bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–10–19
fifty-five papers selected by
Gavin McStay, Liverpool John Moores University
  1. Remimazolam alleviates hippocampal neuronal injury in an in vitro Alzheimer's disease model by promoting PINK1/Parkin-mediated mitophagy.
  2. NDUFAB1 promotes hepatocellular carcinoma progression by disrupting mitochondrial homeostasis and mitophagy pathway.
  3. BNIP3L/BNIP3-Mediated Mitophagy Contributes to the Maintenance of Ovarian Cancer Stem Cells.
  4. SIRT1-PINK1-Parkin axis orchestrated mitophagy and renal repair by dapagliflozin in diabetic nephropathy.
  5. Morin enhances healthspan and neuroprotection in Caenorhabditis elegans via mitochondrial stress adaptation.
  6. C3a/C3aR axis is involved in diabetic kidney injury by regulating podocyte mitophagy in diabetic nephropathy.
  7. Mechanistic study on nonylphenol-induced liver fibrosis via Pink1/Parkin-mediated mitophagy and lipid droplet degradation in hepatic stellate cells.
  8. PINK1 overexpression suppresses p38 MAPK/NF‑κB signaling to attenuate chondrocyte senescence in osteoarthritis.
  9. Exercise as a Therapeutic Strategy Against Mitochondrial Dysfunction in Ischemic Stroke: Molecular Mechanisms and Perspectives for Personalized Treatment.
  10. Mechanisms of high-glucose-induced mitochondrial damage and glycolipid accumulation in largemouth bass.
  11. Early-Life Red Light Exposure Extends Lifespan in C. elegans through ROS-AMPK-Driven Mitochondrial Reprogramming.
  12. Chelerythrine inhibits esophageal squamous cell carcinoma progression via PINK1-Parkin-mediated mitophagy.
  13. Chlorogenic acid modulates mitochondrial damage and mitophagy to repair injured myocardial tissue and cells.
  14. Dendrobine ameliorates mitophagy-mediated endothelial senescence in diabetic kidney disease through activating the SIRT1/FOXO3a pathway.
  15. CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
  16. Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
  17. HMGB1 and mitochondrial dysfunction: a double-edged sword in ageing.
  18. Mitochondrial UPR is required for resveratrol mediated anti-bacterial immunity.
  19. Crosstalk Between Allergic Inflammation and Autophagy.
  20. Apigenin Suppresses NLRP3 Inflammasome Activation and Pyroptosis and Promotes Functional Recovery by Promoting Mitophagy in Experimental Spinal Cord Injured Rats.
  21. [Protective mechanism of Chaihu Shugan San against CORT-induced damage in PC12 cells based on mitochondrial dynamics].
  22. Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.
  23. Matrix Stiffness Promotes DRP1-Mediated Myofibroblast Senescence to Drive Silica-Induced Pulmonary Fibrosis.
  24. Micro- and nanoplastic-induced mitochondrial dysfunction and organelle miscommunication: A toxicological perspective.
  25. Bisphenol A Disrupts Spermatogenesis via Excessive Mitophagy-Driven Ferroptosis.
  26. MK8722 alleviates osteoarthritis by activating Sesn2 and transcriptionally upregulating BNIP3 to promote mitophagy and inhibit chondrocyte ferroptosis.
  27. The mitochondrial side of frailty.
  28. Quercetin ameliorates diminished ovarian reserve via modulating intestinal BNIP3/dct-1-mediated mitophagy and subsequently activating the ovarian TGF-β signaling pathway.
  29. Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.
  30. Lithospermic acid alleviates myocardial ischemia/reperfusion injury by inhibiting mitophagy via the Piezo1-PPP3/calcineurin-TFEB pathway.
  31. Clinical significance of mitochondrial dynamics-related miRNAs in the superacute phase of acute heart failure in patients presenting to the emergency department.
  32. Spontaneous hydrogen-releasing nanoenzyme alleviates osteoarthritis via oxidative stress reduction and mitochondrial dysfunction reversal.
  33. Chronic stress-induced downregulation of MFN1 contributes to fatty liver in chickens.
  34. Ailanthone targets mitophagy-loaded SIRT4 to facilitate the deacetylation of HIF1α, triggering oxidative stress for gastric carcinoma treatment.
  35. Repurposing Doxycycline to Overcome High-Glucose-Induced Mitochondrial Biogenesis-Mediated Chemoresistance in Colorectal Cancer Cells.
  36. SLIT2 modulates NMIIA to regulate mitophagy and suppress hepatocellular carcinoma progression.
  37. From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
  38. VDAC1: The mitochondrial gatekeeper in the battle against hearing loss (Review).
  39. Publisher Correction: Suppression of Rho-associated kinase 1 (ROCK1) promotes human hematopoietic stem cell expansion by attenuating mitochondrial fission.
  40. Lon/Pim1 mediated degradation of presequence translocase-associated motor components Pam16 and Pam18 in Saccharomyces cerevisiae.
  41. Atraric acid activates the FoxO3a/PINK1/Parkin signaling pathway to suppress chronic intermittent hypoxia-induced cardiac oxidative stress, inflammatory responses, and NLRP3 inflammasome activation.
  42. The EP300-Targeting Drug CCS1477 Inhibits the Growth and Development of Diffuse Large B-Cell Lymphoma by Promoting Apoptosis and Mitophagy to Reduce Drug Resistance.
  43. Exendin-4 improves mitochondrial integrity against cisplatin-induced cardiac damage: Targeting p53 and NF-κB pathways.
  44. A novel ligustrazine-based nanodelivery system protects against doxorubicin-induced cardiotoxicity by targeting the SIRT5-DUSP1 axis for mitochondrial repair.
  45. Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.
  46. MiR-20b-Overexpressed BMSC-Derived Exosomes Target SIRT1/BMP2 to Regulate Mitochondrial Autophagy and Osteogenesis in Osteoporosis.
  47. Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
  48. Interplay Between mTORC1 Signaling and Iron Homeostasis in Muscle Atrophy.
  49. Targeting Autophagy via Mitochondrial Uncoupling: Discovery of Novel Serratin Derivative as a Potential Therapeutic for Parkinson's Disease.
  50. Human milk-derived 5'-UMP promotes thermogenesis and mitochondrial biogenesis to ameliorate obesity.
  51. Lasmiditan ameliorates cortico-hippocampal pathology and improves cognition in aging parkinsonian mice.
  52. Modulation of mTOR Within Retinal Pigment Epithelium Affects Cell Viability and Mitochondrial Pathology.
  53. Novel links of ATG4 proteases to cytoskeletal adapters of the obscurin protein family.
  54. KIF5A upregulation by FAK-mediated downregulation of epigenetic modifiers promotes mitochondrial dynamics in neuronal differentiation.
  55. Oxidative Stress, Mitochondrial Quality Control, Autophagy, and Sirtuins in Heart Failure.
  1. Eur J Med Res. 2025 Oct 13. 30(1): 962
    Remimazolam alleviates hippocampal neuronal injury in an in vitro Alzheimer's disease model by promoting PINK1/Parkin-mediated mitophagy.
    Wei Zhang, Bowen Shi, Yuanyuan Xie, Yan Li, Jianke Yang, Ke Zhao.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau proteins. Remimazolam (RMZ), a novel ultra-short-acting benzodiazepine, exhibits neuroprotective effects by enhancing mitochondrial autophagy independently of traditional GABAergic mechanisms. This study investigates the protective role of RMZ against Aβ1-42-induced neuronal damage through PINK1/Parkin-mediated mitophagy. In hippocampal HT22 cells, RMZ significantly attenuated Aβ1-42-induced cytotoxicity, reduced apoptosis, suppressed reactive oxygen species (ROS) production, and decreased lactate dehydrogenase (LDH) release. Moreover, RMZ ameliorated mitochondrial membrane depolarization and tau hyperphosphorylation, while enhancing mitophagy, evidenced by an increased LC3-II/LC3-I ratio, elevated Beclin-1 expression, and decreased P62 levels. Mechanistically, RMZ upregulated PINK1 and Parkin expression, facilitating mitochondrial recruitment and clearance of damaged mitochondria. Importantly, knockdown of PINK1 abolished RMZ's protective effects, confirming the pathway's specificity. These findings suggest that RMZ promotes mitochondrial homeostasis and offers a promising strategy for AD therapy via PINK1/Parkin-mediated mitophagy.
    Keywords:  Alzheimer’s disease; Mitophagy; PINK1/Parkin pathway; Remimazolam
    DOI:  https://doi.org/10.1186/s40001-025-03179-x
  2. Int Immunopharmacol. 2025 Oct 16. pii: S1567-5769(25)01655-8. [Epub ahead of print]167 115664
    NDUFAB1 promotes hepatocellular carcinoma progression by disrupting mitochondrial homeostasis and mitophagy pathway.
    Zhaonv Yao, Xianyi Tan, Huanyu Cui, Hongjun Liang, Ating Zhong, Yuxuan Man, Tingzhuang Yi, Zhengbao Zhang, Xuefeng Guo, Shengkui Tan, Xiaonian Zhu.
      NADH: ubiquinone oxidoreductase subunit AB1 (NDUFAB1), a critical factor of mitochondrial complex I in electron transport chain, is essential for cellular energy metabolism; however, its specific functions and mechanisms in hepatocellular carcinoma (HCC) remain elusive. We found significantly elevated NDUFAB1 expression in HCC tissues, which is correlated significantly with poor patient prognosis and may serve as an independent risk factor (P < 0.05). Loss-of-function experiments revealed that NDUFAB1 knockdown reduced HCC cell proliferation, metastatic potential, and invasive capacity while promoting apoptosis. Furthermore, NDUFAB1 knockdown led to mitochondrial depolarization, impaired ATP production, and ROS accumulation, concomitant with downregulation of fusion proteins (OPA1, MFN1, MFN2) and upregulation of fission proteins (DRP1, MFF). Transmission electron microscopy revealed mitochondrial fragmentation and increased autolysosomes formation. Transcriptome sequencing data further indicated that NDUFAB1 may contribute to HCC pathogenesis by disrupting mitochondrial quality control, particularly through modulation of the mitophagy pathway. Collectively, NDUFAB1 likely promotes HCC progression by disrupting mitochondrial homeostasis, potentially through activation of the mitophagy pathway. These findings demonstrate that NDUFAB1 may be used as an independent prognostic risk factor in HCC patients.
    Keywords:  HCC; Mitochondrial homeostasis; Mitophagy; NDUFAB1
    DOI:  https://doi.org/10.1016/j.intimp.2025.115664
  3. J Cell Mol Med. 2025 Oct;29(19): e70704
    BNIP3L/BNIP3-Mediated Mitophagy Contributes to the Maintenance of Ovarian Cancer Stem Cells.
    Na Li, Tejinder Pal Khaket, Yajing Yang, Linzhou Wang, Shurui Cai, Aidan Li, Elsa Wani, Jessica Miao, Nan Zhang, Qingfei Zheng, Junran Zhang, Xuefeng Liu, Selvendiran Karuppaiyah, Dehua Pei, Qi-En Wang.
      Ovarian cancer remains the most lethal gynaecological malignancy, with tumour recurrence and chemoresistance posing significant therapeutic challenges. Emerging evidence suggests that cancer stem cells (CSCs), a rare subpopulation within tumours with self-renewal and differentiation capacities, contribute to these hurdles. Therefore, elucidating the mechanisms that sustain CSCs is critical for improving treatment strategies. Mitophagy, a selective process for eliminating damaged mitochondria, plays a key role in maintaining cellular homeostasis, including CSC survival. Our study demonstrates that ovarian CSCs exhibit enhanced mitophagy, accompanied by elevated expression of the mitochondrial outer membrane receptors BNIP3 and BNIP3L. Knockdown of BNIP3 or BNIP3L significantly reduces mitophagy and impairs CSC self-renewal, indicating that receptor-mediated mitophagy is essential for CSC maintenance. Mechanistically, we identify that hyperactivated NF-κB signalling drives the upregulation of BNIP3 and BNIP3L in ovarian CSCs. Inhibition of NF-κB signalling, either via p65 knockdown or pharmacological inhibitors, effectively suppresses mitophagy. Furthermore, we demonstrate that elevated DNA-PK expression contributes to the constitutive activation of NF-κB signalling, thereby promoting mitophagy in ovarian CSCs. In summary, our findings establish that BNIP3/BNIP3L-mediated mitophagy, driven by DNA-PK-dependent NF-κB hyperactivation, is essential for CSC maintenance. Targeting the DNA-PK/NF-κB/BNIP3L-BNIP3 axis to disrupt mitochondrial quality control in CSCs represents a promising therapeutic strategy to prevent ovarian cancer recurrence and metastasis.
    Keywords:  BNIP3; BNIP3L; DNA‐PK; NF‐κB; cancer stem cells; mitophagy; ovarian cancer
    DOI:  https://doi.org/10.1111/jcmm.70704
  4. Biochim Biophys Acta Mol Basis Dis. 2025 Oct 15. pii: S0925-4439(25)00422-3. [Epub ahead of print] 168074
    SIRT1-PINK1-Parkin axis orchestrated mitophagy and renal repair by dapagliflozin in diabetic nephropathy.
    Yonggang Ma, Na Luo, Chenguang Yue, Qiannan Sun, Yangyang Wang, Hongyan Zhao, Ruilong Song, Hui Zou, Jiaqiao Zhu, Zongping Liu.
       BACKGROUND: Mitochondrial dysfunction caused by metabolic stress is a key part of diabetic nephropathy. Dapagliflozin exerts significant hypoglycemic and nephroprotective effects; however, the precise mechanisms underlying its renoprotective actions remain to be fully elucidated.
    OBJECTIVE: This study aimed to elucidate the molecular mechanisms through which dapagliflozin mitigates diabetic nephropathy (DN), with particular emphasis on its regulatory role in the Sirt1-Pink1-Parkin axis and the restoration of mitochondrial homeostasis via mitophagy.
    METHODS: Rats were fed a high-fat/high-sugar diet and streptozotocin. They were then divided into groups of various treatments. In vitro, high glucose-induced NRK-52E cell injury was treated with dapagliflozin. Evaluations included renal histopathology, urinary biomarkers, apoptosis, reactive oxygen species, mitochondrial membrane potential, and Sirt1/Pink1/Parkin pathway activation.
