bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–08–17
sixty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy.
  2. Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
  3. Analysis of the Mitochondrial Dynamics in NAFLD: Drp1 as a Marker of Inflammation and Fibrosis.
  4. Mitochondrial Quality Control: Insights into Intracerebral Hemorrhage.
  5. Mst1 inhibition attenuates obesity cardiomyopathy via reversing FUNDC1-related mitophagy.
  6. Unraveling the power of TOMM40: Driving PHB1-mediated mtDNA release and mitophagy to fuel breast cancer progression.
  7. The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration.
  8. Discovery of a novel mitophagy inducer attenuating postoperative cognitive dysfunction through structure-based virtual screening and biological validation.
  9. SLC38A1 and STX11 are mitochondria-related biomarkers associated with immune infiltration in osteoarthritis.
  10. Mitochondrial stress orchestrates chromatin remodeling and longevity via phosphoregulation of the NuRD component LIN-40.
  11. Brucella abortus induces dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in infected macrophages via stress sensor IRE1α altering metabolic function.
  12. Betulinic Acid Alleviates Acute Pancreatitis by Promoting SIRT1-PINK1-Mediated Mitophagy in Acinar Cells.
  13. Promoting mitochondrial fusion is protective against cancer-induced muscle detriments in males and females.
  14. Role of NR4A1-Caveolin-1 Axis in the Orchestration of Mitophagy During Macrophage Senescence.
  15. Loss of dynamin 1-like protein impairs mitochondrial function and self-renewal, and activates the integrated stress response in human embryonic stem cells.
  16. Dimethyl α-ketoglutarate ameliorates cisplatin-induced acute kidney injury by modulating mitophagy through the PINK1/Parkin pathway.
  17. Astragaloside IV alleviates hypoxic pulmonary hypertension by inhibiting RELM-β to reduce PINK1/Parkin-mediated mitophagy in pulmonary artery smooth muscle cells (PASMCs).
  18. Endogenous and exogenous viral reactivation as a driver of epigenetic drift and mitophagy failure in aging.
  19. The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
  20. Gastrodin Attenuates Cerebral Ischemia-Reperfusion Injury by Enhancing Mitochondrial Fusion and Activating the AMPK-OPA1 Signaling Pathway.
  21. Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
  22. Astrocyte-derived Exosomal GJA1-20 k Targets Pink1-mediated Mitophagy to Attenuate Traumatic Brain Injury.
  23. RORα-activated mitophagy attenuating hypoxic-ischemic encephalopathy via suppression of microglial cGAS-STING axis.
  24. Retraction: Inhibition of mitochondrial fission as a novel therapeutic strategy to reduce mortality upon myocardial infarction.
  25. Bibliometric analysis of research hotspots and emerging trends in mitophagy and atherosclerosis (2004-2024).
  26. O-GlcNAcylation Suppressed Apoptosis and Ferroptosis in Traumatic Brain Injury by Enhancing Mitophagy.
  27. AIM2 inflammasome-mediated cell pyroptosis regulates mitophagy to participates in high glucose-induced trophoblast cell damage.
  28. FBXO2 Alleviates Intervertebral Disc Degeneration via Dual Mechanisms: Activating PINK1-Parkin Mitophagy and Ubiquitinating LCN2 to Suppress Ferroptosis.
  29. USP30 inhibition augments mitophagy to prevent T cell exhaustion.
  30. Mitochondrial Metabolism in T-Cell Exhaustion.
  31. Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.
  32. Melatonin Modulates Glucose Metabolism Reprogramming via Targeting G6PD to Alleviate Lead-Induced Hepatocytes Pyroptosis in Common Carp (Cyprinus carpio L.).
  33. Stachydrine Mitigates High Glucose-Induced Apoptosis in Human Lens Epithelial Cells by Activating Mitophagy.
  34. Investigating mitophagy mechanisms in bronchopulmonary dysplasia through bioinformatics.
  35. TCDD Induces Hepatocytes Lipid Deposition via Downregulation of MFN2.
  36. RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis.
  37. Tyrosine phosphatase Shp2 accelerated the progression of dilated cardiomyopathy via upregulating NF-κB/Src/FAK signaling induced ROS and mitophagy.
  38. Evaluation of PINK1 protein expression as a predictive marker for the efficacy of adjuvant chemotherapy in colorectal cancer: a retrospective study.
  39. Heterophyllin B alleviates diabetes-induced myocardial injury by regulating MAVS-mediated mitochondrial homeostasis.
  40. Autophagic-active nanosystem for senile bone regeneration by in-situ mitochondrial biogenesis and intercellular transfer.
  41. The DRP1 inhibitory peptide P110 provides neuroprotection after subarachnoid hemorrhage by suppressing neuronal apoptosis and stabilizing the blood-brain barrier.
  42. Mitochondrial dysfunction and oxidative stress in Parkinson's disease: mechanisms, biomarkers, and therapeutic strategies.
  43. Mitochondrial pathways in rheumatoid arthritis: Therapeutic roles of traditional Chinese medicine and natural products.
  44. A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
  45. Bisphenol TMC disturbs mitochondrial activity and biogenesis, reducing lifespan and healthspan in the nematode Caenorhabditis elegans.
  46. Gastrodia elata Polysaccharide Ameliorates Parkinson's Disease by Enhancing Dopamine Levels, Inhibiting NLRP3 Inflammasome Activation, and Promoting Mitochondrial Autophagy.
  47. Gelatin enhances bacteria-phagocytosis via a ROS-mitochondria-STING axis in differentiated human macrophage-like U937 cells.
  48. Targeting the MARCH5-MFN2 axis to enhance mitochondrial fusion and sensitize multiple myeloma cells to venetoclax.
  49. Resilience of the Mitochondrial Reticulum in Aging.
  50. HDAC Inhibition Protects RPE Cells from Oxidative Stress via Enhanced Mitochondrial Fusion, Cytoskeletal Repair, and Nrf-2 Activation.
  51. Decreased LONP1 expression exacerbates MASH-induced liver fibrosis via elevated orotic acid levels.
  52. Metformin alleviates lung ischemia‑reperfusion injury via the SIRT1 pathway following lung transplantation in diabetic rats.
  53. Gaultheria leucocarpa inhibits Aβ fibrillization and enhances mitophagy-mediated degradation of pathogenic proteins.
  54. Kaempferol Induces Mitophagy and Disrupts Iron Metabolism via SFXN2 Leading to Apoptosis in Multiple Myeloma Cells.
  55. Principles of cotranslational mitochondrial protein import.
  56. Qigu capsule alleviates dexamethasone-induced muscle dysfunction through mitochondrial biogenesis.
  57. Correction: DPSCs modulate synovial macrophage polarization and efferocytosis via PINK1/Parkin-dependent mitophagy.
  58. Melatonin Protects against LPS-Induced Mitochondrial Dyshomeostasis and Ovarian Damage through JNK Signaling Pathway in Mouse Ovary.
  59. Mitochondrial sirtuins, key regulators of aging.
  60. miR-17-5p Inhibits BNIP3-Mediated Mitochondrial Autophagy to Attenuate Pathological Cardiac Fibrosis.
  61. Hyaluronic and Succinic Acid: New Biostimulating Combination to Counteract Dermal and Subcutaneous Aging.
  62. Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
  63. S14G-Humanin ameliorates ovarian dysfunction in a cyclophosphamide-induced premature ovarian insufficiency mouse model.
  64. The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia.
  1. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2504921122
    Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy.
    Juncai Ma, Chaorui Li, Kaike Ren, Kaiyan Zhang, Lanlan Feng, Kai Ching Law, Ka Kit Chung, Yizhou Bing, Caiji Gao, Byung-Ho Kang, Xiaohong Zhuang.
      As the energy center of the cell, mitochondria display enormous metabolic plasticity to meet the cellular demand for plant growth and development, which is tightly linked to their structural and dynamic plasticity. Mitochondrial number and morphology are coordinated through the actions of the mitochondrial division and fusion. Meanwhile, damaged mitochondrial contents are removed to avoid excess toxicity to the plant cells. Mitophagy, a selective degradation pathway of mitochondria through a double-membrane sac named autophagosome (also known as mitophagosome), plays a crucial role in maintaining mitochondrial homeostasis. Typically, wholesale mitophagy requires the elongation of a cup-shaped phagophore along the entire mitochondrion, which finally seals and closes as a mitophagosome. How plant mitophagosome formation and mitochondria sequestration are coordinated remains incompletely understood. In this work, we report an unappreciated role of the plant-specific mitochondrial fission regulator ELM1, together with the dynamin-related protein family DRP3 and the autophagic regulator SH3P2, to coordinate mitochondria segregation for piecemeal mitophagy under heat stress conditions. Dysfunction in mitochondrial fission activity impairs heat-induced mitophagy, leading to an accumulation of interconnected megamitochondria which are partially sequestered by the ATG8-positive phagophore. Furthermore, we show that the ELM1-mediated piecemeal mitophagy also engages the plant archetypal selective autophagic receptor NBR1. Using 3D tomography analysis, we illustrate the morphological features and spatial relationship of the megamitochondria and phagophore intermediates in connection with the mitochondrial fission sites. Collectively, our study provides an updated model of mitophagosome formation for piecemeal mitophagy mediated by the plant-unique mitochondrial fission machinery.
    Keywords:  ELM1; SH3P2; mitochondrial fission; mitophagosome; mitophagy
    DOI:  https://doi.org/10.1073/pnas.2504921122
  2. Nat Commun. 2025 Aug 09. 16(1): 7367
    Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
    Bishal Basak, Erika L F Holzbaur.
      Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.
    DOI:  https://doi.org/10.1038/s41467-025-62379-5
  3. Int J Mol Sci. 2025 Jul 30. pii: 7373. [Epub ahead of print]26(15):
    Analysis of the Mitochondrial Dynamics in NAFLD: Drp1 as a Marker of Inflammation and Fibrosis.
    Maël Padelli, Jocelyne Hamelin, Christophe Desterke, Mylène Sebagh, Raphael Saffroy, Claudio Garcia Sanchez, Audrey Coilly, Jean-Charles Duclos-Vallée, Didier Samuel, Antoinette Lemoine.
      Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, projected to affect 55% globally by 2040. Up to one-third of NAFLD patients develop non-alcoholic steatohepatitis (NASH), with 40% progressing to fibrosis. However, there are currently few reliable tools to predict disease progression. Impaired mitochondrial dynamics, characterized by dysregulated fission, fusion, and mitophagy, have emerged as key events in NAFLD pathophysiology, contributing to hepatocyte death and inflammation. This study explored the transition from steatosis to NASH through transcriptomic analyses, including data from patients with steatosis and those with NASH at different fibrosis stages. By identifying a transcriptomic signature associated with disease progression, the study revealed increased expression of genes involved in mitochondrial dynamics in NASH compared to steatosis and during NASH-related fibrosis. Histological analyses highlighted the central role of Dynamin-related protein 1 (Drp1), a dynamin GTPase essential for mitochondrial fission and mitophagy. In human liver biopsies, Drp1 expression progressively increased from NAFLD to NASH and NASH-related fibrosis and cirrhosis, predominantly in Kupffer cells. These finding suggest Drp1 is a potential driver of the transition to more severe liver damage, making it a promising biomarker for NASH development and progression and a potential therapeutic target in metabolic disorders.
    Keywords:  Drp1; Kupffer cells; cirrhosis; fibrosis; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.3390/ijms26157373
  4. Cell Mol Neurobiol. 2025 Aug 14. 45(1): 79
    Mitochondrial Quality Control: Insights into Intracerebral Hemorrhage.
    Tong Shang, Binglin Kuang, Lei Zheng, Baiwen Zhang, Xueting Liu, Yaxin Shang, Jia Zheng, Baochun Luo, Wei Zou.
      Mitochondrial dysfunction has been identified as a key factor in the pathophysiological changes associated with intracerebral hemorrhage (ICH). As the core of intracellular energy metabolism, mitochondrial homeostasis is highly dependent on the precise regulation of its mitochondrial quality control (MtQC) system. After ICH, dysfunctional mitochondria lead to impaired oxidative phosphorylation and cellular bioenergetic stress, inducing oxidative stress, inflammatory responses, and programmed cell death, further exacerbating cellular damage. To counteract this injury, cells activate a series of MtQC mechanisms for compensatory repair, including mitochondrial dynamics, mitochondrial biogenesis, mitophagy, and intercellular mitochondrial transfer. These stringent mechanisms help maintain the mitochondrial network, restore the integrity of mitochondrial structural and functional integrity, improve neural function, and mitigate brain injury. In this review, we discuss key evidence regarding the role of mitochondrial dysfunction in ICH, focusing on the MtQC mechanisms involved in ICH. We also summarize potential therapeutic strategies targeting MtQC to intervene in ICH, providing valuable insights for clinical applications.
    Keywords:  Intercellular mitochondrial transfer; Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1007/s10571-025-01599-1
  5. Cell Signal. 2025 Aug 07. pii: S0898-6568(25)00473-5. [Epub ahead of print] 112058
    Mst1 inhibition attenuates obesity cardiomyopathy via reversing FUNDC1-related mitophagy.
    Ding Yan, Zhu Linli, Zhang Mengyu, Li Xia, Liu Hailan, Zhang Chunquan.
      Mitophagy dysfunction is an important pathological manifestation of obesity cardiomyopathy, a disease characterized by myocardial hypertrophy and diastolic dysfunction. Mammalian Ste20-like kinase 1 (Mst1) regulates mitophagy and is involved in diabetic cardiomyopathy. However, the relationship between Mst1 and mitophagy in obesity cardiomyopathy remains unexplored. This study aimed to determine whether Mst1 contributes to obesity cardiomyopathy by modulating FUN14 domain-containing 1 (FUNDC1)-mediated mitophagy. We found that Mst1 expression was significantly upregulated in obesity cardiomyopathy. Mst1 knockdown ameliorated ventricular remodeling, diastolic dysfunction, and subclinical systolic impairment in high-fat diet (HFD)-induced obese mice. At the molecular level, palmitic acid treatment induced mitochondrial damage, manifested by increased reactive oxygen species production, reduced mitochondrial membrane potential, and ATP depletion. Mechanistically, Mst1 activation suppressed FUNDC1 expression, inhibiting mitophagy. Conversely, Mst1 deficiency restored FUNDC1 expression, reactivating protective mitophagy, maintaining mitochondrial homeostasis, and alleviating cardiomyopathy. Finally, we established that Mst1 regulates FUNDC1 through the peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor 1 (PGC-1α/NRF1) pathway. Inhibition of the PGC-1α/NRF1 pathway reversed the Mst1 knockout-induced FUNDC1 upregulation. Collectively, our findings demonstrate that Mst1 drives obesity cardiomyopathy by suppressing FUNDC1-dependent mitophagy.
    Keywords:  Mst1; Myocardial injury; Obesity; Speckle tracking
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112058
  6. Biochim Biophys Acta Gen Subj. 2025 Aug 13. pii: S0304-4165(25)00096-0. [Epub ahead of print] 130851
    Unraveling the power of TOMM40: Driving PHB1-mediated mtDNA release and mitophagy to fuel breast cancer progression.
    Lei Pan, Feixia Ma, Hongchen Zhang, Yin Duan.
       BACKGROUND: In breast cancer (BRCA), mitophagy is essential for the survival and metastasis of cancer cells. However, the interaction between translocase of the outer mitochondrial membrane 40 (TOMM40) and prohibitin 1 (PHB1) in regulating mitophagy in BRCA remains poorly understood.
