Emerging evidence confirms a significant association between PD and melanoma, with individuals afflicted with PD displaying a higher susceptibility to melanoma development. The PARK family genes, known for their involvement in PD etiology, emerge as key players in elucidating this intricate relationship. Through a comprehensive review, it becomes evident that different PARK gene mutations exert varied impacts on both PD and melanoma pathogenesis. For instance, mutations in PARK1/4 influence α-synuclein aggregation in both PD and melanoma, while PARK8 mutations modulate autophagy pathways in both PD and melanoma. The roles of PARK2 and PARK13 in melanoma warrant further investigation. Additionally, PARK6 mutations influence mitophagy mechanisms in PD and melanoma, with implications regarding melanoma proliferation through the PI3K/AKT pathway. Therefore, delineating the precise contributions of PARK genes to PD and melanoma pathophysiology holds paramount importance in devising therapeutic strategies for both PD and melanoma.
    Keywords:  PARK gene family; Parkinson’s disease; melanoma; pathogenesis; α-synuclein
    DOI:  https://doi.org/10.3389/fonc.2025.1506744
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