    RESULTS: Dapagliflozin exerted significant protective effects against streptozotocin-induced diabetic nephropathy. Dapagliflozin treatment in vitro restored mitochondrial membrane potential and reduced ROS levels in high glucose-induced NRK-52E cells. High glucose exposure markedly upregulated the expression of mitochondria-associated apoptotic proteins in NRK-52E cells, which was reduced by dapagliflozin. This study revealed that Sirt1/Pink1/Parkin-mediated mitophagy was suppressed in DN and high glucose-induced NRK-52E cells but was activated following dapagliflozin treatment.
    CONCLUSION: Our findings demonstrate that dapagliflozin modulates Sirt1/Pink1/Parkin-mediated mitochondrial autophagy and effectively restores mitochondrial homeostasis in diabetic nephropathy. Modulating mitochondrial autophagy through this pathway may serve as a promising therapeutic strategy for diabetic nephropathy.
    Keywords:  Dapagliflozin; Diabetic nephropathy; Mitochondrial quality control; Mitophagy; Sirt1/Pink1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168074
  5. Mech Ageing Dev. 2025 Oct 15. pii: S0047-6374(25)00096-X. [Epub ahead of print] 112120
    Morin enhances healthspan and neuroprotection in Caenorhabditis elegans via mitochondrial stress adaptation.
    Yong-Ha Jo, Hyun-Ok Song, Dong-Sung Lee, Jeong Hoon Cho.
      Morin, a dietary flavonoid with antioxidant and metabolic activity, promotes healthy ageing in Caenorhabditis elegans. Morin extended lifespan by ~18% and alleviated age-related decline in neuronal integrity, locomotion, learning and memory, and intestinal fat accumulation. Mitochondrial potential was moderately decreased, suggesting mild uncoupler-like activity. Morin downregulated daf-2 and upregulated daf-16, accompanied by enhanced DAF-16::GFP nuclear localization, indicative of IIS/FOXO pathway activation. Gene expression profiling revealed modulation of mitochondrial stress-responsive (atfs-1, fmo-2), antioxidant (gst-4, hsf-1), and lipid metabolism (fat-6, fat-7) genes. Notably, pink-1 and pdr-1 expression increased, whereas morin's neuroprotective effects were abolished in pink-1; pdr-1 mutants, suggesting that its benefits may involve PINK-1/PDR-1-dependent mitophagy or mitochondrial quality control. Collectively, morin enhances stress resilience and mitochondrial homeostasis through IIS/FOXO-associated regulation, supporting its potential as a natural compound that promotes healthspan.
    Keywords:  Caenorhabditis elegans; Mitophagy; healthspan; mitochondrial membrane potential; morin
    DOI:  https://doi.org/10.1016/j.mad.2025.112120
  6. Int J Mol Med. 2025 Dec;pii: 223. [Epub ahead of print]56(6):
    C3a/C3aR axis is involved in diabetic kidney injury by regulating podocyte mitophagy in diabetic nephropathy.
    Mengjie Weng, Xiaoting Wu, Siyi Rao, Kun Nie, Danyu You, Tingting Zheng, Enqin Lin, Jing Zheng, Jiong Cui, Jianxin Wan.
      The C3a/C3aR axis has been confirmed to be associated with the pathogenesis of diabetic nephropathy (DN) and mitochondrial dysfunction; however, the exact mechanisms underlying its role in diabetic podocytopathy remain unclear. The present study investigated the involvement of C3a/C3aR signaling in regulating mitophagy during the progression of DN. Diabetic db/db mice exhibited elevated renal C3 and C3aR levels, concurrent with podocyte injury, proteinuria and glomerular damage. Administration of the C3aR antagonist (C3aRA) SB290157 attenuated podocyte loss, reduced albuminuria and mitigated glomerular pathology. Ultrastructural and functional analyses revealed that C3aRA restored mitochondrial integrity in podocytes, resolving diabetes‑associated fragmentation and bioenergetic deficits. In vitro, high glucose‑exposed human podocytes displayed suppressed mitophagy and mitochondrial dysfunction, which were exacerbated by exogenous C3a. Conversely, C3aRA treatment enhanced mitophagy and preserved mitochondrial membrane potential, while small interfering RNA‑mediated C3aR or PINK1 knockdown abolished these protective effects. Notably, C3aRA activated the PI3K/AKT/FoxO1 pathway, driving both mitochondrial biogenesis and mitophagy. Disruption of this axis via FoxO1 inhibition reversed the therapeutic benefits of C3aRA, confirming its mechanistic centrality. In conclusion, the C3a/C3aR/PI3K/AKT/FoxO1 axis represents a previously unrecognized molecular bridge between complement activation and mitophagy failure in DN. Pharmacological disruption of this pathway could preserve podocyte homeostasis, offering a precision strategy against diabetic kidney injury.
    Keywords:  C3a/C3aR axis; PI3K/AKT/FoxO1 signaling; diabetic nephropathy; mitophagy; podocyte injury
    DOI:  https://doi.org/10.3892/ijmm.2025.5664
  7. Ecotoxicol Environ Saf. 2025 Oct 16. pii: S0147-6513(25)01551-9. [Epub ahead of print]305 119206
    Mechanistic study on nonylphenol-induced liver fibrosis via Pink1/Parkin-mediated mitophagy and lipid droplet degradation in hepatic stellate cells.
    Feng Li, Jie Yu, Songhe Wang, Xiao Yang, Hao Yao, Kai Pan, Huawen Yu, Feng Wang, Jie Xu.
       BACKGROUND: Liver fibrosis (LF) is a common pathological feature in several chronic liver diseases. Nonylphenol (NP) accumulates in the liver and impairs its function. The mechanism by which NP exposure induces LF remains to be elucidated.
    OBJECTIVE: This study aimed to determine whether NP activates Pink1/Parkin-mediated mitophagy to promote lipid droplet degradation in hepatic stellate cells, which then contributes to the development of LF.
    METHODS: Human hepatic stellate cells (LX-2) were categorized into six groups: control, Quizartinib (a Parkin inhibitor), NP, Quizartinib + NP, Mdivi-1 (a mitophagy inhibitor), and Mdivi-1 + NP. Sixty male C57BL/6 mice were randomly assigned to six groups of 10 mice each: control (corn oil), low-dose NP (25 mg/kg), medium-dose NP (50 mg/kg), high-dose NP (100 mg/kg), Parkin knockout (KO, corn oil), and Parkin KO + NP (100 mg/kg). An additional four mice were set aside as a LF model group (Model, received 10 % CCl₄ intraperitoneally at 5 mL/kg, three times per week). All treatments were administered for 35 days.
    RESULTS: In vitro, NP exposure caused LX-2 cells to lose their stellate morphology and become elongated. Furthermore, treatment with 40 μM NP decreased the expression of the lipid droplet-coating protein Perilipin 5 (Plin5) and enhanced the expression of fibrosis markers (alpha-smooth muscle actin [α-SMA], Collagen Ⅰ) and mitophagy-related proteins (Pink1, Parkin, Beclin1, LC3 Ⅱ) (P < 0.05). However, the inhibition of Parkin or mitophagy reversed NP-induced downregulation of Plin5 and upregulation of fibrosis markers and mitophagy-related proteins (P < 0.05). In vivo, NP exposure significantly increased the liver index and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in mice. However, Parkin KO reduced liver dysfunction (P < 0.05). As the NP dose increased, the Plin5 expression decreased in a dose-dependent manner, whereas fibrosis markers (α-SMA, Collagen Ⅰ) and mitophagy-related proteins (Pink1, Parkin, Beclin1, LC3 Ⅱ) increased. Nonetheless, Parkin KO mitigated the reduction of Plin5 and the elevation of fibrosis and mitophagy markers (P < 0.05). NP exposure considerably augmented hepatic collagen deposition in a dose-dependent manner, disrupted mitochondrial integrity, increased autophagosome numbers, and reduced the hepatic lipid droplet content. Nevertheless, Parkin KO reduced these pathological alterations (P < 0.05).
    CONCLUSION: NP induces LF by activating Pink1/Parkin-mediated mitophagy, which promotes lipid droplet degradation in hepatic stellate cells.
    Keywords:  Hepatic stellate cells; Liver fibrosis; Mitophagy; Nonylphenol; Pink1/Parkin
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119206
  8. Int J Mol Med. 2025 Dec;pii: 224. [Epub ahead of print]56(6):
    PINK1 overexpression suppresses p38 MAPK/NF‑κB signaling to attenuate chondrocyte senescence in osteoarthritis.
    Lishi Jie, Yuanhui Zhang, Jiangyu Liu, Houyu Fu, Zaishi Zhu, Zeling Huang, Xiaoqing Shi, Peimin Wang, Songjiang Yin.
      PTEN‑induced putative kinase 1 (PINK1), a master regulator of mitophagy, is implicated in mitochondrial homeostasis, yet its role in knee osteoarthritis (OA) pathogenesis remains unclear. The present study investigated the mechanisms by which PINK1 modulates chondrocyte senescence during OA progression. Utilizing a destabilization of the medial meniscus‑induced OA murine model, decreased PINK1 expression, impaired mitochondrial function and suppressed mitophagy were observed in OA cartilage. In vitro, lipopolysaccharide‑induced chondrocyte senescence was exacerbated by PINK1 knockdown but mitigated by PINK1 overexpression, which restored mitophagy and reduced senescence‑associated β‑galactosidase activity, reactive oxygen species accumulation and mitochondrial membrane potential collapse. RNA sequencing and mechanistic studies identified the p38 MAPK/NF‑κB pathway as a downstream target; PINK1 knockdown amplified the phosphorylation of p38 MAPK/NF‑κB, promoting mitochondrial dysfunction and senescence. By contrast, pharmacological inhibition of p38 MAPK/NF‑κB rescued these effects in PINK1‑deficient chondrocytes. Collectively, PINK1 attenuated OA progression by suppressing chondrocyte senescence via inhibition of the p38 MAPK/NF‑κB pathway, highlighting its potential as a therapeutic target for OA management.
    Keywords:  PTEN‑induced putative kinase 1; chondrocyte senescence; mitophagy; osteoarthritis; p38 MAPK/NF‑κB signaling
    DOI:  https://doi.org/10.3892/ijmm.2025.5665
  9. Prog Biophys Mol Biol. 2025 Oct 15. pii: S0079-6107(25)00054-9. [Epub ahead of print]
    Exercise as a Therapeutic Strategy Against Mitochondrial Dysfunction in Ischemic Stroke: Molecular Mechanisms and Perspectives for Personalized Treatment.
    Xinzheng Wang, Huifen Zhou.
      Ischemic stroke (IS) is a leading cause of disability and mortality worldwide, with mitochondrial dysfunction being a fundamental pathological mechanism. This dysfunction involves a dynamic imbalance, diminished biosynthesis, oxidative stress, and dysregulated autophagy. Exercise, a promising non-pharmacological intervention, can ameliorate this dysfunction, but its precise molecular mechanisms remain to be fully elucidated. This review synthesizes evidence demonstrating that exercise enhances mitochondrial morphology and function through various pathways, including the promotion of mitochondrial biogenesis, the regulation of mitochondrial ROS, and the modulation of mitochondrial dynamics and mitophagy, thereby mitigating functional impairments associated with IS. Critically, the beneficial effects of exercise are dose dependent, highlighting the necessity for personalized exercise prescriptions on the basis of individual patient profiles. Elucidating these mechanisms provides a crucial theoretical foundation for developing exercise-based strategies for the prevention and treatment of IS.
    Keywords:  exercise; ischemic stroke; mitochondrial dysfunction; molecular mechanisms; personalized treatment
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2025.10.002
  10. J Anim Sci Biotechnol. 2025 Oct 15. 16(1): 132
    Mechanisms of high-glucose-induced mitochondrial damage and glycolipid accumulation in largemouth bass.
    Zhihong Liao, Xuanshu He, Xingyu Gu, Tao Ye, Anqi Chen, Yucai Guo, Wei Zhao, Jin Niu.
       BACKGROUND: The carnivorous fish, largemouth bass (Micropterus salmoides), has difficulty metabolizing dietary carbohydrates, frequently resulting in issues with energy metabolism and fatty liver disease. Nevertheless, the molecular mechanisms involved are still not fully understood.
    RESULTS: The results of high-carbohydrate (HC) diets and high-glucose (HG) treatments in largemouth bass hepatocytes showed that high-glucose causes liver damage and glycolipid accumulation. High-glucose promoted the lipogenesis process by activating AMPK/ACC/SREBP-1 pathway and reduced bile acid synthesis by downregulating cholesterol 7-hydroxylase (cyp7a1) and sterol 12-hydroxylase (cyp8b1). Concurrently, HG treatments also caused mitochondrial fission and damage by increasing the expression of dynamin-related protein 1 (Drp1), leading to impaired mitochondria accumulation and mitochondria-dependent apoptosis via the p38 MAPK/Bcl-2/Casp3 pathway. Additionally, HG treatments decreased Sirt1 expression and relocated it from the nucleus to the cytoplasm, where it interacts with autophagosomes and lysosomes, inhibiting Pink1/Parkin-mediated mitophagy. This also led to the cytoplasmic translocation of Pink1 and its co-localization with Sirt1, indicating that Sirt1 regulates high glucose-induced metabolic stress by inhibiting the Pink1/Parkin mitophagy pathway.  CONCLUSION: In summary, HG treatment induces mitochondrial damage and glycolipid accumulation in largemouth bass through mechanisms involving AMPK/SREBP1/ACC1-mediated lipogenesis, bile acid metabolism, Sirt-mediated mitophagy, and p38 MAPK/Bcl-2/Casp3-activated apoptosis.
    Keywords:  Largemouth bass; Mitochondrial function; Pink1/Parkin; Sirt1
    DOI:  https://doi.org/10.1186/s40104-025-01261-2
  11. Aging Dis. 2025 Sep 22.
    Early-Life Red Light Exposure Extends Lifespan in C. elegans through ROS-AMPK-Driven Mitochondrial Reprogramming.
    Yao Zhu, Xin Lin, Huiting Wang, Mingming Song, Tao Yang, Yi Jiao, Chang Liu.