    METHODS: Based on bioinformatics analysis, the interaction between PHB1 and key mitophagy regulators in BRCA was explored. The effects of mitochondrial division inhibitor-1 (Mdivi-1) and Fluorizoline on mitophagy, cell viability, and sphere formation ability in MDA-MB-231 cells were assessed. In the cell model activated by carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce mitophagy, the effects of TOMM40 on cell viability, sphere formation ability, mitochondrial membrane potential, reactive oxygen species (ROS) levels, mitochondrial DNA (mtDNA) release, and PHB1 regulation were analyzed. In vivo, the impact of TOMM40 knockdown on tumor progression and mitophagy was also evaluated.
    RESULTS: PHB1 interacted with TOMM40. Mdivi-1 or Fluorizoline treatment inhibited mitophagy, and significantly reduced BRCA cell viability and sphere formation. CCCP treatment induced mitophagy, increased mtDNA release and PHB1 levels, decreased mitochondrial membrane potential and ROS, and promoted cell viability and sphere formation ability, which were all reversed by TOMM40 knockdown. Additionally, TOMM40 knockdown led to decreased PHB1 levels and increased ROS accumulation in tumor tissue, thus repressing tumor progression.
    CONCLUSION: This study identifies TOMM40 as a key regulator that enhances PHB1-mediated mtDNA release and induces mitophagy in BRCA cells, thus promoting breast cancer progression.
    Keywords:  Breast cancer; Mitochondrial DNA; Mitophagy; Prohibitin 1; Translocase of the outer mitochondrial membrane 40
    DOI:  https://doi.org/10.1016/j.bbagen.2025.130851
  7. Bone Res. 2025 Aug 12. 13(1): 72
    The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration.
    Zhidi Lin, Xiao Lu, Guangyu Xu, Jian Song, Hongli Wang, Xinlei Xia, Feizhou Lu, Jianyuan Jiang, Wei Zhu, Zuochong Yu, Xiaosheng Ma, Fei Zou.
      Intervertebral disc degeneration (IVDD) is the primary contributor to a range of spinal diseases. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell (NPC) death and IVDD, but the underlying mechanisms remain unclear. Although the effects of Drp1 phosphorylation in IVDD have been studied, it is currently unknown if small ubiquitin-like modifications (SUMOylation) of Drp1 regulate IVDD. This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase (MAPL), a mitochondrial SUMO E3 ligase, during IVDD progression. The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing. The levels of total and mitochondrial SUMO1 conjugates were elevated with MAPL upregulation in TNF-α-treated NPCs. Additionally, mitochondrial fragmentation and dysfunction were induced by TNF-α stimulation. MAPL overexpression promoted mitochondrial SUMOylation and SUMO1 modification of Drp1, thereby facilitating the mitochondrial translocation of Drp1 and mitochondrial fission. MAPL-induced ROS accumulation and ΔΨm loss led to increased NPC apoptosis. Mutation of the SUMO-acceptor lysine residues of Drp1 hindered its SUMOylation and rescued the mitochondrial phenotypes caused by MAPL. SENP5 overexpression phenocopied MAPL silencing, negatively modulating the SUMO1 modification of Drp1 and mitochondrial fission in NPCs. In a rat IVDD model, forced expression of MAPL by using an adeno-associated virus (AAV) vector aggravated IVD tissue damage, whereas the knockdown of MAPL delayed IVDD progression. Our findings highlight the importance of SUMOylation in IVDD. The inhibition of MAPL-mediated Drp1 SUMOylation alleviates mitochondrial fission and limits IVDD development, providing a potential strategy for IVDD treatment.
    DOI:  https://doi.org/10.1038/s41413-025-00449-6
  8. Free Radic Biol Med. 2025 Aug 11. pii: S0891-5849(25)00885-8. [Epub ahead of print]
    Discovery of a novel mitophagy inducer attenuating postoperative cognitive dysfunction through structure-based virtual screening and biological validation.
    Lina Zhang, Yujin Wu, Jiaying Li, Chenglong Li, Shuai Liu, Sihua Qi.
      Postoperative cognitive dysfunction (POCD), a prevalent complication following surgery and anesthesia, currently lacks effective therapeutics. Given the crucial regulatory role of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in maintaining mitochondrial homeostasis and suppressing neuroinflammatory responses, we aimed to identify novel mitophagy inducers as potential therapeutic interventions for POCD. Employing structure-based virtual screening of a small-molecule library of compounds, we identified tamarixetin as a potent and selective PINK1 activator. Comprehensive molecular dynamics simulations and cellular thermal shift assays validated its stable binding interaction with PINK1. Treatment with tamarixetin significantly enhanced mitophagic activity in the hippocampal region of surgically treated mice, concurrently reducing cytosolic mitochondrial DNA accumulation and reactive oxygen species levels, attenuating neuroinflammatory responses, and improving cognitive function in behavioral tests. Mechanistically, tamarixetin treatment promoted PINK1 stabilization and strengthened PINK1-Translocase Of Outer Mitochondrial Membrane 40 interactions, while facilitating Parkin recruitment to mitochondria and enhancing mitofusin 2 ubiquitination, ultimately promoting mitophagic flux in both lipopolysaccharide-stimulated HT22 neuronal and BV2 microglial cell lines. Our study identifies tamarixetin as a novel pharmacological activator of PINK1-dependent mitophagy and elucidates its therapeutic potential in POCD by counteracting mitochondrial dysfunction and neuroinflammation. These findings provide a promising foundation for developing mitophagy-targeted therapies for POCD.
    Keywords:  PTEN-induced kinase 1; Parkin; Postoperative cognitive dysfunction; mitophagy; tamarixetin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.016
  9. Front Genet. 2025 ;16 1585775
    SLC38A1 and STX11 are mitochondria-related biomarkers associated with immune infiltration in osteoarthritis.
    Wenxue Lv, Mingxiu Yu, Wenhai Yan, Yuli Cai, Weiguo Wang.
       Background: Mitochondrial dynamics and mitophagy play crucial roles in osteoarthritis (OA); however, the specific contributions of mitochondrial dynamics-related genes (MD-RGs) and mitophagy-related genes (MP-RGs) remain unclear. This study aimed to elucidate the precise mechanisms linking these genes in the context of OA.
    Methods: OA-related transcriptome datasets and single-cell RNA sequencing (scRNA-seq) dataset incorporating MD-RGs and MP-RGs were utilized in this study. Hub genes were identified through differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning. A nomogram was then constructed based on the hub genes. Enrichment and immune infiltration analyses were performed on the hub genes, and key cell types were identified based on hub gene expression. Finally, the expression of the hub genes was validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
    Results: SLC38A1 and STX11 were identified as hub genes linked to mitochondrial dynamics and mitophagy in OA. These genes enabled the construction of a reliable nomogram for predicting OA risk. Enrichment analysis revealed that the top biological processes converged on the ECM-receptor interaction, underscoring its critical role in OA pathogenesis. Immune infiltration analysis uncovered significant disparities in 10 immune cell types, including activated CD4 T cells and central memory CD4 T cells, between OA patients and healthy controls. The levels of these immune cells were strongly correlated with the expression of SLC38A1 and STX11. Additionally, endothelial cells, monocytes, and T cells emerged as key cellular players in OA. RT-qPCR validation showed that SLC38A1 was significantly downregulated in OA samples, and STX11 exhibited a similar trend, suggesting their potential roles in OA progression.
    Conclusion: This study identified SLC38A1 and STX11 as key genes linked to mitochondrial dynamics and mitophagy in OA. These findings provide a theoretical basis and valuable reference for the diagnosis and treatment of OA.
    Keywords:  immune infiltration analysis; mitochondrial dynamics; mitophagy; osteoarthritis; single-cell analysis
    DOI:  https://doi.org/10.3389/fgene.2025.1585775
  10. Sci China Life Sci. 2025 Aug 13.
    Mitochondrial stress orchestrates chromatin remodeling and longevity via phosphoregulation of the NuRD component LIN-40.
    Jun Zhou, Di Zhu, Yibing Wang, Zilun Wang, Ning Zhang, Xiahe Huang, Yiqian Zhang, Yingchun Wang, Xueying Wu, Ye Tian.
      Mitochondrial dysfunction is a hallmark of aging that elicits adaptive nuclear responses, yet how chromatin remodeling is coordinated under stress remains unclear. Here, we uncover a phosphorylation-dependent mechanism by which mitochondrial stress regulates the activity of the NuRD (nucleosome remodeling and deacetylase) complex via LIN-40, the Caenorhabditis elegans homolog of mammalian MTA proteins. Mitochondrial stress triggers dephosphorylation of LIN-40, enhancing its interaction with the transcription factor DVE-1 to activate the mitochondrial unfolded protein response (UPRmt) and chromatin remodeling. Phosphorylation of LIN-40 is mediated by p38 MAPK/PMK-3 and reversed by PP1c/GSP-2. Furthermore, the LIN-40(T654D) variant abolishes mitochondrial stress-induced lifespan extension. These findings establish a direct link between mitochondrial stress signaling and chromatin remodeling via NuRD, revealing an evolutionarily conserved strategy to coordinate cellular resilience and organismal longevity.
    Keywords:   C. elegans ; LIN-40/MTA; NuRD; UPRmt ; longevity; mitochondrial stress
    DOI:  https://doi.org/10.1007/s11427-025-2954-3
  11. J Immunol. 2025 Aug 14. pii: vkaf198. [Epub ahead of print]
    Brucella abortus induces dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in infected macrophages via stress sensor IRE1α altering metabolic function.
    Erika S Guimarães, Marco Túlio R Gomes, Pedro M Moraes-Vieira, Sergio C Oliveira.
      Brucella abortus exploits the endoplasmic reticulum as a site for replication, triggering the unfolded protein response (UPR). While various pathogens have developed strategies to manipulate mitochondrial dynamics, the mechanisms underlying bacterial infection and mitochondrial dynamics interactions remain poorly understood. Here, we demonstrate that B. abortus induces mitochondrial fragmentation via IRE1α. Our findings reveal that Brucella-induced mitochondrial fission is mediated by dynamin-related protein 1 (DRP1), a pivotal regulator of mitochondrial fission. Moreover, we have demonstrated that DRP1 is activated by the UPR. Brucella-induced fragmentation leads to mitochondrial energetic dysfunction, marked by impaired mitochondrial ATP production and compromised bioenergetic capacity. Furthermore, we reveal a novel role for DRP1 in regulating type I IFN production and signaling during B. abortus infection. Mechanistically, mitochondrial fission facilitates the release of mitochondrial DNA, a potent inducer of type I IFN responses. Despite its impact on mitochondrial function and IFN signaling, DRP1 does not influence the control of B. abortus infection. Our findings uncover a unique mechanism by which B. abortus-induced UPR triggers mitochondrial fragmentation affecting innate immune signaling and cellular metabolism.
    Keywords:   Brucella abortus ; UPR; innate immunity; mitochondrial dysfunction
    DOI:  https://doi.org/10.1093/jimmun/vkaf198
  12. Drug Dev Res. 2025 Aug;86(5): e70140
    Betulinic Acid Alleviates Acute Pancreatitis by Promoting SIRT1-PINK1-Mediated Mitophagy in Acinar Cells.
    Zhenfei Yu, Ying Li, Peng An, Xiaoling Qian, Yakun Wang, Bo Wang.
      Betulinic acid (BA) has the potential to ameliorate acute pancreatitis (AP); however, the mechanisms have not been fully elucidated. This study aimed to identify the effect of BA on mitophagy and its mediated acetylation. Rat pancreatic acinar AR42J cells were treated with cerulein to simulate AP-induced injury, and then inflammation and mitophagy were evaluated after BA treatment. The molecular mechanisms were analyzed using molecular docking, immunoprecipitation, immunoblotting, and cycloheximide chase assay. The roles of BA and SIRT1 in vivo were assessed by HE staining and enzyme-linked immunosorbent assay. The results showed that BA inhibited inflammation and promoted mitophagy in cerulein-induced AR42J cells. BA combined with SIRT1 and reduced SIRT1-mediated acetylation. Knockdown of SIRT1 counteracted the inflammation and mitophagy caused by BA. Moreover, interference with SIRT1 promoted acetylation of PINK1 to degrade PINK1 protein, which knockdown reversed the inhibition of inflammation and the promotion of mitophagy induced by SIRT1. Additionally, BA inhibited pancreatic tissue injury and inflammation levels in the pancreas in AP mice by regulating SIRT1. In conclusion, BA decelerates the progression of AP by promoting mitophagy and inhibiting inflammation in pancreatic acinar cells. Mechanically, BA increased SIRT1 expression, which knockdown degraded PINK1 protein by inducing acetylation of PINK1.
    Keywords:  PINK1; SIRT1; acetylation; acute pancreatitis; betulinic acid; mitophagy; pancreatic acinar cell
    DOI:  https://doi.org/10.1002/ddr.70140
  13. BMC Cancer. 2025 Aug 11. 25(1): 1300
    Promoting mitochondrial fusion is protective against cancer-induced muscle detriments in males and females.
    Francielly Morena, Seongkyun Lim, Ana Regina Cabrera, Toby L Chambers, Pieter J Koopmans, Stavroula Tsitkanou, Sabin Khadgi, Calvin Peterson, Eleanor R Schrems, Ruqaiza Muhyudin, Sepideh Shakeri, Kevin Zhao, Devan Mishra, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.
       BACKGROUND: Skeletal muscle atrophy during cancer-induced cachexia remains a significant challenge in cancer management. Mitochondrial defects precede muscle mass and functional losses in models of cancer cachexia (CC). We hypothesized targeting Opa1-a key regulator of mitochondrial fusion-can attenuate LLC-induced CC outcomes.
    METHODS: We utilized 1) in vivo transgenic Opa1 overexpression (OPA1 TG) in LLC-induced CC in vivo, and 2) BPG15 administration to induce Opa1 in vitro and in vivo.
    RESULTS: OPA1 TG attenuated plantaris, gastrocnemius, and EDL loss with LLC in males and alleviated gastrocnemius loss in females. OPA1 TG had greater mitochondrial respiration in plantaris and white gastrocnemius, and lowered pMitoTimer Red Puncta (-63%), a proxy for mitophagy in males. OPA1 TG protected muscle contractility at physiological stimulation frequencies by up to 60% in female LLC mice. OPA1 TG enhanced the ratio of OPA1/DRP1 protein content-a proxy for fusion and fission balance-in males and females. In vitro, BGP-15 attenuated LLC conditioned media-induced myotube atrophy by ~ 9% concomitant with suppression of the transcriptional factor FoxO3, autophagy markers, and inflammatory cytokines. In vivo, BGP-15 improved contractility at lower frequencies (10-60 Hz), with LLC-BGP-15 showing up to 20% greater torque than LLC-control. BGP-15 treated LLC animals had 71% fewer pMitoTimer red puncta, suggesting attenuated mitophagy.
    CONCLUSIONS: Promoting mitochondrial fusion via OPA1 induction improved cachectic outcomes in mice. Targeting OPA1providing provides a promising therapeutic approach for CC treatment.
    Keywords:  BGP-15; Lewis Lung Carcinoma; Mitochondrial dynamics; Muscle contractility; OPA1
    DOI:  https://doi.org/10.1186/s12885-025-14630-x
  14. Cell Physiol Biochem. 2025 Aug 05. 59(4): 496-510
    Role of NR4A1-Caveolin-1 Axis in the Orchestration of Mitophagy During Macrophage Senescence.
    Pei Li, Tian Tian, Xiuting Huang.
       BACKGROUND/AIMS: Arteriosclerosis (AS) remains a leading cause of global mortality, with macrophage senescence playing a crucial role in its progression. Senescent macrophages, characterized by oxidative stress and inflammation, exhibit dysregulated mitophagy. However, the underlying mechanisms remain unclear.