      Specific wavelengths and intensities of light offer potential for modulating mitochondrial function to influence aging which is important for the development of non-invasive and modifiable exogenous anti-aging tools. However, the effects of exposure to different wavelengths of light during the early stages of life on health in adulthood, and the underlying mechanisms, remain poorly understood. In this study, we utilized Caenorhabditis elegans to investigate the effects of early-life (L1 to young adult stage) exposure to different light wavelengths (white, red, blue, green) on healthspan. We found that red light exposure (630 nm, 200 lx) during early life extended lifespan by 10.34% without affecting growth, movement, or reproduction, and improved late-life health indicators. Importantly, it significantly enhanced healthspan in later life, suggesting its potential as a non-invasive anti-aging strategy. Mechanistically, red light transiently suppressed mitochondrial bioenergetic activity, biogenesis, and membrane potential, and altered mitochondrial dynamics. Upon light withdrawal, mitochondrial function progressively recovered, demonstrating enhanced structure and function by day 6. Furthermore, red light stimulated ROS production, activated AMPKα phosphorylation, and triggered downstream mitochondrial quality control (MQC) programs, including the unfolded protein response (UPRMT) and mitophagy. Notably, these protective effects were conserved in human dermal fibroblasts, suggesting the translational applicability of this pathway. Collectively, our study identifies a specific "photophysiological window" during early life through which red light promotes longevity via ROS-mediated activation of AMPK and enhancement of MQC, proposing a non-invasive, safe, evolutionarily conserved, and drug-free strategy to mitigate age-related mitochondrial decline. Therefore, red light can serve as a non-invasive anti-aging strategy to enhance healthspan and potentially alleviate age-related mitochondrial dysfunction.
    DOI:  https://doi.org/10.14336/AD.2025.0791
  12. J Transl Med. 2025 Oct 17. 23(1): 1116
    Chelerythrine inhibits esophageal squamous cell carcinoma progression via PINK1-Parkin-mediated mitophagy.
    Yijian Zhou, Zhuo Wang, Hongzhou Zhao, Yongpan Liu, Yong Lin, Jiaying Zhang, Xinxin Li, Bo Zhang, Jialing Xie, Xiaolu An, Lijia Zhang, Songlin Shi, Kun Zhang, Kuancan Liu.
       BACKGROUND: Chelerythrine (CHE) exhibits notable anti-inflammatory and antitumor properties, while its impact on esophageal squamous cell carcinoma (ESCC), especially the underlying mechanisms remain unclear. In this study, we aim to investigate the roles and mechanism of CHE in the ESCC treatment.
    METHODS: Human ESCC cell lines and organoids were used for in vitro cell experiments, BALB/c nude mice were used for in vivo animal experiments. To investigate the underlying mechanism of CHE treatment, drug library screen, RNA sequencing analysis, TMT-based quantitative proteomic analysis, western blotting analysis, immunofluorescence, immunohistochemistry, quantitative real-time polymerase chain reaction, mitochondrial membrane potential assay, apoptosis assay, detection of mitochondrial reactive oxygen species (mtROS), autophagic flux monitoring, transmission electron microscopy, and seahorse XF-96 metabolic flux analysis were used to assess the effect of CHE and relevant mechanism.
    RESULTS: CHE dose-dependently inhibited the proliferation, migration, and invasion of ESCC cells. CHE also induced cell apoptosis and triggered PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy-mediated cell death by elevating the production of reactive oxygen species in mitochondria and diminishing mitochondrial membrane potential (MMP). However, the production of autophagosomes and autolysosomes induced by CHE altered when used in combination with the autophagy inhibitors 3-methyladenine (3-MA) or bafilomycin A1 (BafA1), indicating that it induced complete autophagic flux in the cells. Mechanistically, CHE affected multiple signaling pathways associated with ubiquitin-mediated proteolysis, mitophagy, and mitochondrial energy metabolism, indicating its close involvement in mitophagy occurrence. In addition, CHE treatment significantly reduced tumor size and weight in nude mice bearing KYSE150 tumors and retarded the growth of organoids derived from patients, it also reduced the ratio of M2 macrophage in tumor microenvironment and cell metabolism.
    CONCLUSIONS: CHE activates PINK1-Parkin-mediated mitophagy and disrupts mitochondrial homeostasis, and it also affects the tumor environment and cell metabolism, ultimately leading to cell death, supporting the potential of CHE for ESCC therapy.
    Keywords:  Chelerythrine; Esophageal squamous cell carcinoma; Mitophagy; PINK1-Parkin pathway
    DOI:  https://doi.org/10.1186/s12967-025-07025-w
  13. Front Pharmacol. 2025 ;16 1658090
    Chlorogenic acid modulates mitochondrial damage and mitophagy to repair injured myocardial tissue and cells.
    Hao Ling, Yu Zhang, Chunli Song.
       Background: Chlorogenic acid (CGA) is a polyphenolic compound widely present in plants. It is primarily extracted from the leaves of Eucommia ulmoides, a native medicinal herb.
    Purpose: This study aimed to investigate the cardioprotective effects of CGA on myocardial infarction (MI) by modulating mitochondrial damage and mitophagy through the PINK1/Parkin signaling pathway.
    Methods: In vitro, H9C2 cardiomyocytes were treated with varying concentrations of CGA to assess cell viability, oxidative stress, mitochondrial function, and mitophagy markers (PINK1/Parkin) and mitophagic flux. In vivo, There are a total of 18 SD rats, which are randomly divided into Sham, MI, and CGA groups. MI was induced in SD rats via coronary artery ligation, followed by tail vein injection of CGA. Echocardiography, histological staining, electron microscopy, immunohistochemistry, Western blot (WB) and metabolomics analysis were conducted to evaluate cardiac function, tissue fibrosis, mitophagy, and metabolic changes.
    Results: CGA significantly improved cell viability and reduced oxidative stress in H9C2 cells. It also stabilized mitochondrial membrane potential, increased ATP levels, upregulated PINK1/Parkin expression and increase autophagy flux, Lysosomal inhibitor treatment elevates expression of Parkin, P62 and LC3-II. In MI rats, CGA reduced ROS levels, improved myocardial tissue integrity, reduced fibrosis, and enhanced cardiac function. Detected by electron microscopy, immunohistochemistry, and WB confirmed increased mitophagy in CGA-treated rats. Metabolomics analysis revealed significant alterations in metabolic pathways, particularly related to organic acids and amino acid metabolism.
    Conclusion: This study demonstrates that CGA exerts cardioprotective effects by modulating mitochondrial damage and promoting mitophagy through the PINK1/Parkin pathway. Our findings provide new insights into the therapeutic potential of CGA for MI treatment and suggest a promising natural compound for myocardial protection.
    Keywords:  chlorogenic acid; mitochondrial damage; mitophagy; myocardial infarction; the PINK1/Parkin pathway
    DOI:  https://doi.org/10.3389/fphar.2025.1658090
  14. Chin Med. 2025 Oct 18. 20(1): 176
    Dendrobine ameliorates mitophagy-mediated endothelial senescence in diabetic kidney disease through activating the SIRT1/FOXO3a pathway.
    Yan Zhang, Xuan Qi, Rui-Xuan Sun, Yong-Fang Gong, Hong-Kai Yang, Wu-Ling Wang, Yan Yang, Yong-Sheng He, Yu-Sheng Shi.
       BACKGROUND: Glomerular senescence plays a vital role in the pathogenesis of diabetic kidney disease (DKD). Dendrobine (Den) exhibits anti-senescence properties and nephroprotective effects; however, its precise impact and underlying mechanisms in ameliorating glomerular senescence in DKD remain unclear.
    METHODS: The db/db mice were orally administered Den (10 and 30 mg/kg) for 8 weeks to evaluate its nephroprotective effect. Network pharmacology analysis was performed to investigate its underlying mechanisms. Senescence-associated β-galactosidase (SA-β-Gal) staining, Western blot, and RT-qPCR were employed to evaluate the beneficial effects of Den on inhibiting senescence in both in vivo and in vitro settings. The effects of Den on mitophagy were evaluated using transmission electron microscopy (TEM) and Western blot. RNA-seq was conducted to explore the molecular mechanisms underlying Den's amelioration of mitophagy-mediated endothelial senescence. siRNA and a pharmacological inhibitor of SIRT1 were utilized to validate the role of the SIRT1/FOXO3a pathway in this process.
    RESULTS: Biochemical and histological analyses indicated Den protected against renal injury in DKD mice. Network pharmacology analysis suggested Den's beneficial nephroprotective effects were associated with cellular senescence. SA-β-Gal staining showed that Den reduced the positive area of SA-β-Gal. Western blot and RT-qPCR results revealed that Den decreased the levels of senescence-associated proteins (p21 and p16) as well as secretory phenotype markers (IL-6, IL-8, IL-1β, MMP1, MMP3, and MMP10). Additionally, Den improved mitophagy levels, as evidenced by increased mitochondrial mean length and mitophagy-associated proteins (PINK1, Parkin, NIX, and BNIP3), along with a decreased proportion of damaged mitochondria. RNA-seq analysis indicated SIRT1 mRNA levels were significantly upregulated following Den treatment. Furthermore, siRNA-mediated knockdown of SIRT1 and Selisistat administration demonstrated that Den's inhibition of mitophagy-mediated endothelial senescence was associated with the activation of the SIRT1/FOXO3a pathway.
    CONCLUSIONS: These findings demonstrate that Den ameliorates endothelial senescence in DKD by enhancing mitophagy through activating the SIRT1/FOXO3a pathway, highlighting a promising therapeutic strategy for DKD patient.
    Keywords:  Dendrobine; Diabetic kidney disease; SIRT1/FOXO3a pathway; Senescence
    DOI:  https://doi.org/10.1186/s13020-025-01234-7
  15. Cell Rep. 2025 Oct 13. pii: S2211-1247(25)01183-0. [Epub ahead of print]44(10): 116412
    CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
    Alison Galloway, Katarzyna Knop, Carolina Gomez-Moreira, Vanessa Xavier, Sarah Thomson, Harunori Yoshikawa, Olga Suska, Radoslaw Lukoszek, Aneesa Kaskar, Angus I Lamond, Thomas MacVicar, Victoria H Cowling.
      During T cell activation, mitochondrial biogenesis and cellular metabolism are altered to meet the elevated energy demands of protein synthesis, rapid proliferation, and effector T cell function. The mechanisms coupling mitochondrial dynamics to T cell status are unclear. Here, we report that RNA cap methyltransferase 1 (CMTR1) is induced in activated T cells, methylating the first nucleotide on mRNA and U2 small nuclear RNA (snRNA), a component of the spliceosome. Using transcriptomic analyses, we identify a functional splicing module regulating mitochondrial dynamics in T cells, which alters the isoforms of proteins controlling mitochondrial fission and fusion. Through epitranscriptomic control of U2 snRNA and splicing, CMTR1 directs protein isoform selection during T cell activation to promote the development of longer mitochondria with increased respiratory capacity. Thus, CMTR1 upregulation supports the energetic demands of T cell activation, survival, and immune responses.
    Keywords:  CMTR1; CP: Immunology; CP: Metabolism; MFF; RNA cap; RNA methylation; T cell; T lymphocyte; metabolism; mitochondria; snRNA; splicing
    DOI:  https://doi.org/10.1016/j.celrep.2025.116412
  16. Curr Biol. 2025 Oct 15. pii: S0960-9822(25)01246-1. [Epub ahead of print]
    Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
    Leeba A Chacko, Hidenori Nakaoka, Richard G Morris, Wallace F Marshall, Vaishnavi Ananthanarayanan.
      Mitochondria are not produced de novo in newly divided daughter cells but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast "mother machine," we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the "sizer" mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division; cells born with lower-than-average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modeling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Altogether, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.
    Keywords:  S. pombe; fission yeast; growth kinetics; homeostasis; microfluidics; mitochondria; yeast mother machine
    DOI:  https://doi.org/10.1016/j.cub.2025.09.046
  17. Open Biol. 2025 Oct;15(10): 240376
    HMGB1 and mitochondrial dysfunction: a double-edged sword in ageing.
    Maheen Wahid, Margaret Cunningham.
      Ageing is an intricate and progressive decline across all biological systems, marked by various molecular and cellular processes termed as the hallmarks of ageing. One of the hallmarks is mitochondrial dysfunction, which is brought about through several pathways: mutations in mitochondrial DNA, elevated reactive oxygen species production, disrupted mitochondrial dynamics and impaired mitophagy. Here, we explore the role of high mobility group box 1 (HMGB1) as a potential contributor to mitochondrial dysfunction, examining how it may influence these pathways through its dual roles as both a protector of mitochondrial integrity and a promoter of inflammatory damage. Furthermore, we consider how mitochondrial dysfunction, possibly mediated by HMGB1, could link to other hallmarks of ageing, positioning HMGB1 as a possible central regulator in the ageing process.
    Keywords:  HMGB1; ageing; mitochondrial dysfunction
    DOI:  https://doi.org/10.1098/rsob.240376
  18. Food Funct. 2025 Oct 17.
    Mitochondrial UPR is required for resveratrol mediated anti-bacterial immunity.
    Yan Zhang, Xiaocong Li, Rui Zhao, Wanting Hu, Xin Xiao, Yi Xiao, Fang Liu.
      The mitochondrial unfolded protein response (UPRmt), a crucial mechanism for maintaining mitochondrial homeostasis, has recently been shown to regulate innate immune responses. Resveratrol, a natural polyphenolic compound abundant in grapes and peanuts, exhibits diverse biological activities including anti-inflammatory, antioxidant, anti-aging, and anticancer effects. However, whether resveratrol modulates innate immunity and its underlying mechanisms remain unclear. In this study, we demonstrated that resveratrol significantly enhanced resistance to Pseudomonas aeruginosa PA14 infection in a dose-dependent manner. This protective effect was mediated not through direct antimicrobial activity, but rather via upregulation of the antimicrobial peptide irg-1 and reduction of intestinal bacterial load. Mechanistically, resveratrol activated the ATFS-1-dependent UPRmt pathway, leading to increased expression of ATFS-1 and its downstream immune- and mitochondrial-protective genes. In human A549 cells, resveratrol attenuated P. aeruginosa PA14 cytotoxicity by activating the UPRmt through ATF5. The conservation of this mechanism was further validated in mice, where resveratrol treatment improved survival, reduced bacterial burden in lung tissue, and upregulated mitochondrial-protective genes. Our study identifies the ATFS-1/ATF5-UPRmt axis as a novel mechanism through which resveratrol enhances innate immunity, providing a foundation for developing natural compound-based anti-infective therapies. These findings advance our understanding of plant polyphenols in immune regulation and offer potential strategies to address antibiotic resistance.
    DOI:  https://doi.org/10.1039/d5fo03539b
  19. Int J Mol Sci. 2025 Oct 07. pii: 9765. [Epub ahead of print]26(19):
    Crosstalk Between Allergic Inflammation and Autophagy.
    Jaewhoon Jeoung, Wonho Kim, Dooil Jeoung.
      Autophagy is a conserved process that involves the degradation of damaged proteins and organelles to restore cellular homeostasis. Autophagy plays a critical role in cell differentiation, immune responses, and protection against pathogens, as well as the development and progression of allergic inflammation. Crosstalk between autophagy and signaling pathways modulates immune responses to inflammatory signals. Here, we discuss the regulatory roles of autophagy in allergic inflammation. Autophagy can promote allergic inflammation by enhancing the secretion of inflammatory mediators. Impaired autophagy resulting from the accumulation of autophagosomes can exacerbate allergic inflammation. Mast cell degranulation and activation require energy provided by mitochondrial respiration. Mast cell activation is accompanied by morphological changes and mitochondrial fragmentation. Mitochondrial fragmentation (mitophagy) induced by oxidative stress involves the degradation of defective mitochondria. Therefore, we discuss the relationship between mitophagy and allergic inflammation. Targeting autophagy and oxidative stress can be a strategy for developing anti-allergy therapeutics. In this review, we also discuss future research directions to better understand allergic diseases with respect to autophagy and develop effective anti-allergy drugs.
    Keywords:  allergy; autophagy; crosstalk; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms26199765
  20. J Inflamm Res. 2025 ;18 13965-13984
    Apigenin Suppresses NLRP3 Inflammasome Activation and Pyroptosis and Promotes Functional Recovery by Promoting Mitophagy in Experimental Spinal Cord Injured Rats.
    Zuomeng Wu, Yunxiao Fang, Yixiang Dong, Yue Qin, Ao Liu, Tianyu Han, Peiwen Song, Cailiang Shen.
       Background: Secondary damage following spinal cord injury (SCI) is closely associated with pyroptosis and mitochondrial dysfunction. Apigenin (API), a natural flavonoid, possesses notable anti-inflammatory and antioxidant properties. However, whether API can inhibit microglial pyroptosis via the mitophagy pathway, thereby exerting neuroprotective effects, remains unclear. This study aimed to elucidate the mechanism by which API mitigates post-SCI inflammatory responses through modulation of the mitophagy-NLRP3 axis.
    Methods: Neurological recovery was assessed using the Basso, Beattie, and Bresnahan scale, neuroelectrophysiological recordings, and histological analyses. The effects of API on NLRP3 inflammasome activation, reactive oxygen species (ROS) generation, and mitochondrial membrane potential were assessed using ELISA, quantitative PCR, immunofluorescence, and JC-1 staining.
    Results: API significantly improved locomotor function in SCI rats, reduced scar formation, and promoted axonal regeneration. Mechanistically, API downregulated NLRP3/ gasdermin D expression in microglia, reduced the release of inflammatory factors, and enhanced mitophagy. Notably, the protective effects of API were reversed by Mdivi-1 and mimicked by Urolithin A, confirming that mitophagy is the primary mechanism mediating API's anti-pyroptotic effects.
    Conclusion: API attenuates microglial pyroptosis and facilitates SCI repair by enhancing mitophagy-mediated clearance of damaged mitochondria and suppressing activation of the ROS/NLRP3 inflammasome pathway in rats. These findings provide important preclinical evidence supporting the development of multi-target neuroprotective strategies derived from natural compounds.
    Keywords:  apigenin; mitophagy; pyroptosis; spinal cord injury
    DOI:  https://doi.org/10.2147/JIR.S549251
  21. Zhongguo Zhong Yao Za Zhi. 2025 Aug;50(16): 4546-4554
    [Protective mechanism of Chaihu Shugan San against CORT-induced damage in PC12 cells based on mitochondrial dynamics].
    Ling-Yuan Zhang, Qi-Qi Zheng, Jia-Li Shi, Pei-Fang Wang, Jia-Li Lu, Jian-Ying Shen.
      In this report, the protective effect and molecular mechanism of Chaihu Shugan San-containing serum on corticosterone(CORT)-induced mitochondrial damage in pheochromocytoma(PC12) cells was studied based on CORT-induced rat PC12 cell model. The cultured cells were divided into five groups: blank control group, CORT group(400 μmol·L~(-1) CORT), Chaihu Shugan San-containing serum group(400 μmol·L~(-1) CORT + 10% Chaihu Shugan San-containing serum), control serum group(400 μmol·L~(-1) CORT + 10% control serum), and fluoxetine group(400 μmol·L~(-1) CORT + 10% fluoxetine-containing serum). The study was carried out by cell activity detection, mitochondrial morphology observation, membrane potential measurement, energy metabolism analysis, and mitochondrial dynamics-related protein detection. The results showed that CORT treatment significantly reduced the survival rate of PC12 cells, altered mitochondrial morphology, and decreased mitochondrial membrane potential and adenosine triphosphate(ATP) synthetic rate. Both Chaihu Shugan San-and fluoxetine-containing serum significantly increased the survival rate of CORT-treated PC12 cells and the ATP synthetic rate in the mitochondria. Unlike fluoxetine, Chaihu Shugan San-containing serum significantly inhibited the decrease in mitochondrial membrane potential caused by CORT and increased the oxygen consumption rate(OCR) values of both mitochondrial maximum respiration and reserve respiration capacity. Western blot analysis showed that CORT induced upregulated protein expressions of dynamin-related protein 1(Drp1) and peroxisome proliferator-activated receptor gamma co-activator 1α(PGC-1α) in PC12 cells and specific protein expression of optic atrophy protein 1(OPA1), yet it repressed the protein expressions of silent information regulator 1(SIRT1) and mitochondrial fusion protein 1(Mfn1) in PC12 cells. Both Chaihu Shugan San-and fluoxetine-containing serum significantly inhibited the protein expression of Drp1. However, only Chaihu Shugan San-containing serum could significantly inhibit the CORT-induced upregulation protein of PGC-1α. RESULTS:: herein suggest that Chaihu Shugan San-containing serum can alleviate CORT-induced damage in PC12 cells, which may be related to the mitochondrial fragmentation/lipid peroxidation protection by Drp1 inhibition, as well as mitochondrial dynamics and energy metabolism mediated by PGC-1α/SIRT1 signaling pathway.
    Keywords:  Chaihu Shugan San; PC12 cell; corticosterone; energy metabolism; mitochondrion
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250423.401
  22. Clin Sci (Lond). 2025 Oct 08. pii: CS20256651. [Epub ahead of print]
    Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.
    Yuanfeng Zhu, Xiaoli Chen, Lin Xia, Shijun Fan, Qian Chen, Yan Wei, Yongling Lu, Xin Liu, Xi Peng.
      Sepsis triggers impaired macrophage bacterial phagocytosis, rendering the host more vulnerable to secondary infections, a manifestation termed sepsis-associated immunosuppression. Glutamine is a vital nutrient in critical illness that not only supports energy production and biomass synthesis but also potentially exerts immunomodulatory effects. The aim of this study was to investigate whether supplementation of glutamine modulates macrophage phagocytosis and mitigates sepsis-induced immunosuppression. Using a murine model of polymicrobial sepsis, we evaluated the effects of glutamine supplementation on bacterial load, cytokine production, and survival. In multiple in vitro assays, we employed molecular and pharmacological approaches to dissect glutamine-dependent signaling pathways in recovering the immunosuppressive macrophages. We found that glutamine deficiency impaired macrophage phagocytosis and exacerbated sepsis-induced immunosuppression. In contrast, exogenous glutamine supplementation restored macrophage function and improved survival in septic mice-effects that were abolished upon macrophage depletion. Mechanistically, glutamine promoted glutamine-fructose-6-phosphate transaminase (GFAT)-dependent protein O-GlcNAcylation, leading to dynamin-related protein 1 (DRP1) oligomerization. Concurrently, glutamine activated a GFAT-mediated, CDK1-dependent pathway that induced DRP1 phosphorylation at Ser616 irrelevant of O-GlcNAcylation. These effects enhanced DRP1-mediated mitochondrial fission, increased mitochondrial calcium efflux, and sustained cytosolic calcium levels essential for phagocytosis. In conclusion, our study demonstrates that glutamine strengthens macrophage phagocytosis and alleviates immunosuppression in sepsis through a dual GFAT-DRP1 mechanism coordinating mitochondrial dynamics and calcium signaling, highlighting the GFAT-DRP1-calcium axis as a potential therapeutic target for treating sepsis-induced immunosuppression.
    Keywords:  DRP1; GFAT; glutamine; immunosuppression; mitochondrial; phagocytosis; sepsis
    DOI:  https://doi.org/10.1042/CS20256651
  23. Aging Cell. 2025 Oct 17. e70275
    Matrix Stiffness Promotes DRP1-Mediated Myofibroblast Senescence to Drive Silica-Induced Pulmonary Fibrosis.
    Xinying Zeng, Jingya Li, Jiaxin Wang, Jiaxin Zhang, Yuhua Wang, Yan Wang, Yifei Wang, Lin Tian, Zhonghui Zhu.
      Silicosis is an occupational lung disease characterized by diffuse pulmonary fibrosis resulting from inhalation of silica particles. As the disease progresses, lung tissue stiffness continuously increases, driving persistent activation and accumulation of myofibroblasts. However, whether these cells undergo senescence in response to prolonged high matrix stiffness and how such senescence impacts fibrosis progression remain unclear. Here, we established an in vitro model using decellularized lung matrices with varying stiffness to simulate the fibrotic mechanical microenvironment. We found that increased matrix stiffness upregulated mitochondrial fission protein DRP1, inducing excessive mitochondrial fragmentation and accumulation of mitochondrial reactive oxygen species (mtROS), leading to oxidative stress, DNA damage, and myofibroblast senescence. Treatment with the mitochondria-targeted antioxidant Mitoquinone mesylate (MitoQ10) effectively alleviated these effects. Moreover, senescent myofibroblast-derived secretions promoted fibroblast activation and collagen deposition via paracrine signaling, exacerbating fibrotic remodeling. These findings identify matrix stiffness-driven cellular senescence as a critical mechanism in silicosis progression, providing a rationale for targeting senescent cells as an antifibrotic therapeutic strategy.
    Keywords:  DRP1; matrix stiffness; mitochondrial stress; myofibroblast senescence; silicosis
    DOI:  https://doi.org/10.1111/acel.70275
  24. Toxicology. 2025 Oct 12. pii: S0300-483X(25)00265-3. [Epub ahead of print]519 154306
    Micro- and nanoplastic-induced mitochondrial dysfunction and organelle miscommunication: A toxicological perspective.
    Tanushree Maharana, Aditi Taranath, Caleb Seth Eleuterio Fernandes, Prabhakar Mishra, Yuvashree Muralidaran.
      Microplastics and nanoplastics (MNPs) and their derivatives, pose significant environmental and biomedical risks due to their pronounced cellular toxicity. These particulates disrupt mitochondrial function and compromise inter-organelle communication, leading to enhanced oxidative stress, calcium dysregulation, impaired ATP production, and activation of cellular stress responses including mitophagy and apoptosis. Mitochondrial dysfunction extends its impact to other organelles such as lysosomes, the endoplasmic reticulum (ER), and the nucleus, resulting in impaired organelle crosstalk, epigenetic modifications, and genomic instability. Plastic additives and adsorbed pollutants exacerbate these effects, further destabilizing cellular homeostasis and contributing to systemic pathologies encompassing metabolic disorders, neurodegeneration, cardiovascular dysfunction, and reproductive toxicity. This review synthesizes current mechanistic insights into the pathways mediating MNPs-induced mitochondrial and organelle dysfunction, emphasizing the critical role of disrupted mitochondrial dynamics, ER stress, and bioenergetic failure. Therapeutic strategies focusing on mitochondria-targeted antioxidants, ER stress modulators, and autophagy regulators show promise but require validation under environmentally relevant conditions. Addressing notable research gaps such as polymer diversity, chronic low-dose exposure, and co-contaminant effects through integrative, multi-disciplinary approaches will enhance understanding of long-term health impacts and inform effective mitigation strategies against the pervasive threat of MNPs pollution.
    Keywords:  Cellular stress; Inter organelle cross talk; MNPs; Mitochondrial dynamics; Oxidative stress; Toxicity
    DOI:  https://doi.org/10.1016/j.tox.2025.154306
  25. Environ Sci Technol. 2025 Oct 17.
    Bisphenol A Disrupts Spermatogenesis via Excessive Mitophagy-Driven Ferroptosis.
    Yi Zhou, Hongwei Duan, Xiangguo Wang, Xihui Sheng, Xiaolong Qi, Bingying Liu, Xingyi Chen, Zihao Fang, Weitao Dong, Longfei Xiao.
      BPA is a globally ubiquitous industrial compound that harms male reproductive health by causing abnormal sperm development and subsequent spermatogonia loss, yet the underlying mechanisms of BPA-induced spermatogenesis disorder remain unclear. Here, we explored BPA's effects on adolescent male mice and GC-1 cells by gavaging mice with BPA at doses of 20, 200, or 2000 μg/kg/d for 4 weeks and treating GC-1 cells with 10 μM BPA for 12 h to establish a damage model. The results revealed that BPA induced spermatogenesis disorder via ferroptosis, which was associated with the activation of excessive mitophagy. RNA-seq analysis elucidated that upregulated BCAT1 plays a key role in this process. Specifically, downregulation of BCAT1 alleviated BPA-induced mitophagy, whereas overexpression of BCAT1 exacerbated these effects. Moreover, the occurrence of BPA-induced spermatogenesis disorder is regulated by the binding of PINK1 via targeting SER227 to BCAT1. Additionally, quercetin, a potential BCAT1 ligand, reduced BCAT1 expression and mitigated BPA-induced mitophagy and ferroptosis both in vitro and in vivo. In summary, our results reveal that quercetin effectively inhibits BPA-induced mitophagy activation, thereby reducing ferroptosis in spermatogonia cells. This study highlights BCAT1 as a potential therapeutic target and provides novel insights into BPA-induced testicular toxicity and therapeutic strategy development.
    Keywords:  BCAT1; bisphenol A; ferroptosis; mitophagy; spermatogenesis disorder
    DOI:  https://doi.org/10.1021/acs.est.5c06718
  26. J Adv Res. 2025 Oct 10. pii: S2090-1232(25)00764-7. [Epub ahead of print]
    MK8722 alleviates osteoarthritis by activating Sesn2 and transcriptionally upregulating BNIP3 to promote mitophagy and inhibit chondrocyte ferroptosis.