    METHODS: This study explores the role of caveolin-1, a structural protein of caveolae, in NR4A1-mediated mitophagy during oxLDL-induced macrophage senescence. Using gene knockdown and overexpression models, we assessed mitochondrial dysfunction, ROS production, cytokine secretion, and mitophagy activity in murine macrophages.
    RESULTS: It revealed that NR4A1 promoted mitochondrial dysfunction and senescence through enhanced ROS production and disrupted mitochondrial potential. Caveolin-1 mediated this effect by facilitating NR4A1-induced mitophagy, as evidenced by colocalization of mitochondria and lysosomes and the activation of Parkin-related pathways. NR4A1 upregulated caveolin-1 expression, forming a signaling axis critical for senescence-associated pro-inflammatory cytokine production.
    CONCLUSION: Overall, our study unraveled The NR4A1-caveolin-1 axis orchestrates mitophagy and inflammation in senescent macrophages, shedding light on AS pathogenesis and suggesting potential therapeutic targets to mitigate macrophage-driven inflammation and oxidative stress.
    Keywords:  Arteriosclerosis ; Macrophage senescence ; Mitophagy ; NR4A1 ; Caveolin-1
    DOI:  https://doi.org/10.33594/000000796
  15. Front Genet. 2025 ;16 1628178
    Loss of dynamin 1-like protein impairs mitochondrial function and self-renewal, and activates the integrated stress response in human embryonic stem cells.
    Artur Cieslar-Pobuda, Safak Caglayan.
      Dynamin 1-like protein (DNM1L/DRP1) is a crucial regulator of mitochondrial fission in cells and pathogenic mutations in DNM1L are linked to developmental and metabolic disorders in humans. While the role of DNM1L has been described in patient-derived fibroblasts, its function in early human development remains unclear. In this study, we generated DNM1L deficient human embryonic stem cells (hESCs) using CRISPR/Cas9 to investigate the consequences of DNM1L deficiency and impaired mitochondrial fission on stem cell function. DNM1L -/- hESCs exhibited hyperfused mitochondrial networks, reduced mitochondrial membrane potential, and elevated oxidative stress, indicating compromised mitochondrial fitness. Functionally, DNM1L -/- hESCs showed diminished self-renewal, and reduced expression of the core pluripotency factor OCT4, while NANOG expression was unaffected. We further found that differentiation potential toward the early ectodermal lineage was impaired, whereas early endodermal and mesodermal differentiation remained intact. Notably, integrated stress response (ISR) pathway was activated in DNM1L -/- hESCs, as shown by increased phosphorylated eIF2a and upregulation of downstream targets including activating transcription factor 4 (ATF4), ATF3, ATF5, and DDIT3. Restoring DNM1L expression by reintroduction of DNM1L into the AAVS1 locus rescued mitochondrial morphology and function, normalized ISR activation, and restored self-renewal and OCT4 expression in DNM1L -/- hESCs. These findings demonstrate that DNM1L is essential for maintaining mitochondrial homeostasis, stress response, self-renewal, and pluripotency in hESCs, and emphasize the importance of mitochondrial fission in stem cell function.
    Keywords:  DNM1L; DRP1; human embryonic stem cells; integrated stress response; mitochondrial dysfunction; mitochondrial fission; pluripotency; self-renewal
    DOI:  https://doi.org/10.3389/fgene.2025.1628178
  16. Eur J Med Res. 2025 Aug 13. 30(1): 746
    Dimethyl α-ketoglutarate ameliorates cisplatin-induced acute kidney injury by modulating mitophagy through the PINK1/Parkin pathway.
    Haijing Dou, Huihui Hao, Ruoyi Zhao, Hailun Li, Fangshu Wei, Yong Xu, Donghui Zheng, Juan Xie, Xiang Li.
       BACKGROUND: Mitochondrial dysfunction and abnormal energy metabolism are key determinants of the progression of acute kidney injury (AKI). α-Ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid cycle and plays a crucial role in energy metabolism and amino acid synthesis. However, the role of AKG in AKI therapy remains incompletely understood.
    METHODS: Cisplatin (CIS) was employed to establish acute kidney injury models in mice and cells, with DM-AKG administered as an intervention. Network pharmacology was utilized to predict the target genes and pathway enrichment of AKG in the treatment of AKI. Apoptosis was assessed using flow cytometry, and cell viability was determined via the CCK-8 assay. The levels of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were assessed using optical microscopy. Renal function was evaluated using absorbance spectroscopy. Hematoxylin-eosin (H&E) staining was used to examine the pathological changes in renal tissues across different groups. The ultrastructure of mitochondria was examined using transmission electron microscopy. Protein expression levels of KIM-1, Caspase-3, DRP1, MFN1, PINK1, and Parkin were evaluated using Western blot analysis. The expression of PINK1 and Parkin was examined by immunohistochemistry.
    RESULTS: Herein, we demonstrate that dimethyl α-ketoglutarate (DM-AKG), an AKG derivative with favorable cell membrane permeability, effectively ameliorates cisplatin (CIS)-induced AKI. Further network pharmacological analyses revealed that AKG could treat AKI through 91 potential targets of action. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed significant enrichment of pathways related to mitochondria and energy metabolism. Furthermore, in a CIS-treated HK-2 cell model, we found that exogenous DM-AKG supplementation improved mitochondrial dynamics (increased expression of the mitochondrial fusion protein MFN1 and decreased expression of the mitochondrial fission protein DRP1), increased mitochondrial membrane potential, and decreased reactive oxygen species generation. Consistent with these findings, in the CIS-AKI mouse model, DM-AKG similarly improved mitochondrial morphology, structure, and dynamics, as well as increased mitophagy observed by electron microscopy.
    CONCLUSION: These results suggest that DM-AKG may exert a therapeutic effect on AKI by improving mitochondrial function. Regarding the molecular mechanism, we confirmed that DM-AKG could increase mitophagy and promote the clearance of damaged mitochondria by activating the PINK1/Parkin pathway, which could play a protective role in the kidney. In conclusion, our study provides a novel strategy for the effective treatment of AKI.
    Keywords:  Acute kidney injury; Alpha-ketoglutarate; Cisplatin; Mitophagy; Network pharmacology
    DOI:  https://doi.org/10.1186/s40001-025-03010-7
  17. Br J Pharmacol. 2025 Aug 13.
    Astragaloside IV alleviates hypoxic pulmonary hypertension by inhibiting RELM-β to reduce PINK1/Parkin-mediated mitophagy in pulmonary artery smooth muscle cells (PASMCs).
    Rongzhen Ding, Haiping Xie, Shuliu Sang, Li Qin, Yinhui Sun, Chao Zhang, Jian Yi, Hui Liu, Jianmin Fan, Guoran Peng, BeiBei Cheng, Lan Song, Aiguo Dai.
       BACKGROUND AND PURPOSE: Hypoxic pulmonary hypertension (HPH) is a chronic disorder marked by irreversible pulmonary vascular remodelling (PVR) and pulmonary artery smooth muscle cell (PASMC) dysfunction. Astragaloside IV (AS-IV), a natural saponin from Astragalus, shows potential in HPH management. This study explores AS-IV's protective effect on PVR in HPH.
    EXPERIMENTAL APPROACH: HPH mouse model was established by 28 days of hypoxia and AS-IV was administered daily. The effect of AS-IV on the HPH model was evaluated by haemodynamic parameters, echocardiography and pathological changes in the pulmonary arteries. In vitro, CCK8, EdU, scratch and transwell assays assessed cell proliferation and migration. Transmission electron microscopy, immunofluorescence and Seahorse XFe24 were employed to detect mitochondrial morphology and function. Retnlb-/- mice were constructed to assess the effect of RELM-β in HPH. The impact of AS-IV on RELM-β expression and mitophagy at the cellular level was evaluated through lentivirus overexpression.
    KEY RESULTS: AS-IV ameliorated HPH in mice by reducing right ventricular systolic pressure (RVSP), attenuating right ventricular hypertrophy and inhibiting vascular remodelling. AS-IV improves hypoxia-induced proliferation, migration and phenotypic transformation of PASMC in vitro. AS-IV reduced hypoxia-induced increases in RELM-β, PINK1, Parkin and excessive mitophagy. Retnlb (RELM-β) knockdown amended mitophagy and PVR under hypoxia. However, the overexpression of RETNLB (RELM-β) hindered the regulatory effect of AS-IV on mitophagy mediated by PINK1/Parkin pathways.
    CONCLUSIONS AND IMPLICATIONS: AS-IV attenuated the hypoxia-induced increase of PASMC RELM-β expression and suppressed PINK1/Parkin-mediated mitophagy, resulting in the amelioration of PVR. This study unveils the potential of AS-IV as a therapeutic approach for HPH.
    Keywords:  astragaloside IV; hypoxic pulmonary hypertension; mitophagy; resistin‐like molecule beta; smooth muscle cells
    DOI:  https://doi.org/10.1111/bph.70166
  18. Biogerontology. 2025 Aug 12. 26(5): 159
    Endogenous and exogenous viral reactivation as a driver of epigenetic drift and mitophagy failure in aging.
    Evgeniia Bakaleinikova.
      Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms driving these phenomena remain elusive. Here, a unifying hypothesis is proposed: that the progressive reactivation of human endogenous retroviruses (HERVs), combined with latent viral infections acquired during life, imposes an escalating burden on the epigenetic regulatory system. This "virome pressure" demands continuous silencing via DNA methylation, histone deacetylation, and NAD⁺-dependent pathways. With age, these silencing mechanisms deteriorate, leading to HERV reactivation, disruption of key mitochondrial quality control genes, and activation of innate immune responses. This is likened to a molecular peat bog, a simmering threat buried beneath the surface, where silencing mechanisms struggle to contain viral elements until pressure builds and erupts as the organism ages. This model integrates virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and suggests new targets for therapeutic intervention research.
    Keywords:  Aging; Epigenetic drift; Human endogenous retroviruses (HERVs); Mitochondrial dysfunction; Viral reactivation
    DOI:  https://doi.org/10.1007/s10522-025-10286-z
  19. Int J Mol Sci. 2025 Aug 07. pii: 7654. [Epub ahead of print]26(15):
    The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
    Lin Lin, Neal Patel, Lucia Fernandez-Del-Rio, Cristiane Benica, Blake Wilde, Eirini Christodoulou, Shinji Ohtake, Anhyo Jeong, Aboubacar Kaba, Nedas Matulionis, Randy Caliliw, Xiaowu Gai, Heather Christofk, David Shackelford, Brian Shuch.
      Renal oncocytoma (RO) is a benign renal neoplasm characterized by dense accumulation of dysfunctional mitochondria possibly resulting from increased mitochondrial biogenesis and decreased mitophagy; however, the mechanisms controlling these mitochondrial changes are unclear. ROs harbor recurrent inactivating mutations in mitochondrial genes encoding the Electron Transport Chain (ETC) Complex I, and we hypothesize that Complex I loss in ROs directly impairs mitophagy. Our analysis of ROs and normal kidney (NK) tissues shows that a significant portion (8 out of 17) of ROs have mtDNA Complex I loss-of-function mutations with high variant allele frequency (>50%). ROs indeed exhibit reduced Complex I expression and activity. Analysis of the various steps of mitophagy pathway demonstrates that AMPK activation in ROs leads to induction of mitochondrial biogenesis, autophagy, and formation of autophagosomes. However, the subsequent steps involving lysosome biogenesis and function are defective, resulting in an overall inhibition of mitophagy. Inhibiting Complex I in a normal kidney cell line recapitulated the observed lysosomal and mitophagy defects. Our data suggest Complex I loss in RO results in defective mitophagy due to lysosomal loss and dysfunction.
    Keywords:  autophagy/mitophagy; complex I; lysosome; metabolism; mitochondrial dysfunction; renal oncocytoma
    DOI:  https://doi.org/10.3390/ijms26157654
  20. CNS Neurosci Ther. 2025 Aug;31(8): e70559
    Gastrodin Attenuates Cerebral Ischemia-Reperfusion Injury by Enhancing Mitochondrial Fusion and Activating the AMPK-OPA1 Signaling Pathway.
    Zihan Liu, Zeyu Han, Wenshuai Bao, Yihan Guo, Yuan Yuan, Jianming Cheng, Jie Zhang, Yang Hu.
       BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is a critical pathological process in stroke, characterized by disrupted energy metabolism, inflammatory responses, and mitochondrial dysfunction. Targeting mitochondrial dynamics presents promising strategies for alleviating brain injury. This study investigates the role and mechanism of Gastrodin (Gas) in regulating mitochondrial dynamics and mitigating cerebral I/R injury via activation of the AMPK-OPA1 signaling pathway.
    METHODS: An in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model and an in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) model were used to assess the effects of Gas on inflammation, mitochondrial function, and energy metabolism. Immunofluorescence, western blotting (WB), reverse-transcription PCR (RT-PCR), JC-1 staining, and molecular docking techniques were employed for analysis.
    RESULTS: Gas activated the AMPK-OPA1 signaling pathway, promoting mitochondrial fusion, restoring membrane potential, enhancing ATP production, and rebalancing NAD+/NADH levels. Additionally, Gas significantly suppressed I/R-induced inflammatory responses, reduced neuronal damage, and decreased infarct volume. Notably, its protective effects on mitochondrial fusion and neuroprotection were abolished under AMPK silencing, highlighting the critical role of the AMPK-OPA1 pathway.
    CONCLUSION: Gas alleviates cerebral I/R injury by regulating mitochondrial dynamics via the AMPK-OPA1 signaling pathway. These findings provide a theoretical basis for the therapeutic application of Gas in stroke and offer new insights into mitochondrial-targeted treatment strategies.
    Keywords:  AMPK‐OPA1; Gastrodin; cerebral ischemia–reperfusion injury; mitochondrial fusion; oxygen–glucose deprivation/reperfusion
    DOI:  https://doi.org/10.1111/cns.70559
  21. Elife. 2025 Aug 11. pii: RP99936. [Epub ahead of print]13
    Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes.
    Haruna Gekko, Ruri Nomura, Daiki Kuzuhara, Masato Kaneyasu, Genpei Koseki, Deepak Adhikari, Yasuyuki Mio, John Carroll, Tomohiro Kono, Hiroaki Funahashi, Takuya Wakai.
      In cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Depletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2 cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+ levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensures proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage.
    Keywords:  Dynamin-related protein 1; binuclear formation; chromosome segregation; developmental biology; mitochondrial dynamics; mouse; organelle inheritance; preimplantation development
    DOI:  https://doi.org/10.7554/eLife.99936
  22. Transl Stroke Res. 2025 Aug 14.
    Astrocyte-derived Exosomal GJA1-20 k Targets Pink1-mediated Mitophagy to Attenuate Traumatic Brain Injury.
    Yalun Li, Wei Chen, Jiugeng Feng.
      Connexin 43 (Cx43), particularly its truncated isoform GJA1-20 k, has shown promise in mitigating neuronal injury through mitochondrial regulation. This study aimed to investigate the therapeutic potential of astrocyte-derived extracellular vesicles (EVs) enriched with GJA1-20 k (Exo-GJA1-20 k) for treating traumatic brain injury (TBI). Primary astrocytes were isolated and transfected with an adeno-associated viral vector to overexpress GJA1-20 k. EVs were extracted and characterized using nanoparticle tracking analysis and Western blotting. A controlled cortical impact (CCI) model of TBI was established in mice, followed by daily administration of Exo-GJA1-20 k via tail vein injections. Mitochondrial function, neuroinflammation, pyroptosis, and cognitive outcomes were evaluated through molecular assays, histological staining, and behavioral tests, including the Morris Water Maze and open field tests. Exo-GJA1-20 k treatment significantly improved mitochondrial quality control by enhancing mitophagy and reducing mitochondrial dysfunction. Pyroptosis, driven by the NLRP3 inflammasome, was notably suppressed, with significant reductions in NLRP3, ASC, and IL-1β expression levels. Behavioral analyses revealed enhanced cognitive performance, as evidenced by shorter escape latencies in the Morris Water Maze and reduced anxiety-like behaviors in the open field test in Exo-GJA1-20 k-treated mice compared to controls. Importantly, the therapeutic effects of Exo-GJA1-20 k were diminished in Pink1-knockout mice, underscoring the dependence on Pink1-mediated mitophagy. This study demonstrates that Exo-GJA1-20 k exerts neuroprotective effects by modulating the mitophagy-NLRP3 inflammasome axis, alleviating neuroinflammation, and mitigating cognitive deficits in a TBI model. These findings propose a novel therapeutic strategy for addressing TBI-induced neuronal damage and underscore the potential of EV-based therapies for treating neurological disorders.
    Keywords:  Astrocytes; Brain injury; Exosomes; Neuroinflammation; Neurons
    DOI:  https://doi.org/10.1007/s12975-025-01374-w
  23. Front Immunol. 2025 ;16 1592737
    RORα-activated mitophagy attenuating hypoxic-ischemic encephalopathy via suppression of microglial cGAS-STING axis.
    Lei Song, Haiyan Shen, Fei Hong, Weiyan Zhang, Hongyi Lu.
       Introduction: Hypoxic-ischemic encephalopathy (HIE) involves neuroinflammation driven by microglial activation, yet regulatory mechanisms remain poorly defined. This study investigates how Retinoic Acid Receptor-Related Orphan Receptor Alpha (RORα) modulates mitophagy to suppress mtDNA-cGAS-STING-NLRP3 signaling in aging microglia, offering therapeutic potential for HIE.
    Methods: A multi-omics approach combining single-cell RNA sequencing (scRNA-seq) of an HIE rat model, Weighted Gene Co-Expression Network Analysis (WGCNA), and LASSO regression identified RORα as a pivotal regulator. In vivo and in vitro HIE models with RORα overexpression were assessed via behavioral tests (morris water maze, tail suspension), reactive oxygen species (ROS) quantification, and molecular profiling (RT-qPCR, Western Blot, ELISA). Mitophagy inhibitor 3-MA was used to validate pathway dependence.
    Results: Multi-omics integration revealed RORα as a hub gene linked to inflammatory and metabolic pathways. RORα activation enhanced mitophagy, reducing mtDNA leakage by 43% and cGAS-STING activity by 68%, which suppressed NLRP3 inflammasome activation (p < 0.01). This correlated with improved cognitive/motor function in HIE rats (p < 0.05) and attenuated ROS/IL-1β levels. Critically, 3-MA reversed RORα's anti-inflammatory effects, confirming mitophagy dependence.
    Conclusion: RORα alleviates HIE by resolving microglial neuroinflammation through mitophagic inhibition of mtDNA-cGAS-STING-NLRP3 signaling. These findings position RORα as a novel therapeutic target for HIE, bridging mitochondrial quality control and neuroimmunology.
    Keywords:  NLRP3 inflammasome; RORα; cGAS-STING pathway; hypoxic-ischemic encephalopathy; mitophagy; neuroinflammation; scRNA-seq
    DOI:  https://doi.org/10.3389/fimmu.2025.1592737
  24. Clin Sci (Lond). 2025 Aug 13. pii: CS20180671_RET. [Epub ahead of print]139(15):
    Retraction: Inhibition of mitochondrial fission as a novel therapeutic strategy to reduce mortality upon myocardial infarction.
      
    DOI:  https://doi.org/10.1042/CS20180671_RET
  25. Front Med (Lausanne). 2025 ;12 1621079
    Bibliometric analysis of research hotspots and emerging trends in mitophagy and atherosclerosis (2004-2024).
    Shuchen Ding, He Zhang, Luxia Song, Xinyi Wang, Lifang Song, Wende Tian, Xuanye Chen, Hao Xu.
       Background: Mitophagy is closely involved in the onset, progression and pathological mechanisms of atherosclerosis. This study set out to provide a comprehensive overview and identify emerging research trends in the field.
    Methods: A systematic literature retrieval was conducted across the Web of Science Core Collection (WoSCC) for publications spanning 2004 to 2024. Bibliometric analyses and knowledge mapping were performed utilizing CiteSpace, VOSviewer, R-Bibliometrix, Scimago Graphica and Excel to evaluate the intellectual landscape of the field.
    Results: The analysis reveals a fluctuating but overall increasing trend in annual publications. The United States and China are the primary contributors to the body of research, with leading institutions predominantly located in China, the United States, and Russia. Notably, the works of Orekhov AN stand out in terms of both quantity and quality. The most cited studies is Forrester SJ's 2018 publication in Circulation Research. Additionally, keyword analysis highlights the prevailing research hotspots, including: (1) key molecules such as NF κB, NLRP3 inflammasome, and mitochondrial DNA; (2) critical pathological processes such as oxidative stress, mitochondrial dysfunction, and mitochondrial dynamics; and (3) and the role of mitophagy within vascular smooth muscle cells, endothelial cells, and macrophages in the pathogenesis of atherosclerosis.
    Conclusion: The study of mitophagy in atherosclerosis has garnered increasing attention, with substantial progress made in understanding its molecular and cellular mechanisms. This work highlights the current research hotspots and identifies prospective directions for future exploration. Further investigation into the intricate mechanisms governing mitophagy may uncover novel therapeutic strategies that could mitigate the progression of atherosclerosis.
    Keywords:  atherosclerosis; bibliometrics; mitophagy; molecules; pathological process
    DOI:  https://doi.org/10.3389/fmed.2025.1621079
  26. Neurochem Res. 2025 Aug 13. 50(4): 260
    O-GlcNAcylation Suppressed Apoptosis and Ferroptosis in Traumatic Brain Injury by Enhancing Mitophagy.
    Li Zhang, Maoxin Fei, Yaonan Peng, Tao Li, Xiangjun Ji, Jinqi Gao, Mi Tian.
      O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a distinctive post-translational modification (PTM), is ubiquitously present in numerous nuclear and mitochondrial proteins. The emerging role of O-GlcNAcylation is increasingly recognized for its involvement in various diseases. However, its role in traumatic brain injury (TBI) has not been explored. This study was aimed to explore the neuroprotection of O-GlcNAcylation in both in vivo and in vitro TBI models. Our results revealed that the levels of O-GlcNAcylation were increased after TBI. Up-regulation of O-GlcNAcylation by Thiamet G (TMG) provided neuroprotection after TBI. Moreover, TMG inhibited TBI-triggered blood-brain barrier (BBB) damage. Furthermore, TMG alleviated apoptosis and ferroptosis caused by TBI. Besides, TMG activated mitophagy after TBI, and the neuroprotection of TMG was attenuated when mitophagy was inhibited. Importantly, TMG also attenuated cell death, decreased apoptosis and ferroptosis, and activated mitophagy after TBI in vitro. Taken together, our data provided the first evidence that O-GlcNAcylation played a crucial role in TBI by activation of mitophagy.
    Keywords:  Apoptosis; Ferroptosis; Mitophagy; O-GlcNAcylation; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s11064-025-04519-3
  27. Gene. 2025 Aug 12. pii: S0378-1119(25)00510-4. [Epub ahead of print]967 149721
    AIM2 inflammasome-mediated cell pyroptosis regulates mitophagy to participates in high glucose-induced trophoblast cell damage.
    Huanhuan Guo, Qi Duan, Yuling Cao, Puchu Duan, Xuewen Kou, Tian Cui, Yanling Zhang.
      This study aimed to elucidate the role of absent in melanoma 2 (AIM2) in high glucose (HG)-induced trophoblast injury. An in vitro gestational diabetes mellitus (GDM) model was established by exposing HTR-8/SVneo cells to 25 nM glucose, followed by AIM2 knockdown. Cell viability, apoptosis, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), wound healing, and Transwell assays, respectively. Oxidative stress markers and inflammatory cytokines were quantified via specific assay kits. Immunofluorescence assays detected expressions of gasdermin D (GSDMD) and microtubule-associated protein 1 light chain 3B (LC3B). Furthermore, Western blot analysis was conducted to assess proteins related to mitophagy and pyroptosis. Results demonstrated a significant upregulation of AIM2 expression upon HG stimulation in HTR-8/SVneo cells. AIM2 silencing enhanced cell viability and migration, while attenuating HG-induced apoptosis, oxidative stress, and inflammatory responses. Mechanistic investigations revealed that AIM2 knockdown inhibited pyroptosis and activated mitophagy. Rescue experiments indicated that the protective effects conferred by AIM2 silencing against HG-induced trophoblast damage were reversed by the mitophagy inhibitor Mdivi-1. Collectively, these findings indicate that AIM2 silencing alleviates HG-induced trophoblast injury by regulating pyroptosis and mitophagy, suggesting AIM2 as a potential therapeutic target for GDM-related placental dysfunction.
    Keywords:  AIM2; Gestational diabetes mellitus; Mitophagy; Pyroptosis; Trophoblasts
    DOI:  https://doi.org/10.1016/j.gene.2025.149721
  28. Adv Sci (Weinh). 2025 Aug 12. e06150
    FBXO2 Alleviates Intervertebral Disc Degeneration via Dual Mechanisms: Activating PINK1-Parkin Mitophagy and Ubiquitinating LCN2 to Suppress Ferroptosis.
    Tongde Wu, Yanjin Wang, Beiduo Shen, Kai Guo, Ziqi Zhu, Yongzhou Liang, Jianhua Zeng, Desheng Wu.
      Intervertebral disc degeneration (IVDD), a leading cause of chronic low back pain, arises from nucleus pulposus (NP) cell dysfunction due to oxidative stress-induced mitophagy impairment and ferroptosis, though regulatory mechanisms remain unclear. F-box only protein 2 (FBXO2), a Kruppel-like factor 10 (KLF10)-regulated F-box protein, is downregulated in degenerated human NP tissues and correlates with disease severity. Overexpression of FBXO2 restores extracellular matrix (ECM) homeostasis by promoting matrix component synthesis and inhibiting catabolic enzymes, while its knockdown exacerbates ECM degradation. Under oxidative stress, FBXO2 activates PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) accumulation. Proteomics reveals that FBXO2 suppresses ferroptosis by attenuating lipid peroxidation, glutathione depletion, and iron overload. Mechanistically, FBXO2 binds lipocalin-2 (LCN2) via its FBA domain, promoting K27-linked polyubiquitination to drive proteasomal degradation of this ferroptosis inducer. FBXO2 co-expression reverses LCN2-induced mitochondrial dysfunction and ferroptosis markers. In vivo, adeno-associated virus 9 (AAV9)-mediated overexpression of FBXO2 ameliorates IVDD in rats, whereas FBXO2 knockout (KO) mice exhibit exacerbated IVDD. LCN2 silencing in FBXO2-deficient mice partially restores disc integrity and matrix component expression. These findings identify FBXO2 as a dual regulator coordinating mitophagy activation and ferroptosis suppression, offering therapeutic potential for IVDD progression.
    Keywords:  FBXO2; LCN2; ferroptosis; intervertebral disc degeneration; mitophagy
    DOI:  https://doi.org/10.1002/advs.202506150
  29. Sci Adv. 2025 Aug 15. 11(33): eadv6902
    USP30 inhibition augments mitophagy to prevent T cell exhaustion.
    Ruohan Zhang, Fengxia Gao, Jianying Li, Jiacheng Jin, Kangxuan Chen, Samhita Chaudhuri, Zhiwei Liao, Tong Xiao, Yang Xu, Haitao Wen, Kai He, Zihai Li, Gang Xin, Nuo Sun.
      The exhaustion of tumor-infiltrating CD8+ T cells poses a substantial challenge in cancer immunotherapy, with mitochondrial health essential for sustaining T cell functionality. Mitophagy, a critical process for mitochondrial quality control, is severely impaired in exhausted CD8+ T cells, yet the underlying mechanisms remain unclear. We identified ubiquitin-specific protease 30 (USP30), a mitochondrial deubiquitinase that inhibits mitophagy, as a key factor up-regulated in exhausted CD8+ T cells. Notably, prolonged antigen stimulation triggers the T cell receptor and nuclear factor of activated T cell 1 signaling, which drives the transcriptional up-regulation of USP30. Excitingly, our interventions targeting USP30 through genetic deletion or pharmacological inhibition effectively restored mitophagy, improved mitochondrial fitness, and rejuvenated CD8+ T cell effector functions. These interventions reinvigorated antitumor responses and markedly suppressed tumor growth. Our findings establish USP30 as a critical regulator of mitophagy and a promising therapeutic target for reversing T cell exhaustion and enhancing the efficacy of cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciadv.adv6902
  30. Int J Mol Sci. 2025 Jul 31. pii: 7400. [Epub ahead of print]26(15):
    Mitochondrial Metabolism in T-Cell Exhaustion.
    Fei Li, Yu Feng, Zesheng Yin, Yahong Wang.
      T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion.
    Keywords:  T-cell exhaustion; metabolic reprogramming; metabolism; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/ijms26157400
  31. Elife. 2025 Aug 13. pii: RP105834. [Epub ahead of print]14
    Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.
    Hiroki Taoka, Tadayoshi Murakawa, Kohei Kawaguchi, Michiko Koizumi, Tatsuya Kaminishi, Yuriko Sakamaki, Kaori Tanaka, Akihito Harada, Keiichi Inoue, Tomotake Kanki, Yasuyuki Ohkawa, Naonobu Fujita.
      Differentiated muscle cells contain myofibrils and well-organized organelles, enabling powerful contractions. Muscle cell reorganization occurs in response to various physiological stimuli; however, the mechanisms behind this remodeling remain enigmatic due to the lack of a genetically trackable system. Previously, we reported that a subset of larval muscle cells is remodeled into adult abdominal muscle through an autophagy-dependent mechanism in Drosophila. To unveil the underlying mechanisms of this remodeling, we performed a comparative time-course RNA-seq analysis of isolated muscle cells with or without autophagy. It revealed both transcriptional dynamics independent of autophagy and highlighted the significance of BNIP3-mediated mitophagy in muscle remodeling. Mechanistically, we found that BNIP3 recruits autophagic machinery to mitochondria through its LC3-interacting motif and minimal essential region, which interact with Atg8a and Atg18a, respectively. Loss of BNIP3 leads to a substantial accumulation of larval mitochondria, ultimately impairing muscle remodeling. In summary, this study demonstrates that BNIP3-dependent mitophagy is critical for orchestrating the dynamic process of muscle remodeling.
    Keywords:  BNIP3; D. melanogaster; Drosophila; autophagy; cell biology; developmental biology; metamorphosis; mitochondria; muscle
    DOI:  https://doi.org/10.7554/eLife.105834
  32. Adv Sci (Weinh). 2025 Aug 11. e01041
    Melatonin Modulates Glucose Metabolism Reprogramming via Targeting G6PD to Alleviate Lead-Induced Hepatocytes Pyroptosis in Common Carp (Cyprinus carpio L.).
    Zhiying Miao, Xiaofeng Ji, Lai Wei, Zhiruo Miao, Shiwen Xu.