    Haochen Wang, Ze Zhao, Jianbang Su, Wenzheng Chen, Haoyan Shi, Tianqi Gao, Minghao Yu, Lunhao Bai, Peng Dong, Qian Zhang, Chao Ji, Jingyu Yang, Yang Liu, Yingliang Wei.
       INTRODUCTION: Osteoarthritis (OA) is commonly accompanied by irreversible destruction of articular cartilage and is difficult to effectively relieve, primarily due to the unclear pathogenesis and the lack of effective therapeutic interventions. Sestrin 2 (Sesn2) is a highly conserved protein that regulates oxidative stress and cellular metabolism; however, its impact on the progression of OA and the detailed mechanisms underlying this process have not been elucidated.
    OBJECTIVES: To investigate the critical role of Sesn2 in OA cartilage degradation and to clarify the underlying mechanism by which MK8722 promotes mitophagy and inhibits chondrocyte ferroptosis through the activation of Sesn2.
    METHODS: We utilized multi-omics data from both human and mouse models to investigate a potential association between Sesn2 and chondrocyte ferroptosis. We established a murine OA model through destabilization of the medial meniscus surgery. Various molecular biological techniques, including western blot, immunofluorescence and flow cytometry, in combination with histological analyses, were employed to elucidate the pivotal role of Sesn2 in the progression of OA.
    RESULTS: Sesn2 expression is decreased in OA articular cartilage, and Sesn2 is a key gene regulating chondrocyte ferroptosis. Intra-articular injection of adeno-associated virus overexpressed Sesn2 in chondrocytes to alleviate OA cartilage damage by inhibiting ferroptosis. In addition, we identified a drug that activates Sesn2, MK8722, which inhibits chondrocyte senescence and ferroptosis by promoting mitophagy to alleviate cartilage destruction. MK8722 activates Sesn2 and transcriptionally upregulates bcl-2 interacting protein 3 (BNIP3), promoting nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression, and then promoting mitophagy. Upregulation of mitophagy subsequently reduces cellular oxidative stress and ferroptosis, thereby alleviating OA cartilage degeneration.
    CONCLUSION: This study underscores the role of Sesn2 as a novel protein that maintains chondrocyte metabolic homeostasis and redox balance, and demonstrates that MK8722, which activates Sesn2, may serve as a promising therapeutic approach for OA.
    Keywords:  BNIP3; Ferroptosis; MK8722; Mitophagy; Osteoarthritis; Sesn2
    DOI:  https://doi.org/10.1016/j.jare.2025.09.060
  27. Curr Opin Clin Nutr Metab Care. 2025 Oct 06.
    The mitochondrial side of frailty.
    Emanuele Marzetti, Rosa Di Lorenzo, Anna Picca.
       PURPOSE OF REVIEW: Frailty, a prevalent geriatric condition marked by reduced physiological reserve and greater vulnerability to stressors, is increasingly linked to mitochondrial dysfunction. This review summarizes current evidence on mitochondrial quality control, bioenergetics, and signaling in frailty, with emphasis on biomarker discovery and translational potential.
    RECENT FINDINGS: Preclinical and human studies have shown that impaired mitochondrial biogenesis, altered dynamics, and defective mitophagy contribute to frailty, sarcopenia, and immune dysregulation. Frail older adults exhibit reduced mitochondrial DNA content, diminished mitochondrial respiratory capacity, elevated reactive oxygen species generation, and distinctive metabolomic changes. Potential biomarkers include mitochondria-derived vesicles, circulating metabolites, and measures of peripheral blood mononuclear cell respiration, which may enable early detection of functional decline. Multivariate profiling approaches have identified sex-specific and shared molecular signatures converging on mitochondrial pathways. Interventions promoting mitochondrial health, including resistance training and targeted immunomodulation, hold promise in slowing frailty progression.
    SUMMARY: Mitochondrial dysfunction lies at the intersection of musculoskeletal, metabolic, and immune changes underpinning frailty. While integrative biomarker panels have defined metabolic signatures, early diagnosis and personalized therapies remain unmet needs. Longitudinal studies are required to establish causality, refine biomarker utility, and guide precision medicine strategies to preserve mitochondrial function, extend healthspan, and improve quality of life in aging populations.
    Keywords:  inflammaging; metabolic dysregulation; mitochondrial quality control; oxidative capacity; physical frailty
    DOI:  https://doi.org/10.1097/MCO.0000000000001175
  28. J Ethnopharmacol. 2025 Oct 13. pii: S0378-8741(25)01428-X. [Epub ahead of print]355(Pt B): 120736
    Quercetin ameliorates diminished ovarian reserve via modulating intestinal BNIP3/dct-1-mediated mitophagy and subsequently activating the ovarian TGF-β signaling pathway.
    Xian Xiao, Mian Zheng, Ying Zhao, Kaili Huang, Yuqing Shi, Yibo Ren, Linlin Chen, Jia Sun, Ran Ye, Zihui Zheng, Qinli Ruan.
       ETHNOPHARMACOLOGICAL RELEVANCE: Diminished ovarian reserve (DOR) is one of the most important reasons for decreasing fertility. Quercetin, a phytochemical, widely exists in food and natural Chinese herbs and can increase female fertility. However, how the phytochemical improves fertility through increasing ovarian reserve remains unclear.
    AIM OF STUDY: The study aims to investigated how quercetin improve ovarian reserve through improving intestinal mitophagy in a DOR mouse and C. elegans model.
    METHODS: Tripterygium glycoside/triptolide (TP) were used to establish DOR model in mice and C. elegans. Brood size was used to evaluate fertility of worms. Oogenesis in worms and proportion of follicles in mice were used to evaluate oocyte reserve. Loss-of-functional mutants and fluorescent protein transgene strains were used to evaluate gene function. PCR and RNAi were used to detect gene or protein function. Tissue-specific RNAi knockdown worms and intestine-specific AAV-Bnip3-RNAi knockdown mice were used to study the signaling transduction from intestine to gonad.
    RESULTS: Quercetin enhanced the fertility in DOR worms by improving the oogenesis, and improved the development and quality of follicles in DOR mice. Quercetin restored mitochondrial function through reducing of mitochondrial-reactive oxygen species (ROS), restoring mitochondrial membrane potential, and enhancing mitophagy in DOR worms. Quercetin increased ovarian reserve in the DOR worms via cooperation of mitophagy downstream dct-1 in gonad and intestine, while also amelioraing intestinal permeability through intestinal dct-1. Notably, dct-1 activation in intestine facilitated the TGF-β signaling pathway in the gonad of DOR worms, which was confirmed in DOR mice. Furthermore, quercetin alleviated intestinal tissue damage by longer villi via BNIP3 (the ortholog of dct-1) in DOR mice. Quercetin upregulated the protein expression of BNIP3 in both the intestine and ovary, and of HIVEP2 (the ortholog of sma-9) in the ovary of DOR mice. Meanwhile, intestine-specific BNIP3 knockdown inhibited the quercetin-induced beneficial effects and HIVEP2 expression in ovary in the DOR mice.
    CONCLUSIONS: Quercetin improved the ovarian reserve through enhancing intestinal BNIP3/dct-1-mediated mitophagy, ameliorating intestinal permeability, and improving ovarian TGF-β signaling pathway.
    Keywords:  Diminished ovarian reserve; Mitophagy; Quercetin; TGF-β
    DOI:  https://doi.org/10.1016/j.jep.2025.120736
  29. EMBO Mol Med. 2025 Oct 15.
    Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.
    Ang Li, Sen Huang, Shu-Qin Cao, Jinyi Lin, Linping Zhao, Feng Yu, Miaodan Huang, Lele Yang, Jiaqi Xin, Jing Wen, Lingli Yan, Ke Zhang, Maoyuan Jiang, Weidong Le, Peng Li, Yong U Liu, Dajiang Qin, Jiahong Lu, Guang Lu, Hanming Shen, Xiaoli Yao, Evandro F Fang, Huanxing Su.
      Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.
    Keywords:  Amyotrophic Lateral Sclerosis; Drug Screening; Isoginkgetin; Mitophagy; PINK1-Parkin
    DOI:  https://doi.org/10.1038/s44321-025-00323-2
  30. Phytomedicine. 2025 Oct 11. pii: S0944-7113(25)01040-2. [Epub ahead of print]148 157402
    Lithospermic acid alleviates myocardial ischemia/reperfusion injury by inhibiting mitophagy via the Piezo1-PPP3/calcineurin-TFEB pathway.
    Xin Chen, Honglin Xu, Zhongyang Yu, Shujin Pang, Ruixue Chen, Shangfei Luo, Xianmei Pan, Rentao Wan, Youfen Yao, Xiaoting Chen, Qiaorui Tan, Bin He, Yajuan An, Lingjun Wang, Yining Guo, Jing Li.
       INTRODUCTION: Myocardial ischemia/reperfusion injury poses a human health threat, and lithospermic acid (LA) has shown potential as a therapeutic agent.
    OBJECTIVES: To investigate the preventive effects of LA and elucidate its modulation of Piezo-Type Mechanosensitive Ion Channel Component 1 .
    METHODS: Cardiac function was evaluated using cardiac ultrasound, Evans blue/TTC staining, and hematoxylin-eosin staining. To evaluate the effects of LA on cardiomyocyte inflammation, necroptosis, and mitophagy, we performed immunofluorescence, Western blotting, flow cytometry, and RT-qPCR. Additionally, RNA sequencing, cellular thermal shift assay, small molecule agonists/inhibitors, and cardiomyocyte-specific Piezo1 knockout mice were employed to further elucidate the molecular mechanisms and confirm that LA targeted Piezo1 to alleviate myocardial I/R injury.
    RESULTS: LA treatment markedly ameliorated myocardial I/R injury. This improvement correlated with reduced inflammation, decreased accumulation of reactive oxygen species, attenuated cardiomyocyte necroptosis, and inhibited mitophagy. Mechanistically, LA reduced calcium influx and inhibited mitophagy in cardiomyocytes, which contributed to the observed alleviation of inflammation, lower ROS levels, and decreased cell necrosis. Further studies revealed that LA targeted Piezo1, suppressing calcium influx, decreasing calcineurin activity, and modulating nuclear translocation of transcription factor EB to inhibit mitophagy. Notably, the beneficial effects of LA on myocardial I/R injury were partially abolished in Piezo1 cardiomyocyte-specific knockout mice, underscoring the crucial role of Piezo1 in mediating the therapeutic effects of LA.
    CONCLUSION: These findings highlight LA is a prospective therapeutic agent to improve cardiac function after myocardial I/R injury, offering a new direction for regulating Piezo1.
    Keywords:  Lithospermic acid; Mitophagy; Myocardial ischemia/reperfusion injury; Piezo1; TFEB
    DOI:  https://doi.org/10.1016/j.phymed.2025.157402
  31. Int J Cardiol. 2025 Oct 15. pii: S0167-5273(25)01010-1. [Epub ahead of print] 133967
    Clinical significance of mitochondrial dynamics-related miRNAs in the superacute phase of acute heart failure in patients presenting to the emergency department.
    Akihiro Shirakabe, Yoshiyuki Ikeda, Yoshihiro Uchikado, Hirotake Okazaki, Masato Matsushita, Tomofumi Sawatani, Shota Shigihara, Kenichi Tani, Masaki Morooka, Nobuaki Kobayashi, Mitsuru Oishi, Junichi Sadoshima, Kuniya Asai.
       BACKGROUND: Mitochondria are dynamic organelles whose morphology can change through fusion and fission. The role of these mitochondrial dynamics in cardiomyocytes has not been evaluated in patients with acute heart failure (AHF).
    METHODS AND RESULTS: Two hundred seventy-three AHF patients and 374 control patients who attended a cardiovascular outpatient clinic were prospectively analyzed. Blood samples were collected within 15 min of admission from AHF patients (AHF group) and control patients who visited a daily cardiovascular outpatient clinic (control group). Mitochondrial dynamics-related RNAs were compared between the two groups, and long-term prognosis (1000-day mortality) was evaluated across RNA quartiles. The miR-140-3p and miR-485-3p levels in the AHF group (median 6.73, range 2.75-14.55; median 0.45, range 0.13-1.86) were significantly (p = 0.002 and p = 0.049) lower than those in the control group (median 8.61, range 3.37-34.12; median 0.78, range 0.15-3.52), respectively. Cardiac biomarkers, including N-terminal pro-BNP, heart-type fatty acid-binding protein, and high-sensitivity troponin, were significantly higher in the low-miR-140-3p group than in the middle- and high-miR-140-3p groups. Kaplan-Meier curve analysis revealed that all-cause mortality within 1000 days was significantly higher in the low-140-3p group than in the middle- and high-miR-140-3p groups. Cox regression analysis revealed that the low-140-3p group was an independent predictor of 1000-day mortality (hazard ratio 1.567; 95 % confidence interval 1.004-2.444; p = 0.048).
    CONCLUSION: Impaired mitochondrial dynamics were observed in the acute phase of AHF. In particular, a mitochondrial fission-related miRNA (miR-140-3p) was independently associated with adverse outcomes.
    Keywords:  Heart failure; Mitochondrial dynamics; Mortality; miRNA
    DOI:  https://doi.org/10.1016/j.ijcard.2025.133967
  32. J Nanobiotechnology. 2025 Oct 11. 23(1): 662
    Spontaneous hydrogen-releasing nanoenzyme alleviates osteoarthritis via oxidative stress reduction and mitochondrial dysfunction reversal.
    Qi Wang, Minyi Zhang, Weihao Jiang, Dejian Li, Beijie Qi, Shi Shi, Shuo Shi, Chengqing Yi.