      Lead (Pb) is a prevalent toxic contaminant that accumulates in freshwater ecosystems, posing severe toxicity to non-target species such as fish and contributing to the pathogenesis of liver disease. Melatonin (Mel) is a well-known natural antioxidant that has been found to improve liver function through its potent anti-inflammatory properties. However, whether and how Mel alleviates Pb-triggered hepatotoxicity remains unclear. Mitochondria play a vital role in glucose metabolism, and glucose metabolic reprogramming is characterized by elevated glycolysis, resulting in lactate accumulation, which is a precursor for histone lactylation, an epigenetic modification. In this study, it is demonstrated that Pb triggers glucose metabolism reprogramming, resulting in lactate accumulation. Specifically, lactate links glycolysis and mitochondrial homeostasis via histone H3 lysine 18 lactylation (H3K18la), which modulates the activity of dynamin-related protein 1 (DRP1). Furthermore, DRP1 actively mediates mitochondrial fragmentation, thereby facilitating inflammatory signals derived from the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Additionally, the results first demonstrate that Mel redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) by targeting glucose-6-phosphate dehydrogenase (G6PD). In summary, Mel targets G6PD to suppress glycolysis-driven H3K18la and DRP1 transcription, thereby maintaining mitochondrial homeostasis to alleviate hepatocytes pyroptosis dependent on cGAS-STING pathway under Pb exposure.
    Keywords:  glucose metabolism reprogramming; glucose‐6‐phosphate dehydrogenase; histone H3 lysine 18 lactylation; lead; melatonin
    DOI:  https://doi.org/10.1002/advs.202501041
  33. Exp Eye Res. 2025 Aug 13. pii: S0014-4835(25)00339-2. [Epub ahead of print] 110568
    Stachydrine Mitigates High Glucose-Induced Apoptosis in Human Lens Epithelial Cells by Activating Mitophagy.
    Guijia Wu, Xiteng Chen, Wei Wang, Zhenyu Kou, Han Mao, Yijing Wang, Lijie Dong, Tingting Lin, Fang Tian.
      Diabetic cataract (DC) is a prevalent complication of diabetes. This condition often leads to significant visual impairment and, in some cases, blindness. Recent studies have highlighted the potential protective effects of natural plant extracts in the context of DC. Stachydrine (STA), an alkaloid derived from Leonurus heterophyllus Sweet, has been identified as a natural compound with superior bioavailability and fewer side effects than conventional antioxidants. However, its protective role in high-glucose-induced lens epithelial cell damage remains to be fully elucidated. In this study, we established a high-glucose model using HLE-B3 cells and assessed apoptosis following STA treatment. Mitochondrial network morphology was analyzed using the ImageJ software. To further investigate the role of autophagy in STA's effects, we employed the autophagy inhibitor 3-Methyladenine (3-MA). Our results indicated that high glucose exposure decreased autophagosome formation and lysosomal activity, while STA treatment significantly increased both. Furthermore, STA enhanced LC3B expression and reduced P62 levels, counteracting the effects of high glucose. Regarding mitochondrial morphology, STA effectively restored the shape, branching, and area, all of which were diminished by high glucose exposure. Additionally, STA effectively ameliorated mitochondrial network damage induced by high glucose. Notably, when the cells were treated with 3-MA, STA's protective effects on apoptosis and mitochondrial morphology were significantly reversed. In conclusion, our findings suggest that STA exerts protective effects against high-glucose-induced damage by regulating mitophagy, and this autophagy-dependent mechanism may hold therapeutic potential for the treatment of diabetic cataract.
    Keywords:  3-MA; Cell apoptosis; Diabetic cataract; Mitophagy; Stachydrine
    DOI:  https://doi.org/10.1016/j.exer.2025.110568
  34. Pediatr Res. 2025 Aug 09.
    Investigating mitophagy mechanisms in bronchopulmonary dysplasia through bioinformatics.
    Chenshuai Li, Yalei Wang, Xinying Wang, Yali Li.
       BACKGROUND: Bronchopulmonary dysplasia (BPD) is a prevalent respiratory disease in premature infants and is accompanied by impaired lung function, increased infection risk, and other long-term complications. This study aimed to elucidate the molecular mechanisms of BPD, especially mitophagy.
    METHODS: Bioinformatics analyses were performed to identify differentially expressed genes (DEGs) in BPD. Weighted gene co-expression network analysis (WGCNA) was used to explore gene modules associated with mitophagy, functional enrichment analyses to identify key biological processes, and immune infiltration to assess immune cell differences.
    RESULTS: Among the 720 DEGs identified, 419 were upregulated and 301 were downregulated: these may serve as potential BPD biomarkers. WGCNA revealed that the turquoise module was strongly related to mitophagy (r = -0.6061, p < 0.05), indicating its significance in BPD pathogenesis. Enrichment analyses highlighted leukocyte migration and neutrophil extracellular trap formation, suggesting immune-mediated inflammatory response. Eight hub genes (S100P, CDC42EP3, CEACAM3, CKLF, RGL4, DOK3, B4GALT5, and MCEMP1) were identified as potential therapeutic targets. Immune infiltration analysis revealed significant differences in neutrophils and activated CD8+T cells, underscoring the immune system's role in BPD.
    CONCLUSION: Key molecular players and pathways involved in BPD were elucidated, providing insights for future targeted therapies addressing immunity and mitophagy in BPD.
    IMPACT: This study identifies CEACAM3 and CDC42EP3 as key genes involved in mitophagy and immune dysregulation in bronchopulmonary dysplasia (BPD). It provides novel insights into the TNF-α/NF-κB signaling pathway and its role in the pathogenesis of BPD. This study advances biomarker discovery by associating CEACAM3 with neutrophil infiltration and CDC42EP3 with CD8+ T cell activity. The selected machine learning and bioinformatics approaches enhance the diagnostic accuracy and therapeutic targeting of BPD. These findings lay the foundation for future translational research in guiding personalized interventions for high-risk neonates.
    DOI:  https://doi.org/10.1038/s41390-025-04319-z
  35. J Appl Toxicol. 2025 Aug 11.
    TCDD Induces Hepatocytes Lipid Deposition via Downregulation of MFN2.
    Changming Xing, Yongjun Ai, Yue Wu, Xiping Wang, Haoyu Ding, Chunxi Wei, Guangfei Xu, Wenxing Sun.
      The persistent environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been implicated in hepatic lipid metabolism disorders and steatosis. However, the precise mechanisms underlying TCDD-induced hepatic lipid deposition remain incompletely elucidated. Mitofusin 2 (MFN2), a key mitochondrial dynamics protein, plays a critical role in lipid metabolism, as its deficiency leads to metabolic dysregulation. In this study, we investigate the role of MFN2 in TCDD-induced lipid deposition. Our findings demonstrate that TCDD exposure significantly reduces MFN2 protein expression both in vivo and in vitro, while concomitantly decreasing mitochondrial membrane potential and increasing reactive oxygen species (ROS) levels in Huh7 cells. Notably, overexpression of MFN2 effectively mitigates TCDD-induced pathological effects, preventing lipid accumulation, restoring mitochondrial membrane potential, and reducing ROS levels. Mechanistically, although TCDD does not alter the MFN2 mRNA expression, it promotes protein degradation through enhanced ubiquitination in vitro. These findings demonstrate that TCDD induces lipid accumulation in Huh7 cells through ubiquitination-mediated degradation of MFN2. Our study thus identifies MFN2 as a novel target in TCDD-induced hepatic steatosis.
    Keywords:  MFN2; ROS; TCDD; mitochondrial membrane potential
    DOI:  https://doi.org/10.1002/jat.4890
  36. bioRxiv. 2025 Jul 14. pii: 2025.07.11.664440. [Epub ahead of print]
    RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis.
    Simran Motwani, Somya Bhandari, Shivani Chitkara, Rajat Ujjainiya, Shantanu Sengupta, Arnab Mukhopadhyay.
      Adaptive modulation of physiological traits in response to environmental variability, particularly dietary fluctuations, is essential for organismal fitness. Such adaptability is governed by complex gene-diet interactions, yet the molecular circuits integrating microbe-derived metabolites with host metabolic and stress response pathways remain less explored. Here, we identify the conserved mechanistic target of rapamycin complex 2 (mTORC2) component, RICTOR, as a critical regulator of dietary plasticity in Caenorhabditis elegans , specifically in response to bacterially derived vitamin B12 (B12). Loss of rict-1 , the C. elegans ortholog of RICTOR, confers enhanced osmotic stress tolerance and longevity on B12-rich bacterial diets. These phenotypic adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the folate-methionine cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism. The latter catalyzes the formation of succinyl-CoA, subsequently converted to succinate via the tricarboxylic acid (TCA) cycle. Elevated succinate levels were found to induce mitochondrial fragmentation, thereby activating mitophagy, an autophagic process indispensable for the increased stress resilience and longevity observed in the rict-1 mutants. Crucially, this Met-C-mitophagy axis is modulated by microbial inputs, with B12 and methionine acting as proximal dietary signals. Our findings delineate a mechanistic framework through which RICTOR restrains host sensitivity to microbial-derived metabolites, thus maintaining mitochondrial homeostasis and regulating lifespan. This work reveals a pivotal role for RICTOR in insulating host physiology from environmental nutrient-driven perturbations by modulating organellar quality control pathways.
    DOI:  https://doi.org/10.1101/2025.07.11.664440
  37. Sci Rep. 2025 Aug 12. 15(1): 29522
    Tyrosine phosphatase Shp2 accelerated the progression of dilated cardiomyopathy via upregulating NF-κB/Src/FAK signaling induced ROS and mitophagy.
    Jingxia Hao, Hua Wang, Bo Li, Jingshi Chen, Wenlu Wang, Yingxue Wang, Yingqian Zhang.
      The purpose of this study was to investigate whether tyrosine phosphatase Shp2 can promote the progression of dilated cardiomyopathy by upregulating intracellular oxidative stress and subsequently promoting mitophagy. Macrophage-specific Shp2 knockout mice were cultured and a dilated cardiomyopathy model was established. Ultrasonography, Masson staining and WGA staining were used to detect the condition of mouse hearts. Immunofluorescence, Western blot and EL were used to detect the expression of relevant proteins in mouse myocardial tissues. Transmission electron microscopy was used to examine the morphology of mouse myocardial cells and their internal mitochondria. Primary BMMs from wild-type mice and specific Shp2 knockout mice were co-cultured with normal myocardial cell. Western blot was used to detect the expression of relevant proteins in BMMs and myocardial cells. Transwell assay was used to measure the migration and invasion ability of BMMs, and immunofluorescence staining was used to detect the expression level of PINK protein in myocardial cells to validate the Western blot results. Dilated cardiomyopathy was ameliorated in DCM mice with specific knockout of Shp2, which showed attenuation of heart structure, degree of fibrosis in myocardial tissue, and degree of cardiomyocyte dilatation. And the degree of autophagy in myocardial tissue was significantly reduced as observed by western blot and transmission electron microscopy. Subsequent cellular experiments also verified that specific knockdown of Shp2 inhibited the invasion of BMMs. And it also mediated the ROS/NF-κB/Src/FAK signalling pathway to inhibit the expression of related autophagy and apoptosis proteins. Tyrosine phosphatase Shp2 accelerated the progression of dilated cardiomyopathy via upregulating NF-κB/Src/FAK signaling induced ROS and mitophagy.
    Keywords:  BMMs; Dilated cardiomyopathy; Mitophagy; Oxidative stress; SHP-2
    DOI:  https://doi.org/10.1038/s41598-025-04375-9
  38. BMC Gastroenterol. 2025 Aug 13. 25(1): 582
    Evaluation of PINK1 protein expression as a predictive marker for the efficacy of adjuvant chemotherapy in colorectal cancer: a retrospective study.
    Takatsugu Fujii, Masataka Hirasaki, Yasuo Kamakura, Tomonori Kawasaki, Satoshi Yamasaki, Yasuhiro Ishiyama, Chikashi Hiranuma, Tetsuya Hamaguchi, Yasumitsu Hirano, Shinichi Sakuramoto.
       BACKGROUND: PTEN-induced kinase 1 (PINK1) is involved in mitochondrial quality control via mitophagy, and recent studies have reported that its overexpression is associated with chemoresistance and poor prognosis in multiple malignant tumors. However, the clinical significance of PINK1 expression in colorectal cancer remains unclear. In this study, we investigated the association among PINK1 protein expression, clinicopathological factors, and prognosis in patients with colorectal cancer who underwent adjuvant chemotherapy after curative surgery.
    METHODS: We retrospectively analyzed 83 patients with colorectal cancer who underwent curative surgery and fluoropyrimidine-based adjuvant chemotherapy in 2016. Expression of PINK1 and autophagy-related protein LC3 was evaluated by immunohistochemical staining, and the percentage of positive cells and staining intensity were scored. The association between PINK1 expression and the prognosis of 25 patients with confirmed recurrence was analyzed in detail. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models. Furthermore, in 11 cases with RNA sequencing analysis available among the recurrent cases, gene expression profiles were compared based on PINK1 expression levels, and biological characteristics were evaluated.
    RESULTS: PINK1 high expression was observed in 42.2% of the cases. No significant association was found between PINK1 and LC3 expression and overall survival (OS) or recurrence-free survival (RFS). However, in the recurrence group (n = 25), PINK1 high expression was significantly associated with a shorter OS (p = 0.024). In multivariate analysis, histological differentiation grade and high PINK1 expression were identified as independent prognostic factors (PINK1: hazard ratio 5.345, 95% confidence interval, 1.343-21.276; p = 0.017). RNA sequencing revealed increased expression of genes associated with autophagy and amino acid transport in the high PINK1 expression group.
    CONCLUSIONS: High PINK1 expression is associated with poor prognosis in colorectal cancer recurrence and may be involved in the promotion of chemotherapy resistance and cellular stress tolerance. PINK1 is a promising biomarker as a prognostic predictor and a new therapeutic target for adjuvant chemotherapy after surgery.
    Keywords:  Adjuvant chemotherapy; Autophagy; Chemoresistance; Colorectal cancer; LC3; PINK1; Single nucleotide polymorphism
    DOI:  https://doi.org/10.1186/s12876-025-04197-z
  39. J Nutr Biochem. 2025 Aug 12. pii: S0955-2863(25)00237-2. [Epub ahead of print] 110075
    Heterophyllin B alleviates diabetes-induced myocardial injury by regulating MAVS-mediated mitochondrial homeostasis.
    Lan Li, Zheting Liu, Haoran Hu, Qiuru Wang, Jing Wang, Liang Jin, Shujing Zhang, Jihua Wei, Lu Zhao, Ziying Chen, Qian Liu, Keyang Zhu, Ling Zhang.
      Diabetic cardiomyopathy (DCM), a major cause of diabetic mortality, lacks effective therapies. This study investigated the cardioprotective role of Heterophyllin B (HET-B), a natural compound and its underlying mechanisms in DCM. Using streptozotocin-induced DCM mice and high glucose (HG)-treated H9C2/neonatal cardiomyocytes, we assessed cardiac function, mitochondrial homeostasis, and apoptosis. HET-B significantly improved cardiac function, indicated by increased ejection fraction (EF) and fractional shortening (FS). It also reduced cardiomyocyte apoptosis (in vivo/vitro), and ameliorated HG-induced mitochondrial damage, characterized by dysfunction, fragmentation, and excessive reactive oxygen species (ROS) production. HET-B enhanced mitochondrial fusion protein OPA1 expression and reduced Bax/Bcl2, cytochrome C (Cyt C) release and caspase-3 cleavage. Molecular docking and cellular thermal shift assays identified mitochondrial antiviral-signaling protein (MAVS) as a potential target of HET-B. HET-B reversed MAVS downregulation induced by HG/DCM in vitro and in vivo. Importantly, MAVS knockdown via siRNA abolished HET-B's protection against HG-induced apoptosis and mitochondrial damage. Furthermore, HET-B restored HG-impaired autophagic flux, reducing autolysosome accumulation and normalizing LC3-II. Collectively, HET-B, a natural compound, attenuates diabetic myocardial injury by targeting MAVS, thereby enhancing autophagy, preserving mitochondrial homeostasis, and inhibiting apoptosis, positioning it as a promising DCM therapeutic candidate.
    Keywords:  Autophagy; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.110075
  40. Bioact Mater. 2025 Nov;53 773-788
    Autophagic-active nanosystem for senile bone regeneration by in-situ mitochondrial biogenesis and intercellular transfer.
    Meihua Zhang, Xiaoqing Sun, Ming Lu, Xingyou Wang, Shuyao Liu, Xiaoqin Hu, Jing He, Bin Luo, Yao Wu.
      Natural intercellular mitochondrial transfer has been recognized as a pivotal mechanism in the treatment of various diseases. Bone marrow mesenchymal stem cells (BMSCs), owing to their low bioenergetic demands and inherent homing capacity, are considered highly promising mitochondrial donor cells. However, this strategy is limited in senile osteoporosis (SOP) because large amounts of ROS produced by mitochondrial oxidative stress in senescent BMSCs (S-BMSCs) impairs their viability and function. Here, we report that in-situ treatment of senescent bone marrow-derived macrophages (S-BMDMs) with a cerium-based nanosystem (CNS) composed of antioxidant and energy-active units, which exhibits superior autophagy-activating capability, effectively restores the viability and osteogenic function of S-BMSCs by promoting mitochondrial biogenesis and transfer. Transcriptomic profiling revealed that the SIRT1-PGC-1α axis, significantly associated with autophagy activation, drives mitochondrial biogenesis in S-BMDMs. The efficient intercellular mitochondrial transfer ameliorates the senescent bone microenvironment, rescues S-BMSCs functionality, and enhances bone formation. In conclusion, the autophagy-activating CNS, by effectively rejuvenating S-BMDMs and promoting mitochondrial biogenesis and transfer, provides an innovative therapeutic strategy for SOP-associated bone regeneration.
    Keywords:  Autophagy activation; Cerium-based nanosystem; Mitochondrial biogenesis; Mitochondrial transfer; Senile osteoporosis
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.07.034
  41. Free Radic Biol Med. 2025 Aug 08. pii: S0891-5849(25)00880-9. [Epub ahead of print]240 1-14
    The DRP1 inhibitory peptide P110 provides neuroprotection after subarachnoid hemorrhage by suppressing neuronal apoptosis and stabilizing the blood-brain barrier.
    Shuangying Hao, Junrui Luo, Shuai Yuan, Wenbo Chen, Xinhong Zhang, Cheng Zhao, Hao Xu, Zhiqiang Liu, Dingding Zhang.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are key pathological features of early brain injury (EBI) following subarachnoid hemorrhage (SAH). Increasing evidence highlights mitochondria-associated ER membranes (MAMs) as central regulators of ER proteostasis and mitochondrial quality control. Given the dual role of dynamin-related protein 1 (DRP1) in modulating MAMs integrity and mitochondrial dynamics, we hypothesized that pharmacological inhibition of DRP1 would exert neuroprotective effects in SAH by preserving inter-organelle communication and restoring mitochondrial bioenergetics. To test this hypothesis, we employed an endovascular perforation model to induce SAH in mice and used oxyhemoglobin-treated HT22 hippocampal neurons to mimic SAH in vitro. Both models demonstrated a significant increase in DRP1 and phosphorylated DRP1 (p-DRP1) expression at 24 h and 72 h post-injury. Treatment with the selective DRP1 inhibitor P110 effectively reduced DRP1 and p-DRP1 levels, attenuated neuronal apoptosis and blood-brain barrier disruption, and improved neurological outcomes. Mechanistically, P110 treatment significantly mitigated SAH-induced inflammation, MAMs formation, mitochondrial calcium overload, reactive oxygen species production, ATP depletion and cytochrome c release. Collectively, these findings suggest that DRP1 inhibition via P110 confers neuroprotection after SAH by modulating inflammation, MAMs Formation, and mitochondrial dysfunction.
    Keywords:  DRP1; Inflammation; Mitochondria-associated ER membranes; Neuroprotection; P110; Subarachnoid hemorrhage
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.011
  42. Tissue Barriers. 2025 Aug 14. 2537991
    Mitochondrial dysfunction and oxidative stress in Parkinson's disease: mechanisms, biomarkers, and therapeutic strategies.
    Pothu Usha Kiran, Jigar Haria, Reena Rani, Sudhir Singh.
       BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by motor symptoms and progressive degeneration of dopaminergic neurons. Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress are major contributors to PD pathogenesis.
    OBJECTIVES: This review explores the molecular mechanisms underlying PD, emphasizing mitochondrial dysfunction and oxidative stress. It also examines genetic and environmental contributors, emerging biomarkers, and future treatment strategies.
    METHODS: An extensive literature review was conducted, focusing on mitochondrial biology, oxidative stress, genetic mutations, and environmental toxins relevant to PD. Investigations into treatment options - including redox therapies, gene therapies, and lifestyle approaches - were also examined.
    RESULTS: Mitochondrial dysfunction in PD includes disrupted oxidative phosphorylation and elevated reactive oxygen species (ROS). This also affects calcium homeostasis, especially in substantia nigra neurons. Genetic mutations (PINK1, Parkin, DJ-1, LRRK2, GBA) impair mitophagy and antioxidant defenses. Environmental toxins (e.g. MPTP, rotenone) further damage mitochondrial function and contribute to dopaminergic neuron loss. Emerging biomarkers involve measurements of lipid peroxidation and mitochondrial DNA damage. Promising therapeutic strategies include mitochondria-targeted antioxidants (e.g. MitoQ), PINK1-based gene therapy, Parkin activation, ketogenic diet, and exercise-induced mitochondrial biogenesis.
    CONCLUSIONS: Mitochondrial dysfunction and oxidative stress are central to PD pathophysiology. Strategies targeting these mechanisms may slow disease progression. Future research should emphasize combination therapies and early intervention trials, alongside biomarker integration, to enhance clinical outcomes.
    Keywords:  Mitochondrial dysfunction; Parkinson’s disease; oxidative stress
    DOI:  https://doi.org/10.1080/21688370.2025.2537991
  43. Phytomedicine. 2025 Jul 28. pii: S0944-7113(25)00745-7. [Epub ahead of print]146 157106
    Mitochondrial pathways in rheumatoid arthritis: Therapeutic roles of traditional Chinese medicine and natural products.
    Hui Li, Shufan Fu, Ping Shen, Xiaojun Zhang, Yinfeng Yang, Jinchen Guo.
       BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, cartilage destruction and systemic complications. Mitochondrial dysfunction has emerged as a critical contributor to RA pathogenesis by disrupting apoptosis regulation, immune signaling and redox balance, thereby promoting immune cell activation and joint damage. Traditional Chinese Medicine (TCM) and natural products offer unique therapeutic advantages due to their multi-component, multi-target properties, particularly in restoring mitochondrial homeostasis. However, a comprehensive synthesis of their mitochondrial-targeted mechanisms in RA remains lacking.
    PURPOSE: This study aims to elucidate the role of mitochondrial dysfunction in RA progression and systematically summarize the therapeutic mechanisms and potential of TCM and natural products targeting mitochondrial pathways.
    METHODS: A systematic literature search (2005-2025) was conducted using PubMed, Web of Science, ScienceDirect and Google Scholar with keywords related to mitochondrial dysfunction, RA and TCM/natural products. Studies included in vitro, in vivo and clinical evidence of mitochondrial-targeting compounds.
    RESULTS: A total of 128 studies were summarized from an initial pool of 297 articles. Findings indicate that TCM and natural compounds improve RA outcomes by modulating oxidative stress, reducing pro-inflammatory cytokines, restoring mitochondrial dynamics, enhancing mitophagy and regulating immune responses.
    CONCLUSION: TCM and natural products demonstrate significant promise in restoring mitochondrial function and alleviating RA symptoms through multi-targeted pathways. Future research should focus on pharmacokinetics, standardization of formulations and biomarker-driven clinical trials to enhance translational potential and validate therapeutic efficacy.
    Keywords:  Immune regulation; Mitochondrial dysfunction; Natural products; Rheumatoid arthritis; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.phymed.2025.157106
  44. Autophagy. 2025 Aug 11.
    A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
    Qing Shen, Madiha Natchi Samu Shihabdeen, Fan Yang, Naweed I Naqvi.
      Ferroptosis remains an underexamined iron- and lipid peroxides-driven cell death modality despite its importance to several human and plant diseases and to immunity thereof. Here, we utilized chemical cell biology, molecular genetics and biochemical analyses to gain insights into how the fungal pathogen Magnaporthe oryzae undergoes ferroptosis strictly in the spore cells to successfully transit to infectious development. We reveal a complex functional interdependency and crosstalk between intrinsic ferroptosis and autophagy-mediated mitochondrial degradation. Mechanistically, the requirement of mitophagy for ferroptotic cell death was attributed to its ability to maintain a pool of metabolically active mitochondria. Pharmacological disruption of the electron transport chain or membrane potential led to complete inhibition of ferroptosis, thus simulating the loss of mitophagy phenotypes. Conversely, increased mitochondrial membrane potential in a mitophagy-defective mutant alleviated the ferroptosis defects therein. Graded inhibition of mitochondrial coenzyme Q biosynthesis with or without ferroptosis inhibitor liproxstatin-1 distinguished its antioxidant function in such regulated cell death. Membrane potential-dependent regulation of ATP synthesis and iron homeostasis, as well as dynamics of tricarboxylic acid cycle enzyme AcoA (aconitase A) in the presence or absence of mitophagy, mitochondrial poisoning or iron chelation further linked mitochondrial metabolism to ferroptosis. Last, we present an important bioenergetics- and redox-based mitochondrial regulon essential for intrinsic ferroptosis and its precise role in fungal pathogenesis leading up to the establishment of the devastating rice blast disease.
    Keywords:  Cell death; coenzyme Q; iron; mitochondrial metabolism; mitophagy; rice blast
    DOI:  https://doi.org/10.1080/15548627.2025.2546944
  45. Ecotoxicol Environ Saf. 2025 Aug 09. pii: S0147-6513(25)01139-X. [Epub ahead of print]303 118794
    Bisphenol TMC disturbs mitochondrial activity and biogenesis, reducing lifespan and healthspan in the nematode Caenorhabditis elegans.
    Laxmi Rathor, Ho Jeong Lee, Taylor McElroy, Steven Beck, Julia Bailey, Yi Sheng, Stephanie Wohlgemuth, Sung-Hwan Kim, Hun Hwan Kim, Rui Xiao, Jeong-Doo Heo, Sung Min Han, Moonjung Hyun.
      Rising concerns about Bisphenol A (BPA) toxicity have prompted the search for safer alternatives. However, concerns persist regarding the safety of replacements like bisphenol TMC (BPTMC), a rapidly emerging BPA substitute. Utilizing the in vivo model organism Caenorhabditis elegans (C. elegans), whose shared genes mirror human biology, we aim to unveil the potential toxicity of BPTMC on a live animal. C. elegans exposed to 1 mM BPTMC exhibited developmental delays, reduced reproduction, and diminished longevity. Furthermore, investigation across multiple developmental stages of C. elegans revealed increased mortality, heightened oxidative stress, and impaired thermal stress resistance. Notably, exposure to BPTMC resulted in mitochondrial unfolded protein response (mitoUPR) and abnormalities, including reduced oxygen consumption and lowered mitochondrial membrane potential. Additionally, BPTMC increased reactive oxygen species levels but decreased mitochondrial population. Transcriptome analysis revealed that BPTMC induces alterations in the expression of genes associated with mitochondrial biogenesis. Our findings raise crucial concerns about BPTMC as a safe BPA alternative. The observed widespread toxicity across key life stages suggests a need for further investigation into the potential toxicity of BPTMC on human health and environmental consequences.
    Keywords:  Bisphenol TMC; Caenorhabditis elegans; Healthspan; Lifespan; Mitochondria; Toxicity
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118794
  46. Am J Chin Med. 2025 Aug 13. 1-32
    Gastrodia elata Polysaccharide Ameliorates Parkinson's Disease by Enhancing Dopamine Levels, Inhibiting NLRP3 Inflammasome Activation, and Promoting Mitochondrial Autophagy.
    Shidai Li, Ming Li, Yangping Li, Si Liang, Li Ling, Hongjie Wang, Jiguang Guo.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic (DA) neuron loss and neuroinflammation. Current therapies fail to halt disease progression, which underscores the need for new treatments. This study investigated the neuroprotective effects and mechanisms of Gastrodia elata polysaccharide (GEP) in MPTP-induced PD mice. GEP was administered for two weeks, and motor function was assessed using behavioral tests. Immunohistochemical and Western Blot analyses evaluated DA neuron survival, microglial activation, and NLRP3 inflammasome components. GEP-medicated serum (GMS) was applied to SH-SY5Y neuroblastoma cells exposed to neuroinflammatory conditions, and metabolomic analysis identified key metabolites. GEP improved motor function, reduced DA neuron loss, and increased tyrosine hydroxylase expression. It suppressed microglial activation, decreased NLRP3 inflammasome components, and lowered pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). GMS reduced ROS levels, enhanced mitochondrial membrane potential, and promoted autophagy in SH-SY5Y cells. Metabolomic analysis revealed elevated dopamine levels in GMS, linked to NLRP3 inflammasome inhibition, and reduced neuroinflammation. GMS also activated the PINK1/Parkin pathway to promote mitochondrial autophagy and prevent apoptosis. GEP alleviates PD symptoms by targeting neuroinflammation, mitochondrial dysfunction, and dopamine regulation, which highlights its potential as a therapeutic candidate. Further research is needed to explore its long-term efficacy and clinical applications.
    Keywords:  Gastrodia elata Polysaccharides; Microglia; Mitochondrial Autophagy; NLRP3 Inflammasome; PINK1/Parkin Pathway; Parkinson’s Disease
    DOI:  https://doi.org/10.1142/S0192415X25500673
  47. Mol Immunol. 2025 Aug 14. pii: S0161-5890(25)00205-6. [Epub ahead of print]186 48-62
    Gelatin enhances bacteria-phagocytosis via a ROS-mitochondria-STING axis in differentiated human macrophage-like U937 cells.
    Xiaoli Sun, Meiling Li, Yuhang Ma, Kaihui Chen, Shunuo Jiang, Toshihiko Hayashi, Kikuji Itoh, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Weiwei Liu, Takashi Ikejima.
      The recruitment of macrophages to a pathological site is accompanied by the change in surrounding extracellular matrix. The pathological foci in a highly inflammatory status contain certain amounts of gelatin, the denatured form of collagen. We previously revealed that precoating the cell dishes with gelatin, but not type I collagen, enhances bacteria-phagocytosis capacity of phorbol 12-myristate 13-acetate (PMA)-treated macrophage-like human histiocytic lymphoma U937 cells. The present study further reveals that gelatin-precoating increases the amount of reactive oxygen species (ROS) in PMA-treated U937 cells, which contributes to the enhanced phagocytosis of bacteria, including both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. ROS in cells on gelatin-precoated culture plates cause impairments on mitochondria, as shown by the reduced mitochondrial membrane potential and ATP levels, as well as the increase in oxidative lesions in mitochondrial DNA. These mitochondrial damages lead to the activation of stimulator of interferon genes (STING) pathway, which enhances the bacteria-phagocytosis in PMA-treated U937 cells. Simultaneously, mitophagy-related proteins, such as PINK1, parkin and LC3 II, all increase following the elevation of ROS levels. Of note, mitophagy restricts the mitochondrial disorders, forming a feedback negative regulation for the effects of ROS, and works against bacteria-phagocytosis. This study reveals a core function of ROS-mitochondria-STING axis during gelatin-enhanced bacteria-phagocytosis in PMA-stimulated macrophage-like U937 cells, and provides possibility for clinically applying gelatin as a protectant for bacterial infection in some lesions.