      Osteoarthritis (OA), a chronic and degenerative joint disease, has become increasingly prevalent due to the aging population, posing a significant societal burden. However, despite progress, effective therapeutic options for osteoarthritis remain limited. In OA, chronic inflammation mediates a hypoxic microenvironment, leading to increased cellular energy demands. Over time, this causes mitochondrial dysfunction, favoring the accumulation of ROS, thereby perpetuating inflammation. Furthermore, reduced autophagy in aging chondrocytes hinder the clearance of damaged mitochondria, exacerbating oxidative stress. Herein, we have developed a simple and environmentally friendly strategy to fabricate hydrogen-releasing nanozymes (Se-HMPB@AB@COS) that spontaneously release hydrogen gas, effectively treating osteoarthritis through antioxidant, anti-inflammatory, and mitochondrial dysfunction reversal mechanisms. During the process of hydrogen therapy, small hydrogen molecules can readily penetrate mitochondria, specifically reducing the levels of •OH thereby protecting mitochondrial function. Our research further unveils that hydrogen therapy can effectively enhance mitophagy and delay chondrocyte senescence. In vivo, Se-HMPB@AB@COS encapsulated with chondroitin sulfate significantly promotes the synthesis of collagen II, inhibits the degradation of extracellular matrix, and reduces inflammatory factors. Overall, this study innovatively synthesized a hydrogen-releasing nanozyme, demonstrating its effectiveness in inhibiting oxidative stress, inflammation, promoting mitophagy and extracellular matrix synthesis, thereby reducing cartilage and mitochondrial damage, and delaying OA progression.
    Keywords:  Hydrogen therapy; Mitophagy; Nanozyme; Osteoarthritis; Prussian blue
    DOI:  https://doi.org/10.1186/s12951-025-03716-0
  33. Front Vet Sci. 2025 ;12 1646921
    Chronic stress-induced downregulation of MFN1 contributes to fatty liver in chickens.
    Ke Zhang, Hui Yu, Huimin Chen, Ziting Guan, Xiaoyu Wang, Jie Liu, Mindie Zhao, Ruqian Zhao, Dancheng Yang, Lei Wu.
       Background: Chronic stress is a major contributor to Fatty Liver Syndrome (FLS) in fast-growing broilers, leading to physiological dysfunctions that compromise growth and immune response. This study aimed to investigate the effects of chronic stress on hepatic lipid metabolism and mitochondrial dynamics in broilers.
    Method: Forty 1-day-old male AA broilers were randomly allocated into two groups (n = 20): control (CON) and corticosterone-treated (CORT). From day 38, the CORT group received twice-daily subcutaneous injections of CORT (4 mg/kg/day) for 7 days to simulate in vivo chronic stress model. The loss-of-function approaches in cell culture models were also applied to investigate the role of MFN1 in CORT-induced mitochondrial dysfunction.
    Results: Chronic CORT treatment induced significant hepatic steatosis and liver injury in broilers. Furthermore, CORT disrupted mitochondrial function, as indicated by excessive mitochondrial fragmentation, a pronounced decrease in mitochondrial membrane potential (MMP), and aberrant oxidative stress responses in both in vivo and in vitro models. Studies showed that glucocorticoid receptor (GR)-mediated downregulation of mitofusin 1 (MFN1) plays a critical role in CORT-induced disruption of lipid metabolism. Importantly, restoration of MFN1 expression effectively rescued mitochondrial morphology and function and attenuated lipid accumulation in hepatocytes.
    Conclusion: This study reveals a key mechanism by which chronic stress impairs mitochondrial fusion via GR-mediated suppression of MFN1, driving fatty liver development in broilers. These findings underscore the critical role of MFN1 in mitochondrial dynamics and lipid metabolism, offering novel insights for potential therapeutic strategies against fatty liver disease in poultry.
    Keywords:  chronic stress; glucocorticoid; glucocorticoid receptor; mitochondrial fusion; mitofusin 1
    DOI:  https://doi.org/10.3389/fvets.2025.1646921
  34. Phytomedicine. 2025 Sep 19. pii: S0944-7113(25)00922-5. [Epub ahead of print]148 157283
    Ailanthone targets mitophagy-loaded SIRT4 to facilitate the deacetylation of HIF1α, triggering oxidative stress for gastric carcinoma treatment.
    Xiaolei Lian, Mengge Dai, Xiangyu Xu, Huijun Zhao, Shaotong Li, Xianzhi Liu, Yajun Lian, Ting Ma, Xiaolei Lian.
       BACKGROUND: Gastric carcinoma poses a major global threat to human health, highlighting an urgent need for effective clinical therapies. Ailanthone (AIL) is the main active component of Ailanthus altissima and has shown antitumour effects in different cancer types, including gastric cancer. However, the molecular mechanisms underlying its anti-gastric cancer activity remain unclear.
    PURPOSE: The research aimed to explore the efficacy and underlying molecular mechanisms of AIL in treating gastric carcinoma.
    METHODS: The anti-proliferative effects of AIL on gastric cancer cells were evaluated using MTT, colony formation, and EdU incorporation assays. Transcriptomics was conducted to explore potential targets and signalling pathways. Western blotting, flow cytometry, single cell gel electrophoresis, glutathione and malondialdehyde assays, immunofluorescence staining, and siRNA transfection were employed to elucidate regulatory mechanisms of AIL on reactive oxygen species (ROS) production and cell apoptosis. Moreover, transmission electron microscopy (TEM), mitochondria isolation, and co-immunoprecipitation (Co-IP) assay were applied to detect mitophagy. Finally, the xenograft mice bearing MGC-803 cells were employed to detect the effects of AIL on tumour growth in vivo.
    RESULTS: AIL significantly suppressed gastric cancer cell proliferation. Transcriptomics analysis revealed that AIL markedly disrupted the oxidative stress pathway, which triggered ROS accumulation-induced apoptosis. TEM results confirmed that AIL specifically inhibited mitophagy, causing mitophagy substrate deacetylase SIRT4 accumulation, which promoted transcription factor hypoxia-inducible factor-1 alpha (HIF1α) deacetylation and reduced its stability. Reduced HIF1α stability decreased antioxidant protein heme oxygenase 1 (HO-1) expression, which boosted ROS levels. SIRT4 knockdown restored HIF1α acetylation. Further, AIL inhibited tumour growth in xenograft mice bearing MGC-803 cells, while exhibiting low toxicity.
    CONCLUSIONS: Our results revealed that AIL targeted mitophagy-loaded SIRT4 to regulate redox homeostasis, inducing mitochondrial dysfunction-mediated cell apoptosis and inhibiting gastric cancer growth. These findings provide strong evidence for the potential clinical use of AIL in gastric cancer treatment.
    Keywords:  Ailanthone; Deacetylation; Gastric cancer; HIF1α; Mitophagy; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.phymed.2025.157283
  35. J Cell Mol Med. 2025 Oct;29(19): e70795
    Repurposing Doxycycline to Overcome High-Glucose-Induced Mitochondrial Biogenesis-Mediated Chemoresistance in Colorectal Cancer Cells.
    Chang-Han Wu, Ching-Wen Huang, Yen-Cheng Chen, Kwan-Ling Yip, Zhi-Feng Miao, Wei-Chih Su, Tsung-Kun Chang, Hsiang-Lin Tsai, Yung-Sung Yeh, Hsiao-Sheng Liu, Jaw-Yuan Wang.
      Chemoresistance is a major contributor to treatment failure in most patients with cancer. Hyperglycaemia enhances chemoresistance in stage III colorectal cancer (CRC) patients, potentially through a mechanism involving c-Myc. Phospho-PGC-1α (p-PGC-1α), a transcription coactivator, regulates energy metabolism with c-Myc and is a key regulator of mitochondrial biogenesis. We hypothesised that high glucose (HG) promotes mitochondrial biogenesis by upregulating c-Myc and p-PGC-1α, thus enhancing chemoresistance in CRC cells, and that inhibiting mitochondrial biogenesis alleviates this chemoresistance. In vitro, HG significantly increased mitochondrial mass (p < 0.001), oxygen consumption rate (p < 0.001), cell migration (p < 0.05) and oxaliplatin resistance (p < 0.001) in LoVo and HCT116 cells. p-PGC-1α and COX4 protein expression were increased in the HG and oxaliplatin-resistance groups in LoVo and HCT116 cells (all p < 0.001) and decreased in the doxycycline group (p < 0.001). In vivo, doxycycline combined with oxaliplatin more notably reduced tumour volume than oxaliplatin alone in hyperglycaemic BALB/c nude mice (p < 0.05). c-Myc, p-PGC-1α and COX4 protein expression were significantly higher in tissues with CRC and hyperglycaemia who experienced relapse than in those with CRC and normoglycaemia who did not experience relapse (all p < 0.05). Overall, this study demonstrated that HG upregulates p-PGC-1α and COX4 expression to enhance oxaliplatin resistance by promoting mitochondrial biogenesis and indicates that doxycycline can overcome the chemoresistance induced by HG. Repurposing of doxycycline might reduce chemoresistance in hyperglycaemic CRC patients receiving adjuvant chemotherapy.
    Keywords:  chemoresistance; doxycycline repurpose; hyperglycaemia; mitochondrial biogenesis; p‐PGC‐1α overexpression
    DOI:  https://doi.org/10.1111/jcmm.70795
  36. BMC Cancer. 2025 Oct 14. 25(1): 1561
    SLIT2 modulates NMIIA to regulate mitophagy and suppress hepatocellular carcinoma progression.
    Yong Qin, Junbin Zhou, Shimiao Li, Xiaofeng Liu, Shengqian Xu.
      Hepatocellular carcinoma (HCC) is characterized by aggressive progression and metastasis, driven by complex molecular interactions. This study elucidates the functional roles of slit guidance ligand 2 (SLIT2) and non-muscle myosin IIA (NMIIA) in HCC and explores their mechanistic interplay. Immunofluorescence and quantitative PCR (Q-PCR) analyses demonstrated significant downregulation of SLIT2 and upregulation of NMIIA in HCC tissues, with SLIT2 expression inversely correlating with tumor stage and metastatic propensity, as validated by The Cancer Genome Atlas (TCGA) dataset. Functional assays revealed that SLIT2 overexpression attenuated HCC cell proliferation, migration, and invasion, whereas NMIIA overexpression markedly enhanced these oncogenic properties. Mechanistically, NMIIA facilitated epithelial-mesenchymal transition (EMT) and mitophagy, potentiating tumor progression. Conversely, SLIT2 overexpression inhibited myosin regulatory light chain (MRLC) phosphorylation, thereby suppressing NMIIA activity, EMT, and mitophagy. SLIT2 also diminished cell adhesion, while NMIIA enhanced adhesion and colony-forming capacity. In vivo xenograft studies corroborated that SLIT2 depletion accelerated tumor growth. These findings establish the SLIT2/NMIIA axis as a critical modulator of HCC progression and a promising therapeutic target.
    Keywords:  Epithelial-mesenchymal transition; Hepatocellular carcinoma; Mitophagy; Non-muscle myosin IIA; Slit guidance ligand 2
    DOI:  https://doi.org/10.1186/s12885-025-14951-x
  37. Mol Cell Biol. 2025 Oct 17. 1-27
    From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
    Phoebe J Leeming, Julia Mercuri-Svik, Diana Stojanovski.
      Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.
    Keywords:  Mitochondria; mitochondrial disease; protein import; protein quality control
    DOI:  https://doi.org/10.1080/10985549.2025.2566671
  38. Biomed Rep. 2025 Dec;23(6): 184
    VDAC1: The mitochondrial gatekeeper in the battle against hearing loss (Review).
    Zhong-Jia Ding, Yin Wang.
      The development of hearing loss is strongly associated with mitochondrial damage, particularly downstream of mitochondrial autophagy, which is a process that is coincidentally key for selectively removing damaged mitochondria. Voltage-dependent anion channel 1 (VDAC1) is an important protein in the mitochondrial outer membrane that regulates various essential biological processes, including energy metabolism, calcium ion transport and cell apoptosis. VDAC1 can bidirectionally regulate cell fate, where its oligomerization can exacerbate oxidative stress, leading to cell damage and even death. By contrast, its ubiquitination supports cell survival by regulating mitochondrial autophagy, thereby improving mitochondrial quality control. VDAC1 can significantly contribute to the prevention and management of hearing loss. The present review summarizes how the ubiquitination and oligomerization modifications of VDAC1 can balance cell survival and death, while also exploring current hypotheses on mechanisms associated with hearing loss. These findings emphasize the research prospects of VDAC1 as a novel target for hearing loss treatment.
    Keywords:  cell apoptosis; hearing loss; mitochondrial autophagy; oxidative stress; voltage-dependent anion channel 1
    DOI:  https://doi.org/10.3892/br.2025.2062
  39. Leukemia. 2025 Oct 13.
    Publisher Correction: Suppression of Rho-associated kinase 1 (ROCK1) promotes human hematopoietic stem cell expansion by attenuating mitochondrial fission.
    Xuepeng Wang, Baskar Ramdas, Ramesh Kumar, Ji Zhang, Reuben Kapur.
      
    DOI:  https://doi.org/10.1038/s41375-025-02786-1
  40. Biochem J. 2025 Oct 10. pii: BCJ20243016. [Epub ahead of print]
    Lon/Pim1 mediated degradation of presequence translocase-associated motor components Pam16 and Pam18 in Saccharomyces cerevisiae.
    Yerranna Boggula, Arpan Chatterjee, Gaurav Simaiya, Amita Pal, Akash Srinivasan, Naresh Babu Sepuri.
      Mitochondrial protein homeostasis depends mainly on the efficient import and folding of nuclear-encoded proteins, and defects in this process can lead to proteotoxicity, which is harmful to the cell. Mitochondrial chaperones and proteases are essential defense mechanisms that ensure dysfunctional proteins' proper concentration, folding, and degradation. Lon protease 1 (Pim1 in yeast) is the mitochondrial matrix protease known to prevent protein aggregation by degrading unfolded proteins. Here, we show that two essential components of ATP-dependent presequence translocase and associated motor (PAM complex)- Pam18 and Pam16 are specifically targeted for degradation by the proteolytically active Lon/Pim1, both in vitro and in vivo. Further, overexpression of Pam18 and Pam16 exacerbates the growth defect of the delta pim1 strain. Hence, our study reveals, for the first time, that components involved in protein import are substrates of Pim1, which could have potential implications for regulating mitochondrial protein import and proteostasis.
    Keywords:  Lon/Pim1 protease; Mitochondria; Protein turnover; Proteolysis; Proteostasis; Saccharomyces cerevisiae; mitochondrial protein import; presequence translocase-associated motor
    DOI:  https://doi.org/10.1042/BCJ20243016
  41. Chem Biol Interact. 2025 Oct 13. pii: S0009-2797(25)00403-X. [Epub ahead of print] 111773
    Atraric acid activates the FoxO3a/PINK1/Parkin signaling pathway to suppress chronic intermittent hypoxia-induced cardiac oxidative stress, inflammatory responses, and NLRP3 inflammasome activation.