    Keywords:  Bacteria-phagocytosis; Gelatin; Macrophage; Mitophagy; ROS; STING
    DOI:  https://doi.org/10.1016/j.molimm.2025.08.011
  48. J Transl Med. 2025 Aug 14. 23(1): 917
    Targeting the MARCH5-MFN2 axis to enhance mitochondrial fusion and sensitize multiple myeloma cells to venetoclax.
    Ilenia Valentino, Maria Eugenia Gallo Cantafio, Roberta Torcasio, Pierpaolo Murfone, Ludovica Ganino, Alessia Gallo, Nicola Cuscino, Ida Perrotta, Federico Tallarigo, Maria Mesuraca, Massimo Gentile, Giuseppe Viglietto, Nicola Amodio.
       BACKGROUND: Accumulating evidence suggests that mitochondrial fission and fusion events are imbalanced in cancer due to defective activity of their key regulators. In this study, we investigated the functional role of the E3 ubiquitin ligase Membrane-Associated Ring-CH-Type Finger 5 (MARCH5) in regulating cell growth, metabolic reprogramming and drug resistance in multiple myeloma (MM) through the negative regulation of the mitochondrial fusion driver mitofusin 2 (MFN2).
    METHODS: Cell viability and apoptosis were evaluated in MM cell lines or in co-culture with stromal cells using the CellTiter-Glo® Cell Viability Assay and Annexin V/7-AAD staining, respectively. Clonogenic potential was assessed using methylcellulose-based colony formation assays. Protein stability was determined via cycloheximide chase experiments, while protein-protein interactions by co-immunoprecipitation. Mitochondrial ultrastructure was analyzed by transmission electron microscopy. Oxygen consumption was measured using high-resolution respirometry in live cells. Transcriptomic profiling was performed using the Illumina NGS platform, and mRNA and protein levels were quantified by quantitative RT-PCR and Western blot, respectively. In vivo anti-tumor efficacy was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells, using an MFN2-inducible model or following intraperitoneal administration of leflunomide. Immunohistochemistry was used to analyze tumor xenografts and mouse organs.
    RESULTS: Knockdown of MARCH5 led to a pronounced elongation of mitochondria accompanied by increased expression of MFN2, likely resulting from reduced MARCH5-mediated ubiquitylation. Functionally, silencing MARCH5 impaired mitochondrial oxidative phosphorylation (OXPHOS) and reduced ATP production, ultimately leading to mitochondrial dysfunction and apoptosis in MM cells. Notably, similar phenotypic and functional effects were observed following either genetic overexpression or pharmacological activation of MFN2 using leflunomide, both in vitro and in vivo in a murine xenograft model of MM. Transcriptomic profiling of MARCH5-depleted cells revealed downregulation of gene sets associated with mitochondrial electron transport chain (ETC) and ATP synthesis, pathways implicated in the development of venetoclax resistance. Consistently, both MARCH5 knockdown and MFN2 upregulation enhanced the sensitivity of MM cells to venetoclax.
    CONCLUSION: Shifting mitochondrial dynamics toward fusion by targeting the MARCH5-MFN2 axis impairs ETC and OXPHOS, thereby sensitizing MM cells to venetoclax. These findings provide preclinical evidence for the potential therapeutic use of MFN2 inducers to enhance venetoclax responsiveness of MM patients.
    Keywords:  MARCH5; Mitochondrial dynamics; Multiple myeloma; Venetoclax
    DOI:  https://doi.org/10.1186/s12967-025-06942-0
  49. Am J Physiol Endocrinol Metab. 2025 Aug 12.
    Resilience of the Mitochondrial Reticulum in Aging.
    Robert G Leija, José Pablo Vázquez-Medina, George A Brooks.
      Resting and maximal exercise respiratory rates (V̇O2) decline in aging. Those losses have been attributed to impaired mitochondrial function, but the data are inconsistent with healthy aging. To interrogate the hypothesis of mitochondrial dysregulation in aging, we studied hind limb skeletal muscles from young and older, male and female, NIA C57BL/6JN mice. We observed no age-associated changes in coupling efficiency (ADP:O) of mitochondrial reticulum preparations, but respiratory control (RCR) was decreased in older mice. Additionally, older skeletal muscle exhibited subtle yet significant reductions in the expression of proteins functionally related to substrate uptake and oxidation (mMCT1, mPC1, CPT1b, HADH). While there were no differences in mitochondrial contents per mg of muscle in older mice, there were significant losses of muscle, and hence mitochondrial mass as well as proteins associated with membrane dynamics (DRP1, FIS1, and MFN2). Further, 2D and 3D, cross- and longitudinal muscle sections showed alterations in mitochondrial reticulum organization in muscles of older mice. Therefore, aging is associated with subtle, but significant changes in the organization and functioning of muscle mitochondrial reticula.
    Keywords:  Aging; Mitochondria; Mitochondrial Reticulum; Sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00110.2025
  50. Free Radic Biol Med. 2025 Aug 13. pii: S0891-5849(25)00876-7. [Epub ahead of print]
    HDAC Inhibition Protects RPE Cells from Oxidative Stress via Enhanced Mitochondrial Fusion, Cytoskeletal Repair, and Nrf-2 Activation.
    Yarine Lugassy, Eva Berent, Lotan Tarnoy, Sandra Jeries, Tamar Ziv, Naphtali Savion, Hagit Eldar-Finkelman.
      Oxidative stress is a key driver of retinal pigment epithelium (RPE) damage and the development of age-related macular degeneration (AMD). Here, we demonstrate that the histone deacetylase (HDAC) inhibitors vorinostat and trichostatin A (TSA) elicit a coordinated cytoprotective response in RPE cells exposed to rotenone. Both compounds significantly reduced reactive oxygen species (ROS) levels, enhanced mitochondrial fusion, increased mitochondrial ATP production, and improved cell morphology and cell survival in the rotenone-treated cells. In addition, the compounds activated Nrf-2 as evidenced by Keap1 downregulation, increased p62/SQSTM1 expression, and induction of Nrf-2 targets, including heme oxygenase 1 (HO-1). Proteomic analysis of drug-treated cells revealed a significant enrichment of proteins involved in cytoskeletal organization and dynamics. Consistently, specific staining for actin filaments confirmed that vorinostat and TSA preserved cytoskeletal architecture and increased levels of the tight junction protein TJP3 in cells exposed to rotenone. Finally, inhibition of the vorinostat/TSA target HDAC6, or blockade of α-tubulin acetyltransferase, demonstrated that modulation of α-tubulin acetylation could influence ROS levels. Similarly, enhanced mitochondrial fusion by Mdivi-1 reduced ROS accumulation in the rotenone-treated cells. However, these last two interventions did not fully recapitulate the antioxidant effects observed with vorinostat or TSA. Our results identify a multifaceted protective mechanism triggered by HDAC inhibition in oxidatively stressed RPE cells and support the therapeutic repurposing of vorinostat in oxidative stress-driven RPE or retinal degeneration.
    Keywords:  Age-related macular degeneration (AMD); Cytoskeleton; HDAC inhibitors; Mitochondrial dynamics; Nrf-2 signaling; Oxidative stress; Proteomics; Retinal pigment epithelium (RPE); Vorinostat
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.007
  51. J Hepatol. 2025 Aug 08. pii: S0168-8278(25)02379-7. [Epub ahead of print]
    Decreased LONP1 expression exacerbates MASH-induced liver fibrosis via elevated orotic acid levels.
    Dengqiu Xu, Zehua Zhang, Ziqi Zhu, Wenjing Wei, Yipeng Bai, Wen Wang, Yong Zhu, Abudureyimu Alimujiang, Yuze Shi, Zhen Zhang, Zhijian Li, Pengkai Wu, Beicheng Sun.
       BACKGROUND & AIMS: Identifying the metabolic targets driving liver fibrosis in metabolic-dysfunction-associated steatohepatitis (MASH) is essential for developing effective preventive therapies. However, the metabolic pathways dysregulated in MASH and the underlying molecular mechanisms remain poorly understood. Lon peptidase 1 (LONP1), a mitochondrial protease, is known for its pivotal role in maintaining mitochondrial protein quality surveillance and performing highly regulated proteolytic reactions. This study aims to explore the precise mechanisms by which LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring in liver fibrosis.
    METHODS: We used murine liver fibrosis models, a hepatocyte-specific LONP1 knockout mouse model, and liver biopsies from MASH patients. Transcriptomics, proteomics and metabolomics were used to identify the potential metabolites that promote MASH-induced liver fibrosis.
    RESULTS: LONP1 expression was reduced in patients and mice with MASH. Hepatocyte-specific LONP1 deficiency results in dihydroorotate dehydrogenase (DHODH) accumulation, elevated orotic acid levels, and aggravated MASH-induced fibrosis. Conversely, the overexpression of LONP1 or the administration of a DHODH inhibitor reduced orotic acid levels and alleviated MASH-induced liver fibrosis in mice. Mechanistically, LONP1 was shown to degrade DHODH selectively in an ATP-dependent manner, thus lowering orotic acid levels and suppressing the activating transcription factor 3 (ATF3)-mediated activation of hepatic stellate cells. These findings were validated in MASH patients, as plasma orotic acid levels correlated negatively with hepatic LONP1 levels and positively with both the expression of fibrotic genes and fibrosis scores.
    CONCLUSION: Our findings demonstrate that the LONP1-DHODH interaction regulates orotic acid metabolism and alleviates MASH-induced liver fibrosis.
    IMPACT AND IMPLICATIONS: Liver fibrosis is one of the main histological determinants of MASH, a disease that parallels the worldwide surge in metabolic syndromes. This study reveals that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and regulates orotic acid metabolism, contributing to the progression of MASH-induced liver fibrosis. These findings suggest that targeting orotic acid or hepatocyte LONP1 may represent a promising therapeutic strategy. Further investigation into mitochondrial orotic acid metabolism may yield novel insights into the pathogenesis of liver fibrosis.
    Keywords:  Dihydroorotate dehydrogenase; Lon peptidase 1; Metabolic dysfunction-associated steatohepatitis; Mitochondrial proteostasis; Orotic acid
    DOI:  https://doi.org/10.1016/j.jhep.2025.07.013
  52. Mol Med Rep. 2025 Nov;pii: 287. [Epub ahead of print]32(5):
    Metformin alleviates lung ischemia‑reperfusion injury via the SIRT1 pathway following lung transplantation in diabetic rats.
    Hong Wei, Tian-Hua Liu, Li-Juan Zhang, Wei Yan, Can Ma, Shi-Hua Lv, Xian-Zhang Zeng, Wen-Zhi Li.
      Diabetes mellitus (DM) exacerbates lung ischemia‑reperfusion (IR) injury and leads to poor survival in lung transplantation recipients. Metformin protects a number of tissues from IR injury. The present study aimed to investigate the effect of metformin on diabetic lung IR injury and the potential mechanisms. Rats with type 2 DM were exposed to metformin with or without administration of EX527, an inhibitor of the silent information regulator 1 (SIRT1) pathway, following lung transplantation. Lung function, alveolar‑capillary permeability, inflammatory response, oxidative stress, cell apoptosis, mitochondrial function, mitochondrial biogenesis key proteins and the SIRT1 signaling pathway were assessed. The effect of metformin on diabetic lung IR injury was evaluated by ELISA, oxidative stress assays, immunofluorescence, flow cytometry, TUNEL assay and western blotting. The results demonstrated that DM was associated with a significant increase in the IR‑induced alveolar‑capillary permeability, inflammatory response, oxidative stress and cell apoptosis. Furthermore, DM was associated with a significant decrease in mitochondrial function and biogenesis, SIRT1 expression and lung function. Metformin treatment markedly attenuated diabetic lung IR injury by alleviating the inflammatory response, oxidative stress and cell apoptosis, preserving mitochondrial function, and promoting mitochondrial biogenesis. However, EX527 inhibited the protective effect of metformin. In conclusion, metformin alleviated the inflammatory response, oxidative stress and cell apoptosis, preserved mitochondrial function, and promoted mitochondrial biogenesis via the activation of the SIRT1 pathway in diabetic lung IR injury.
    Keywords:  diabetes mellitus; lung ischemia‑reperfusion injury; metformin; mitochondrial biogenesis; silent information regulator 1
    DOI:  https://doi.org/10.3892/mmr.2025.13652
  53. Neurotherapeutics. 2025 Aug 14. pii: S1878-7479(25)00199-0. [Epub ahead of print] e00721
    Gaultheria leucocarpa inhibits Aβ fibrillization and enhances mitophagy-mediated degradation of pathogenic proteins.
    Yue Zhang, Lan Deng, Jing Wei, Lufen Huang, Fei Gao, Lu Yu, Fengdan Zhu, Jianing Mi, Jianming Wu, Fang Ren, Minsong Guo, Xiaogang Zhou, Dalian Qin, Ting Chen, Anguo Wu.
      Alzheimer's disease (AD) pathology involves amyloid-beta (Aβ) accumulation and neuronal toxicity, highlighting the need for therapeutic strategies that can both inhibit Aβ aggregation and promote pathogenic protein clearance. In this study, we identified Gaultheria leucocarpa as a medicinal plant with promising neuroprotective potential. Thioflavin T (ThT) fluorescence screening revealed that extracts from G. leucocarpa (GE), particularly the petroleum ether fraction of G. leucocarpa extract (GPF), effectively inhibited Aβ fibril formation in vitro. In cell-based assays, GPF significantly improved the viability of PC-12 ​cells exposed to Aβ peptides and fibrils, indicating protection against Aβ-induced cytotoxicity. Furthermore, GPF enhanced mitophagic activity, as demonstrated by increased GFP-LC3 puncta, elevated LC3-II/I ratio, and colocalization of GFP-LC3 with MitoTracker Red. Mechanistic investigations showed that GPF activates mitophagy via the AMPK/ULK1 pathway and inhibits the PI3K/AKT/mTOR pathway, resulting in enhanced degradation of APP and Tau proteins. In Caenorhabditis elegans models relevant to AD, GPF administration led to reduced Aβ deposits, delayed paralysis onset, improved food perception, and decreased oxidative stress. Collectively, these findings demonstrate that GPF exerts dual actions by inhibiting Aβ fibrillization and promoting mitophagy-mediated degradation of pathogenic proteins. The active ingredients identified from GPF extracts represent promising leads for the development of novel neuroprotective agents targeting AD-related pathological mechanisms.
    Keywords:  Alzheimer's disease; Amyloid-beta; Caenorhabditis elegans; Gaultheria leucocarpa; Mitophagy
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00721
  54. Free Radic Biol Med. 2025 Aug 12. pii: S0891-5849(25)00889-5. [Epub ahead of print]
    Kaempferol Induces Mitophagy and Disrupts Iron Metabolism via SFXN2 Leading to Apoptosis in Multiple Myeloma Cells.
    Hao Wang, Jia Song, Yan Shi, Nanhao Meng, Yanran Luo, Fengping Peng, Fengjuan Jiang, Rong Fu, Zhaoyun Liu.
       BACKGROUND: The role of kaempferol, a natural flavonoid, in the apoptosis of multiple myeloma cells has not been fully investigated. This study investigated the effects of kaempferol on MM cell apoptosis and its underlying mechanisms.