    Mengxin Li, Wanqi Wu, Boran Hu, Huizhen Chen, Jun Wang, Shasha Zhang, Tianyue Guan, Hujing Lu, Jiawen Zhou, Panpan Zhao, Yong Sun.
      Obstructive sleep apnea syndrome (OSAS)-induced cardiac injury is closely associated with chronic intermittent hypoxia (CIH), but its molecular mechanisms and potential intervention strategies require further exploration. Atraric acid (AA), a compound extracted from oakmoss, has garnered attention due to its anti-inflammatory and antioxidant properties. However, its protective effects on the cardioprotective effects in the context of CIH have not been systematically investigated. Through the establishment of CIH mouse models and H9C2 cell IH injury models, combined with histopathological analysis, mitochondrial function assessment, qPCR, immunofluorescence, and Western blot, the protective effects and molecular mechanisms of AA against CIH-induced myocardial injury were evaluated. Experimental groups included a control group, CIH group, and AA intervention groups with varying doses. AA treatment significantly alleviated CIH-induced cardiac damage, suppressed ROS accumulation, mitochondrial dysfunction, and oxidative stress, and activated Pink1/Parkin pathway-mediated mitophagy by promoting FoxO3a nuclear translocation. Meanwhile, AA inhibited NLRP3 inflammasome activation and inflammatory responses. The protective effects of AA were reversed by autophagy inhibition or ROS enhancement, suggesting an interaction mechanism between mitophagy and inflammation regulation. This study is the first to demonstrate that AA mitigates CIH-related myocardial injury by enhancing mitophagy via the FoxO3a-PINK1/Parkin pathway while synergistically suppressing oxidative stress and NLRP3 inflammasome activation. These findings provide novel therapeutic targets for OSAS-associated cardiac complications and establish a theoretical foundation for the clinical translation of AA, though further clinical validation is warranted.
    Keywords:  Chronic intermittent hypoxia; Inflammation; Myocardial injury; NLRP; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cbi.2025.111773
  42. Anticancer Agents Med Chem. 2025 Oct 10.
    The EP300-Targeting Drug CCS1477 Inhibits the Growth and Development of Diffuse Large B-Cell Lymphoma by Promoting Apoptosis and Mitophagy to Reduce Drug Resistance.
    Rujia Si, Yihan Zhang, Bowen Hu, Yuxin Du, Dan Zou, Shaodi Wen, Xiaoyue Du, Chen Peng, Xin Chen, Shulei Fu, Shiying Zhu, Fan Du, Xiaofeng Sha, Ning Ding, Cong Xu, Bo Shen.
       INTRODUCTION: Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) develop primary resistance or relapse, owing to the high heterogeneity and aggressive nature of the disease. Consequently, novel drugs are urgently needed to improve outcomes in patients who are resistant.
    METHODS: This study quantified the anti-proliferative effects of CCS1477 in vitro using the Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, and lactate dehydrogenase measurement. Flow cytometry and Western blot analyses were performed concurrently to investigate the induction of apoptosis and the activation of mitophagy. The efficacy and safety of CCS1477 were evaluated in in vivo models. To elucidate the mechanism, cell lines with EP300 knockdown and overexpression were established. Functional assays and Western blot analyses revealed that EP300 regulates apoptosis, mitophagy, and c-MYC-mediated drug-resistant phenotypes.
    RESULTS: This study demonstrated that CCS1477, a highly selective EP300/CBP bromodomain inhibitor, significantly suppressed the progression of diffuse large B-cell lymphoma. The study revealed that CCS1477 dosedependently inhibited the proliferation of diffuse large B-cell lymphoma cells and induced apoptosis and mitophagy. Mechanistically, EP300 downregulation promoted apoptosis and activated the PINK1-dependent mitophagy pathway while suppressing c-MYC-mediated drug resistance genes, ultimately inhibiting DLBCL cell proliferation. In animal models, CCS1477 significantly reduced tumor volume and extended doubling time, providing the first evidence of its in vivo antitumor activity against DLBCL.
    DISCUSSION: Through systematic in vitro and in vivo investigations, this study validated the significant therapeutic promise of EP300/CBP inhibitor CCS1477 for diffuse large B-cell lymphoma. However, the mechanistic basis for differential sensitivity across DLBCL subtypes, along with long-term efficacy and potential adverse effects, requires comprehensive investigation. Notably, EP300 has been verified as a novel prognostic biomarker and therapeutic target; this work establishes an innovative epigenetic-targeted strategy for relapsed/refractory diffuse large B-cell lymphoma.
    CONCLUSION: By selectively targeting EP300, CCS1477 orchestrates a dual pro-death mechanism involving both intrinsic apoptosis execution and PINK1-driven mitochondrial clearance, resulting in significant inhibition of diffuse large B-cell lymphoma pathogenesis.
    Keywords:  CCS1477; Diffuse large B-cell lymphoma; EP300; apoptosis; drug resistance.; mitophagy
    DOI:  https://doi.org/10.2174/0118715206430859250915050817
  43. Eur J Pharmacol. 2025 Oct 09. pii: S0014-2999(25)00987-2. [Epub ahead of print] 178233
    Exendin-4 improves mitochondrial integrity against cisplatin-induced cardiac damage: Targeting p53 and NF-κB pathways.
    Hnin Ei Ei Khine, Supachoke Mangmool, Warisara Parichatikanond.
      Heart failure is a devastating consequence of chemotherapy, with mitochondrial dysfunction playing a key role in cardiac damage. Cisplatin (CP), a widely used chemotherapeutic agent, induces cardiotoxicity by increasing apoptosis and triggering inflammation. This study provides evidence that exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) receptor agonist, exerts cardioprotective effects in H9c2 cardiomyoblasts against CP-induced injury. Ex-4 administration markedly restored mitochondrial bioenergetics, as evidenced by improved oxygen consumption and extracellular acidification rates, while preserving mitochondrial morphology and reversing fragmentation caused by CP. The observed effects were correlated with upregulation of markers involved in mitochondrial biogenesis (PGC1α, NRF1, ATP5A) and fusion process (OPA1, MFN1), accompanied by downregulation of mitochondrial fission markers (DNM1, FIS1). Ex-4 attenuated intracellular and mitochondrial reactive oxygen species (ROS) levels, suppressed caspase-3/7 activity, and shifted apoptotic balance by enhancing Bcl-2 levels while diminishing BAX expression. Moreover, Ex-4 suppressed CP-triggered inflammatory responses by reducing TNFα and IL6 levels. Mechanistically, Ex-4 activated pro-survival signals (p-Akt and p-Erk1/2) and exerted cardioprotective effects through inhibition of p53 and NF-κB-dependent cascades. Pharmacological inhibition of p53 (pifithrin-α) or NF-κB (JSH-23) further amplified the protective effect of Ex-4 against CP-induced mitochondrial abnormalities, apoptosis, and inflammation, whereas activation of p53 (nutlin-3) or NF-κB (NF-κB activator 1) reversed these protective outcomes. Thus, Ex-4 emerges as a potent modulator of mitochondrial dysfunction and cellular stress through suppression of the p53 and NF-κB pathways, offering a promising therapeutic approach to mitigate CP-induced cardiotoxicity.
    Keywords:  Cardiotoxicity; Cisplatin; Exendin-4; Mitochondrial dysfunction; NF-κB; p53
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178233
  44. J Nanobiotechnology. 2025 Oct 15. 23(1): 681
    A novel ligustrazine-based nanodelivery system protects against doxorubicin-induced cardiotoxicity by targeting the SIRT5-DUSP1 axis for mitochondrial repair.
    Hongshuo Shi, Boxian Pang, Fenglei Zhang, Zhijiang Guo, Wenshi Xu, Man Zheng, Yang You, Guobin Liu, Yifeng Nie, Jianxiao Liang, Xing Chang.
       BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) injury primarily contributes to anthracycline-associated end-stage cardiovascular mortality. Ligustrazine (LIG), a natural compound extracted from Ligusticum chuanxiong, a medicinal plant, has cardioprotective effects. However, therapeutic applications of LIG are limited owing to its poor water solubility, rapid degradation, and low bioavailability. These limitations can be overcome by encapsulating LIG into nanocarriers. We highlight the therapeutic potential of LIG drug delivery technology (LIG-Na) for DIC by integrating bioinformatics, single-cell sequencing, spatial transcriptomics, and transgenic animal models, and investigate the mechanisms underlying mitochondrial homeostasis (MQH).
    METHODS: We used bioinformatics to predict DIC-related mechanisms and established DOX-induced models using SIRT5/DUSP1/PHB2CKO mice and DUSP1 transgenic mice (SIRT5/DUSP1/PHB2TG). The pathological mechanisms of LIG-Na-mediated alleviation of cardiac injury were examined using echocardiography, WB, TEM, and fluorescence staining. In addition, mitochondrial functional and morphological changes were evaluated using qPCR, ELISA, and confocal laser scanning microscopy following si/adRNA-mediated silencing of SIRT5/DUSP1/PHB2 in cardiomyocytes to further assess the targeted therapeutic effects of LIG-Na.
    RESULTS: DOX treatment induced severe mitochondrial dysfunction, which was effectively normalized by LIG-Na. Although these protective effects were completely abolished in SIRT5/DUSP1/PHB2CKO mice, these remained unaffected in SIRT5/DUSP1/PHB2TG mice.
    CONCLUSION: LIG-Na ameliorated DOX-mediated cardiac dysfunction and MQH dysregulation through the SIRT5/DUSP1-PHB2S91 phosphorylation axis, thereby effectively suppressing mitochondrial dysfunction and mitigating DIC in mice.
    Keywords:  DUSP1; Doxorubicin-induced cardiotoxicity; Ligustrazine drug delivery technology; Mitochondrial quality homeostasis; SIRT5
    DOI:  https://doi.org/10.1186/s12951-025-03667-6
  45. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2415153122
    Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.
    Jeffrey T Mindrebo, Gabriel C Lander.
      AAA+ enzymes use energy from ATP hydrolysis to remodel diverse cellular targets. Structures of substrate-bound AAA+ complexes suggest that these enzymes employ a conserved hand-over-hand mechanism to thread substrates through their central pore. However, the fundamental aspects of the mechanisms governing motor function and substrate processing within specific AAA+ families remain unresolved. We used cryoelectron microscopy to structurally interrogate reaction intermediates from in vitro biochemical assays to inform the underlying regulatory mechanisms of the human mitochondrial AAA+ protease, LONP1. Our results demonstrate that substrate binding, rather than nucleotide binding, activates the assembly and allosterically regulates proteolytic activity. The N-terminal domain plays a critical role in this process and facilitates the initial stages of substrate selection and engagement. Moreover, structures of LONP1 actively degrading a substrate in the presence of ATP provide important context to the conventional understanding of the hand-over-hand translocation mechanism, suggesting that ATP hydrolysis is likely not limited to a single position in the right-handed spiral during the hand-over-hand translocation mechanism.
    Keywords:  AAA+ motors; ATP hydrolysis; LONP1; allostery; cryo-EM
    DOI:  https://doi.org/10.1073/pnas.2415153122
  46. FASEB J. 2025 Oct 31. 39(20): e71110
    MiR-20b-Overexpressed BMSC-Derived Exosomes Target SIRT1/BMP2 to Regulate Mitochondrial Autophagy and Osteogenesis in Osteoporosis.
    Zhe Wang, Fang Han, Ying Zheng, Jianwei Shen, Qiang Chen, Jian Feng, Xiangyi Sun, Yu Zhang, Zhihua Yang.
      Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts and promote osteogenesis (OP), and the miRNAs carried by BMSCs-derived exosomes (BMSC-Exo) regulate osteoblast differentiation in bone-related diseases. Additionally, abnormal mitochondrial autophagy in osteoblasts mediated by the SIRT1/PINK1/Parkin signaling axis affects differentiation and contributes to OP progression. Our preliminary study has demonstrated that miR-20b can target SIRT1 and osteogenic protein BMP2. The aim of the present study was to investigate the effect of BMSC-Exo harboring miR-20b to mediate the SIRT1/BMP2 in OP. Initially, through the successful isolation and characterization of BMSC-Exo in vitro, we co-cultured these exosomes with osteoblasts and observed a significant enhancement in osteoblast differentiation, alkaline phosphatase activity, and mineral accumulation. Subsequent cell transfection experiments revealed that miR-20b-overexpressed BMSC-Exo further augmented osteogenic differentiation of osteoblasts, whereas interference with BMP2 expression attenuated this pro-osteogenic effect. In a bilateral ovariectomised rat model of OP, we demonstrated that miR-20b-overexpressed BMSC-Exo treatment promoted bone formation and mitigated bone damage. Additionally, these exosomes restored mitochondrial membrane potential and autophagy, which were reversed by SIRT1 interference. Finally, osteoblasts isolated from OP model rats were used to further validate that miR-20b-overexpressed BMSC-Exo enhanced osteoblast differentiation and facilitated osteogenesis by activating SIRT1. These findings have collectively underscored the therapeutic potential of miR-20b-enriched BMSC-Exo in regard to OP treatment, providing a foundation for developing novel, targeted therapies for OP.
    Keywords:  SIRT1/BMP2; bone marrow mesenchymal stem cell; exosomes; miR‐20b; mitochondrial autophagy; osteoblast; osteoporosis
    DOI:  https://doi.org/10.1096/fj.202501050RR
  47. Sci Adv. 2025 Oct 17. 11(42): eadx8662
    Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
    Sofia La Vecchia, Saurav Doshi, Petros Antonoglou, Tanima Kundu, Wafa Al Santli, Kleopatra Avrampou, Matthew T Witkowski, Anna Pellattiero, Federico Magrin, Kristina Ames, Amit Verma, Kira Gritsman, Xiaoyang Su, Andrea Mattarei, Iannis Aifantis, Luca Scorrano, Christina Glytsou.
      Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.
    DOI:  https://doi.org/10.1126/sciadv.adx8662
  48. Free Radic Biol Med. 2025 Oct 12. pii: S0891-5849(25)01271-7. [Epub ahead of print]
    Interplay Between mTORC1 Signaling and Iron Homeostasis in Muscle Atrophy.
    Eunbin Jee, Walaa Ouf, Jonghan Kim, Yuho Kim.