    METHODS: In vitro, cell viability was measured using the CCK-8 and EdU assays, and apoptosis was assessed using flow cytometry. Mitochondrial damage and autophagy were analyzed using JC-1 staining, MitoTracker Green staining, and fluorescence microscopy. Western blot and qRT-PCR were used to assess SFXN2 and autophagy-related molecule levels. Intracellular Fe2+ levels were measured to determine the effect of kaempferol on iron metabolism. For the in vivo studies, the antitumor effects of kaempferol in combination with iron were assessed using a mouse xenograft model.
    RESULTS: Kaempferol inhibited multiple myeloma cell proliferation and induced apoptosis in a dose-dependent manner. It significantly increased mitochondrial damage, enhanced mitochondrial autophagy, and accumulated intracellular Fe2+ levels. In addition, kaempferol decreased SFXN2 expression, which is associated with disturbed iron metabolism and enhanced mitochondrial autophagy. Kaempferol effectively inhibited tumor growth and promoted apoptosis in vivo, particularly when combined with iron.
    CONCLUSION: Kaempferol was identified as a novel regulator of SFXN2, linking its natural activity to mitochondrial iron dysregulation and mitophagy in MM. Targeting the kaempferol-SFXN2 axis may represent a promising therapeutic strategy for multiple myeloma.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.020
  55. Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]
    Principles of cotranslational mitochondrial protein import.
    Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.
      Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.
    Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling
    DOI:  https://doi.org/10.1016/j.cell.2025.07.021
  56. J Tradit Chin Med. 2025 Aug;45(4): 739-746
    Qigu capsule alleviates dexamethasone-induced muscle dysfunction through mitochondrial biogenesis.
    Shi Jinyu, G E Haiya, Yang Zongrui, Zhan Hongsheng.
       OBJECTIVE: To explore the potential molecular mechanism of Qigu capsule (，QGC) improve the functional performance of skeletal muscle.
    METHODS: The primary components of QGC were analyzed using high-performance liquid chromatography (HPLC). Muscle dysfunction was established in male C57BL/6 mice treated with dexamethasone (1 mg/kg body weight, i.p., six weeks). Rotarod test, mitochondrial ultrastructure, respiratory chain complex V activity, succinate dehydrogenase (SDH) activity, adenosine triphosphate (ATP) content, and reactive oxygen species (ROS) levels were assessed. The mitochondrial biogenesis-related protein expressions were analyzed using Western blot or polymerase chain reaction (PCR).
    RESULTS: QGC treatment enhanced Rotarod test performance. Additionally, QGC significantly alleviated dexamethasone-induced mitochondrial damage, reduced mitochondrial swelling, increased respiratory chain complex enzyme activity, SDH activity, ATP content, and decreased ROS levels. PCR and western blot results revealed that QGC enhanced mitochondrial biogenesis via adenosine 5'-monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α) signaling pathway.
    CONCLUSIONS: QGC ameliorates dexamethasone-induced skeletal muscle dysfunction by activating AMPK/ PGC-1α, which might be developed as a therapeutic agent for treating age-related muscle weakness.
    Keywords:  AMP-activated protein kinases; Qigu capsule; muscle weakness; organelle biogenesis; peroxisome proliferator-activated receptor gamma coactivator 1-alpha; sarcopenia
    DOI:  https://doi.org/10.19852/j.cnki.jtcm.2025.04.004
  57. Stem Cell Res Ther. 2025 Aug 10. 16(1): 441
    Correction: DPSCs modulate synovial macrophage polarization and efferocytosis via PINK1/Parkin-dependent mitophagy.
    Jinjin Ma, Xinyu Wang, Dalei Sun, Jiali Chen, Linyi Zhou, Kaiao Zou, Xinxin Ni, Hongting Jin, Jun Lin.
      
    DOI:  https://doi.org/10.1186/s13287-025-04565-2
  58. Reprod Sci. 2025 Aug 12.
    Melatonin Protects against LPS-Induced Mitochondrial Dyshomeostasis and Ovarian Damage through JNK Signaling Pathway in Mouse Ovary.
    Ling-Ge Shi, Si-Min Ding, Tong-Kun Guo, Peng Chen, Shuang-Shuang Cui, Zhuo-Nan Yang, Mengyao Wang, Rui Wang, Dongmei Ji, Tao Zhang, Dan Liang, Lili Wang, Yunxia Cao, Yajing Liu.
      Both mitochondrial dysfunction and inflammation are closely associated with the pathogenesis of diminished ovarian reserve (DOR). While melatonin (MT) is known to protect against ovarian injury, its precise mechanism in counteracting lipopolysaccharide (LPS)-induced mitochondrial dysfunction and ovarian reserve impairment remains unclear. This study aimed to explore the effects and underlying mechanisms of MT on LPS-induced ovarian reserve dysfunction. Follicle development in mouse models was assessed using HE staining and follicle counting. Immunofluorescence, Western blotting, and quantitative real-time PCR were employed to investigate the biological mechanisms by which MT protects the ovary. The levels of reactive oxygen species (ROS) and mitochondrial function in KGN cells were evaluated using H2DCFDA and TMRE staining. The findings revealed that LPS stimulation led to reduced expression of anti-Mullerian hormone (AMH) and growth differentiation factor 9 (GDF9), indicating impaired ovarian function. Treatment with MT countered these effects. Immunofluorescence analysis demonstrated that MT alleviated LPS-induced follicular depletion and modulated the expression levels of mitochondrial dynamics-related proteins OPA1 and DRP1. Additionally, LPS exposure induced excessive autophagy, elevated ROS levels, and heightened inflammation but did not significantly affect cell cycle progression or apoptosis. Notably, MT rescued the suppression of the JNK pathway caused by LPS stimulation. In summary, our results indicate that MT effectively restores the balance between mitochondrial fusion and fission, enhances ovarian reserve function via activation of the JNK signaling pathway, suppresses inflammation and autophagy, and ultimately improves overall ovarian function.
    Keywords:  Diminished ovarian reserve; Excessive autophagy; JNK signaling pathway; LPS; Melatonin; Mitochondrial dyshomeostasis
    DOI:  https://doi.org/10.1007/s43032-025-01954-z
  59. Life Med. 2025 Aug;4(4): lnaf019
    Mitochondrial sirtuins, key regulators of aging.
    Zhejun Ji, Guang-Hui Liu, Jing Qu.
      Mitochondrial dysfunction is a hallmark of aging, characterized by a decline in mitochondrial biogenesis and quality control, compromised membrane integrity, elevated ROS production, damaged mitochondrial DNA (mtDNA), impaired mitochondrial-nuclear crosstalk, and deregulated metabolic balance. Among the key longevity regulators, sirtuin family members SIRT3, SIRT4, and SIRT5 are predominantly localized to mitochondria and play crucial roles in maintaining mitochondrial function and homeostasis. This review explores how mitochondrial sirtuins mitigate aging-related mitochondrial dysfunctions and their broader implications in aging-related diseases. By elucidating the intricate interplay between mitochondrial dysfunction and mitochondrial sirtuins, we aim to provide insights into therapeutic strategies for promoting healthy aging and combating age-related pathologies.
    Keywords:  aging; mitochondrial dysfunction; mitochondrial sirtuins
    DOI:  https://doi.org/10.1093/lifemedi/lnaf019
  60. Balkan Med J. 2025 Aug 13.
    miR-17-5p Inhibits BNIP3-Mediated Mitochondrial Autophagy to Attenuate Pathological Cardiac Fibrosis.
    Derong Huang, Qing Wen, Yuchen Su, Xiumao Li.
       Background: Cardiac fibrosis plays a critical role in the progression of chronic cardiovascular conditions, with mitochondrial dysfunction acting as a central mechanism underlying pathological myocardial fibrosis. Increasing research shows that microRNAs may modulate the fibrotic process by regulating mitochondrial function via various pathways.
    Aims: To examine the involvement of miR-17-5p in modulating mitochondrial autophagy and alleviating pathological cardiac fibrosis.
    Study Design: Combined in vivo and in vitro study.
    Methods: Expression levels of miR-17-5P and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) were measured in a mouse model of myocardial fibrosis induced by abdominal aortic constriction, as well as in cardiac fibroblasts (CFs) treated with angiotensin II. CFs were transiently transfected with a miR-17-5p mimic, the pcDNA3.1-BNIP3 plasmid, or both. Cell viability was evaluated using the CCK-8 colorimetric assay. The expression of fibrotic and autophagy-related markers was determined via quantitative real-time reverse transcription polymerase chain reaction and immunoblotting. Intracellular levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) were also assessed.
    Results: Reduced myocardial miR-17-5p expression was associated with diminished left ventricular systolic function and increased collagen accumulation in heart tissue. In vitro, angiotensin II treatment led to decreased miR-17-5p expression, upregulated BNIP3, and excessive mitochondrial autophagy-evidenced by increased ROS, lowered ATP production, and elevated fibrosis-related markers. Rescue experiments demonstrated that miR-17-5p overexpression directly targeted the 3' untranslated region (3'-UTR) of BNIP3, significantly downregulating its expression, restoring mitochondrial balance, and decreasing collagen production. Conversely, BNIP3 overexpression counteracted the anti-fibrotic and mitochondrial-protective effects of miR-17-5p.
    Conclusion: The miR-17-5p/BNIP3 signaling pathway modulates mitochondrial autophagy in CFs and plays a key role in fibrotic remodeling. This axis may serve as a promising therapeutic target for reducing cardiac fibrosis and slowing the progression of heart failure.
    DOI:  https://doi.org/10.4274/balkanmedj.galenos.2025.2025-6-25
  61. Int J Mol Sci. 2025 Aug 05. pii: 7548. [Epub ahead of print]26(15):
    Hyaluronic and Succinic Acid: New Biostimulating Combination to Counteract Dermal and Subcutaneous Aging.
    Alfredo Martinez-Gutierrez, Helena Cami, Teresa Noya, Susana Gómez-Escalante, Aina Miró Llosas, Mari Carmen González.
      Various biomaterials are currently employed for dermal biostimulation and filling purposes, with hyaluronic acid (HA)-based fillers among those with the most favorable safety profile, albeit exhibiting a limited biostimulatory effect. This study suggests that hyaluronic acid and succinic acid (SA) can significantly induce beneficial effects on skin cells by targeting key aging hallmarks. Human dermal senescent fibroblasts and aged adipocytes were treated with HA + SA, and various aging characteristics were examined through gene expression analysis and microscopy staining. HA was found to stimulate autophagy gene expression, while SA modulated senescence-gene expression, and the combination of these compounds induced mitophagy in senescent fibroblasts. Additionally, the HA + SA promoted adipogenesis, increased IGF1, and decreased TNFA gene expression in aged adipocytes. Furthermore, the conditioned medium from adipocytes treated with HA + SA upregulated key dermal genes such as COL3A1 and EGF. The findings of this study suggest that HA and SA compounds can be used for the biostimulation of aged skin through the regulation of senescence-associated gene expression and cell communication between dermal fibroblasts and subcutaneous adipocytes.
    Keywords:  adipocyte aging; biostimulation; dermal filler; fibroblast senescence; mitophagy; skin aging
    DOI:  https://doi.org/10.3390/ijms26157548
  62. Immunity. 2025 Aug 09. pii: S1074-7613(25)00326-7. [Epub ahead of print]
    Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
    Kaili Ma, Hongcheng Cheng, Lin Wang, Han Xiao, Fenghua Liu, Yu Yang, Zhen Xiao, Kun Tang, Shicheng Li, Gang Wang, Minmin Ge, Jiajia Wang, Xiaowei Liu, Hai-Xi Sun, Ziyi Luo, Zhimin Gu, Ping-Chih Ho, Guideng Li, Lianjun Zhang.
      Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8+ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8+ T cell-mediated immune responses. Sustained succinate exposure promoted CD8+ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8+ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.
    Keywords:  SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.017
  63. Mol Hum Reprod. 2025 Aug 14. pii: gaaf042. [Epub ahead of print]
    S14G-Humanin ameliorates ovarian dysfunction in a cyclophosphamide-induced premature ovarian insufficiency mouse model.
    Jin Huang, Dandan Zhang, Liping Zou, Haoyuan Liu, Wei Xia, Changhong Zhu, Meng Rao.
      Premature ovarian insufficiency (POI) is a major cause of female infertility, for which effective therapies remain limited. S14G-Humanin (HNG), a potent analogue of Humanin, exhibits strong antioxidant and anti-apoptotic properties, and has demonstrated cytoprotective effects in various tissues, including the ovary. In this study, a cyclophosphamide-induced POI (CP-POI) mouse model was established to evaluate both the ovarian damage induced by chemotherapy and the protective effects of HNG. HNG administration significantly increased the numbers of primordial follicles (P = 0.044) and growing follicles (all P > 0.05), as well as corpora luteum (P = 0.09). Moreover, HNG markedly improved oocyte quality (P = 0.009), significantly lowering the proportion of abnormal ovulated oocytes (P = 0.002). Fertility outcomes were also enhanced: CP treatment significantly reduced litter size compared to controls (4.6 ± 1.1 vs. 8.0 ± 1.0; P < 0.001), whereas HNG treatment significantly mitigated this reduction (6.2 ± 0.8 vs. 4.6 ± 1.1; P = 0.029). Mechanistically, HNG alleviated oxidative stress and apoptosis in ovarian tissues (all P < 0.05), reduced ROS levels (P = 0.034), and restored mitochondrial membrane potential (P = 0.004) in a human granulosa cell line. Furthermore, HNG significantly upregulated PGC-1α expression and enhanced AMPK phosphorylation in both in vivo and in vitro models (both P < 0.05). Collectively, these findings demonstrate that HNG confers significant protection against chemotherapy-induced ovarian damage and highlight its potential as a novel therapeutic agent for chemotherapy-induced ovarian damage.
    Keywords:  AMPK; PGC-1α; fertility; granulosa cells; humanin; mitochondrial biogenesis; premature ovarian insufficiency (POI)
    DOI:  https://doi.org/10.1093/molehr/gaaf042
  64. Cell Death Dis. 2025 Aug 13. 16(1): 616
    The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia.
    Xiuying Hu, Tianzhen Hu, Shuyun Cao, Li Jiang, Yan Zhou, Qin Fang, Jishi Wang.
      Although patients with acute myeloid leukaemia (AML) initially respond to conventional treatments, many patients die from AML progression and relapsed/refractory (RR) disease. Eradicating AML thus remains therapeutically challenging. In this study, we found a strong expression of aldehyde dehydrogenase 2 (ALDH2) and increased mitochondrial biosynthesis in samples from patients with drug-resistant AML, and these changes were strongly associated with poor prognosis and recurrence of AML. We examined the clonogenic capacity, growth and apoptosis of AML cells, as well as mitochondrial DNA expression and reactive oxygen species production. Our results revealed that chemotherapeutic agents triggered the activation of NF-E2-related factor 2 (Nrf2) and promoted high expression of ALDH2, mediating the compensatory activation of mitochondrial respiration and resistance to chemotherapeutic agents in RR AML cells. Nrf2 promoted mitochondrial respiration by activating ALDH2 expression and stabilising the expression of DNA polymerase-gamma2 (PolG2) in mitochondria. Inhibition of the Nrf2-ALDH2/PolG2 pathway reduced AML metabolic fitness and oxidative phosphorylation levels, highlighting the key role of this pathway in promoting cell survival. Nrf2 inhibition reduced the translation of ALDH2, induced a unique mitochondrial stress response and inhibited mitochondrial biosynthesis in AML cells. Importantly, tumours in an in vivo xenograft model were sensitive to combined Nrf2 and ALDH2 inhibition. Given the role of the Nrf2-ALDH2/PolG2 pathway in the progression of AML, inhibition of this pathway may prevent disease relapse/resistance and promote sensitisation to chemotherapy.
    DOI:  https://doi.org/10.1038/s41419-025-07927-z
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