      The mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in maintaining skeletal muscle homeostasis by regulating cell growth, protein degradation, and nutrient sensing. Beyond its role in muscle growth and atrophy, recent findings suggest that mTORC1 also regulates cellular iron metabolism. Although iron is essential for energy production and mitochondrial function in skeletal muscle, both iron deficiency and overload contribute to muscle degeneration through dysfunctional mitochondria, oxidative stress, and activation of catabolic pathways. In this review, while focusing on the role of mTORC1 in iron-dependent muscle disorders such as cancer cachexia, sarcopenia, and Duchenne muscle dystrophy, we explore how altered mTORC1 activity affects major protein degradation systems, including the ubiquitin-proteasome system, autophagy, and mitophagy, under iron imbalance in skeletal muscle. We also highlight the emerging evidence linking mTORC1 signaling to iron metabolism in skeletal muscle, with a focus on the regulation of iron transport, ferritinophagy, and the autophagosome-lysosome system. The crosstalk between mTORC1 and iron metabolism in muscle atrophy provides novel insights into the molecular mechanisms underlying muscle disorders. Collectively, these perspectives suggest new therapeutic strategies for treating muscle diseases associated with disrupted iron homeostasis and impaired mTORC1 signaling.
    Keywords:  Duchenne muscle dystrophy; autophagy; cachexia; iron deficiency; iron overload; mTORC1; mitophagy; sarcopenia; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.257
  49. Biochimie. 2025 Oct 15. pii: S0300-9084(25)00235-4. [Epub ahead of print]
    Targeting Autophagy via Mitochondrial Uncoupling: Discovery of Novel Serratin Derivative as a Potential Therapeutic for Parkinson's Disease.
    Alexander Yu Rudenko, Ekaterina А Guseva, Ratislav M Ozhiganov, Boris P Myasnikov, Maria V Belopolskaya, Olga V Fadeeva, Elena О Morgun, Olga A Averina, Elena A Tukhovskaya, Gulsara A Slashcheva, Igor A Dyachenko, Elena I Marusich, Mariia Mokhina, Rose-Lys Zaranaina, Yuriy A Ikhalaynen, Igor A Rodin, Ljudmila S Khailova, Yuri N Antonenko, Vladimir I Polshakov, Maxim L Lovat, Viktor G Kartsev, Arkady N Murashev, Petr V Sergiev.
      Autophagy, a highly conserved cellular degradation pathway, plays a critical role in maintaining cellular homeostasis across eukaryotes. Dysregulation of autophagy has been implicated in numerous diseases, including neurodegenerative disorders such as Parkinson's disease. Although natural compounds like urolithin A and its synthetic analogue serratin (AN2) have been shown to induce autophagy, their limited potency and safety profiles necessitate the development of improved alternatives. In this study, a library of 27 novel AN2 analogues was synthesized and screened for autophagy-inducing activity. Among them, ORA471 emerged as a lead compound, exhibiting superior autophagy and mitophagy activation compared to AN2, along with reduced cytotoxicity in human fibroblast (VA-13) and neuroblastoma (SH-SY5Y) cell lines. Mechanistic investigations revealed that ORA471 induces autophagy primarily via the AMPK/ULK1 signaling pathway and acts as a mitochondrial uncoupler, dissipating membrane potential and enhancing respiration in isolated rat liver mitochondria. In vivo, ORA471 demonstrated low toxicity in Caenorhabditis elegans, zebrafish (Danio rerio), and mice (maximum tolerated dose: 300 mg/kg). Notably, it significantly improved motor function in a zebrafish model of MPTP-induced Parkinson's disease without eliciting adverse effects. These findings highlight ORA471 as a promising therapeutic candidate for the treatment of autophagy-related disorders, particularly Parkinson's disease.
    Keywords:  Autophagy; Parkinson's disease; mitochondrial dysfunction; mitophagy; serratin
    DOI:  https://doi.org/10.1016/j.biochi.2025.10.011
  50. Front Nutr. 2025 ;12 1661778
    Human milk-derived 5'-UMP promotes thermogenesis and mitochondrial biogenesis to ameliorate obesity.
    Ling Zhang, Zhou Peng, Caiyu Lin, Haixia Hu, Juan Du, Siqi Huang, Shan Huang, Jianfang Gao, Xirong Guo.
       Background: Traditional obesity interventions are often unsuitable for children. Breastfeeding has been shown to reduce obesity risk, potentially through bioactive metabolites in human milk. Here, we identified a human milk-derived metabolite, uridine 5'-monophosphate (5'-UMP), whose role in lipid metabolism and thermogenesis remains largely unknown.
    Methods: Untargeted metabolomics was performed on colostrum samples from obese and healthy mothers to identify obesity-associated metabolites. Zebrafish larvae and human preadipocytes were used to evaluate the anti-obesity effects of 5'-UMP. Lipid accumulation was assessed by Oil Red O and Nile Red staining, while mitochondrial function was analyzed using transgenic zebrafish [Tg(Xla. Eef1a1: mlsEGFP)] and fluorescent imaging.
    Results: Pyrimidine metabolism was significantly enriched in obese mothers, with orotate and 5'-UMP levels altered. Targeted analysis confirmed the presence of 5'-UMP in colostrum. Zebrafish toxicity assays confirmed 5'-UMP safety up to 200 μM. In the high-fat diet-induced zebrafish obesity model, 5'-UMP treatment significantly reduced abdominal lipid accumulation. In adipocytes, 5'-UMP enhanced mitochondrial respiration and increased mRNA and protein expression of PGC1-α and UCP1. Furthermore, mitochondrial fluorescence intensity and protein levels of NRF1 and MFN2 were elevated, indicating enhanced mitochondrial biogenesis and activity.
    Conclusion: Maternal obesity is associated with changes in the human milk metabolome. 5'-UMP, a nucleotide metabolite enriched in human milk, promotes thermogenesis and mitochondrial activation, effectively ameliorating obesity in zebrafish and human adipocytes. These findings support its potential as a safe, milk-derived therapeutic candidate for pediatric obesity intervention.
    Keywords:  5′-UMP; childhoodobesity; human milk; maternal obesity; mitochondrial biogenesis; pyrimidine metabolism; thermogenesis
    DOI:  https://doi.org/10.3389/fnut.2025.1661778
  51. Exp Neurol. 2025 Oct 12. pii: S0014-4886(25)00367-X. [Epub ahead of print]395 115502
    Lasmiditan ameliorates cortico-hippocampal pathology and improves cognition in aging parkinsonian mice.
    Atsushi Ishii, Jasmine R Meredith, Mandi J Corenblum, Kelsey Bernard, Paige V Wene, Nainika Menakuru, Paul V Santiago, Rick G Schnellmann, Lalitha Madhavan.
      While the etiopathology of Parkinson's disease (PD) is complex, mitochondrial dysfunction is established to have a central role. Thus, mitochondria have emerged as targets of therapeutic interventions aiming to slow or modify PD progression. We have previously identified serotonergic 5-HT1F receptors as novel mediators of mitochondrial biogenesis (MB) - the process of producing new mitochondria. Given this, here, we assessed the therapeutic potential of the FDA-approved 5-HT1F receptor agonist, lasmiditan, in a chronic progressive PD model (Thy1-aSyn 'line 61' mice). It was observed that systemic lasmiditan exhibited robust brain penetration and reversed cognitive deficits in young (4-5.5 months old) Thy1-aSyn mice (1 mg/kg, every other day). Anxiety-like behavior was also improved while motor function remained unaffected. These behavioral changes were associated with enhanced MB and mitochondrial function and reduced alpha-synuclein aggregation particularly in cortico-hippocampal regions. In older (10-11.5 months old) mice, although the effects were milder, daily lasmiditan administration increased MB and bettered cognitive abilities. In essence, these findings indicate that repurposing lasmiditan could be a potential strategy to address PD-related cognitive decline.
    Keywords:  5-HT1F receptor; Aging; Lasmiditan; Mitochondria biogenesis; Parkinson's disease; Thy1-aSyn
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115502
  52. Int J Mol Sci. 2025 Sep 26. pii: 9442. [Epub ahead of print]26(19):
    Modulation of mTOR Within Retinal Pigment Epithelium Affects Cell Viability and Mitochondrial Pathology.
    Gloria Lazzeri, Michela Ferrucci, Paola Lenzi, Maria Anita Giambelluca, Francesca Biagioni, Carla Letizia Busceti, Alessandro Frati, Francesco Fornai.
      The relevance of well-structured mitochondria in sustaining the integrity of the retinal pigment epithelium (RPE) is increasingly evident. Conversely, altered mitochondria are a culprit of age-related macular degeneration (AMD), which is influenced by the activity of mechanistic target of rapamycin (mTOR). In the present manuscript, the mitochondrial status of RPE cells was investigated by light and electron microscopy following the administration of various doses of compounds, which modulate mTOR. The study combines MitoTracker dyes and mitochondrial immunohistochemistry with in situ mitochondrial morphometry. Various doses of 3-methyladenine (3-MA), curcumin, and rapamycin were administered alone or in combination. The activity of autophagy and mTOR was quantified following each treatment. Administration of 3-MA led to activation of mTOR, which was associated with severe cell death, altered membrane permeability, and altered ZO-1 expression. In this condition, mitochondrial mass was reduced, despite a dramatic increase in damaged mitochondria being reported. The decrease in healthy mitochondria was concomitant with alterations in key mitochondria-related antigens such as Tomm20, Pink1, and Parkin. Specific mitochondrial alterations were quantified through in situ ultrastructural morphometry. Both curcumin and rapamycin counteract mTOR activation and rescue mitochondrial status, while preventing RPE cell loss and misplacement of decreased ZO-1 expression. Mitigation of mTOR may protect mitochondria in retinal degeneration.
    Keywords:  MitoTracker Green; MitoTracker Red; PINK1; Parkin; Tomm20; ZO-1; autophagy; curcumin; mitochondrial morphology; mitochondrial ultrastructure; rapamycin
    DOI:  https://doi.org/10.3390/ijms26199442
  53. Autophagy. 2025 Oct 15. 1-3
    Novel links of ATG4 proteases to cytoskeletal adapters of the obscurin protein family.
    Virginia Actis Dato, Kyohei Fujita, Stephan Lange.
      The obscurin family, containing the giant protein OBSCN (obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF) and its closely related OBSL1 (obscurin like cytoskeletal adaptor 1) as well as SPEG (striated muscle enriched protein kinase) are a group of intracellular proteins that contain serially linked immunoglobulin (Ig) and fibronectin type III (Fn3) domains, along with signaling modules such as protein kinase domains. Hence, obscurins harbor multi-faceted roles for the architecture and organization of cell- and organelle membrane proteins. Besides mediating cellular signaling and promoting protein homeostasis, obscurin proteins are also proposed to act as versatile cytoskeletal linkers. Due to their close homology, many functions for OBSCN are evolutionary conserved in OBSL1 and SPEG. However, their expression patterns differ widely, with OBSL1 being ubiquitously expressed in all cell types, while OBSCN and SPEG are more restricted to cross-striated muscles. Recent evidence indicates that autophagy-linked peptidases of the ATG4 family interact with the cytoskeletal adapter proteins OBSL1 and OBSCN. Peptidases of the ATG4 family process Atg8-family proteins (e.g. LC3) in their immature state (i.e. as pro-peptides like pro-LC3) or their bioactive lipidated state (i.e. LC3-II) and facilitate their conversion to the delipidated state (i.e. LC3-I). Loss of interaction between ATG4 peptidases and obscurin family proteins affects cellular macroautophagy/autophagy and mitophagy, leading in situations of cellular stress to depletion of ATG4 and accumulation of the lipidated state for Atg8-family proteins (e.g. LC3-II).
    Keywords:  ATG4; ATG8; OBSCN; OBSL1; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2572530
  54. FEBS Lett. 2025 Oct 13.
    KIF5A upregulation by FAK-mediated downregulation of epigenetic modifiers promotes mitochondrial dynamics in neuronal differentiation.
    Soumen Manna, R Kirtana, Jagdish Mishra, Samir Kumar Patra.
      Neuronal differentiation depends on mitochondrial transport and networking toward the developing axon and dendrites. Herein, we report that the motor protein kinesin family member 5A (KIF5A) is essential for neuronal maturation through regulation of mitochondrial structure and dynamics. Focal adhesion kinase (FAK) signaling promotes differentiation through enhanced expression of KIF5A and downregulation of epigenetic modifiers, DNMT1 and KDM5A. FAK activity is phosphorylation-dependent to facilitate neuronal differentiation by KIF5A and repression of DNMT1 and KDM5A. This is the first report showing that FAK signaling controls epigenetic regulation of motor proteins by downregulation of epigenetic modifiers. Thus, molecular mechanisms for neurodevelopment and plausible therapeutic targets against neurodegenerative disorders are explored in this article.
    Keywords:  DNMT1 and KDM5A; FAK signaling; KIF5A; mitochondria; neuronal differentiation
    DOI:  https://doi.org/10.1002/1873-3468.70177
  55. Int J Mol Sci. 2025 Oct 09. pii: 9826. [Epub ahead of print]26(19):
    Oxidative Stress, Mitochondrial Quality Control, Autophagy, and Sirtuins in Heart Failure.
    Jan Krekora, Marcin Derwich, Jarosław Drożdż, Elzbieta Pawlowska, Janusz Blasiak.
      Heart failure (HF) has become an emerging problem, especially in regions where life expectancy is increasing. Despite its prevalence, the mechanisms behind HF development are not well understood, which is reflected in the lack of curative therapies. Mitochondria, autophagy, and sirtuins form a crucial triad involved in HF pathogenesis, interconnected by oxidative stress. Identifying a common pathway involving these three components could be valuable in developing new treatment strategies. Since HF is the end result of several cardiovascular diseases, this review highlights the main HF precursors and explores the roles of mitochondrial quality control (mtQC), autophagy, and sirtuins in HF development. Dysfunctional mitochondria may play a key role by enhancing oxidative stress and influencing autophagy and sirtuins, both of which possess antioxidant properties. The dual nature of autophagy-its pro-life and pro-death roles-may contribute to different outcomes in HF related to oxidative stress. As mtQC, autophagy, and sirtuins may interact, we present data on their mutual dependencies in HF. However, the specificity of these interactions remains unclear and needs further investigation, which could help identify new therapeutic targets. In conclusion, the interplay between mtQC, autophagy, and sirtuins may be crucial in HF pathogenesis and could be leveraged in developing HF treatments.
    Keywords:  autophagy; heart failure; mitochondria; oxidative stress; sirtuins
    DOI:  https://doi.org/10.3390/ijms26199826
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