bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–08–03
sixty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
  2. CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
  3. An emerging role of mitochondrial quality control in bone metabolism: from molecular mechanisms to targeted therapeutic interventions.
  4. Role of Prohibitins as Guardians of mitochondrial homeostasis.
  5. SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.
  6. Rab14 promotes Parkin mediated mitophagy.
  7. Kindlin-1 promotes mitophagy by inhibiting PINK1 degradation to enhance hepatocellular carcinoma progression and modulates sensitivity to donafenib.
  8. Comprehensive Insights Into Mitophagy: Mechanisms, Disease Associations, and Therapeutic Implications.
  9. Mitophagy: A Potential Therapeutic Target for Tuberculosis Immunotherapy.
  10. Protection of Dipsacoside B Against Cerebral Ischemia/Reperfusion Injury via Activating PINK1/Parkin-Mediated Mitophagy.
  11. Atrazine-induced hippocampal neurotoxicity: Involvement of Drp1-mediated mitochondrial fission.
  12. ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
  13. Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.
  14. Nanotechnology-targeted modulation of mitophagy in cancer therapy: Progress and challenges.
  15. MCTR1 alleviates remifentanil-induced hyperalgesia by regulating mitochondrial fission protein DRP1 in rats.
  16. PDE4D Regulates Mitochondrial Homeostasis and Adult Hippocampal Neurogenesis via the cAMP/CREB Signaling Pathway in Chronic Stress-Induced Depressive-Like Behavior.
  17. RFX2-BNIP3 axis-driven adaptive mitophagy promotes resistance to ACK1-targeted therapy in non-small cell lung cancer.
  18. Repositioning of a nutraceutical, scoparone, in the management of MK-801-induced schizophrenia-like behavior in Mice: An insight into SIRT1/PGC-1α/TFAM pathway.
  19. Targeting DRP1Ser637 Phosphorylation Alleviates Acidic Bile Salt-Induced NF-κB Activation via Mitochondrial Protection.
  20. Myrtenol ameliorates ulcerative colitis by modulating ANXA1/PINK1/Parkin-mediated mitophagy.
  21. A structural switch reveals how to disarm USP30 and unlock mitophagy.
  22. Effect of Peanut Shell Extract and Luteolin on Gut Microbiota and High-Fat Diet-Induced Sequelae of the Inflammatory Continuum in a Metabolic Syndrome-like Murine Model.
  23. S100A9 inhibition ameliorates HFpEF by modulating mitochondrial fission and oxidative stress.
  24. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  25. HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction.
  26. Evidence of biological aging through mitochondrial DNA damage and dysregulation of mitophagy-related genes in veterans with delayed sulfur mustard toxicity.
  27. Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.
  28. NQO1 antagonizes PM2.5-induced apoptosis of Sertoli cells by activating the UPRmt pathway.
  29. Perspectives on mitochondrial dysfunction in the regeneration of aging skeletal muscle.
  30. Modern methods of detecting mitophagy.
  31. Unleashing the potential of ferroptosis, autophagy, and mitochondrial dynamics as emerging modalities in cancer treatment.
  32. PTPN2 Inhibition Disrupts Mitochondrial Renewal and Blocks TFRC-Mediated Mitophagy to Exert Anti-Tumor Activities in ALK-Positive Anaplastic Large Cell Lymphoma.
  33. Mitophagy related gene signature for prognosis and therapeutic evaluation in KIRC.
  34. Exercise-Based Cardiac Rehabilitation Improves Left Ventricular Dysfunction, Mitophagy, and Oxidative Stress Postmyocardial Infarction.
  35. Mitophagy's impacts on cancer and neurodegenerative diseases: implications for future therapies.
  36. Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
  37. The effect of USP17 knockdown on autophagic ferroptosis in gastric cancer by regulating the BNIP3-NCOA4-FTH1 axis.
  38. Semaglutide Mitigates Ischemic Brain Injury by Inhibiting Ferroptosis via Modulation of FoXO1 and DRP1 Pathways.
  39. Protective Effects of N-Acetylcysteine in Alleviating Cocaine-Mediated Microglial Activation and Neuroinflammation.
  40. New rhodium(III)-triphenylphosphine complexes with 5-halogenate-8-hydroxyquinoline as ligands: synthesis, characterization, cytotoxicity, and mechanism of action.
  41. Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.
  42. The novel effects of the cardiovascular drug ranolazine on the alleviation of age-related cognitive decline and the underlying mechanisms.
  43. Treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization via activating mitophagy post-TBI.
  44. Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
  45. Mitochondrial dysfunction in postoperative cognitive dysfunction: From preclinical mechanisms to multimodal diagnostics and precision intervention.
  46. Investigating the Mechanism of Emodin in Rheumatoid Arthritis Through the HIF-1α/NLRP3 Pathway and Mitochondrial Autophagy.
  47. The mitochondria-targeted hydrogen sulfide donor AP39 reduces cortical stroke volume and improves motor function in a photothrombotic stroke model in mice in a sex-dependent manner.
  48. Targeting Mitochondrial Dysfunction by Natural Products for the Treatment of Diabetic Kidney Disease.
  49. The role of autophagy in the pathogenesis and treatment of multiple sclerosis.
  50. High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway.
  51. A High-Fat Diet Induces Oxidative Stress in OPA1+/- Mouse Cortices: A Critical Double Challenge.
  52. AFG2A-related encephalopathy: Effectiveness of ketogenic diet in epilepsy and mitochondrial dynamics modulation.
  53. Sex-specific Impact of Selective Reduced Uterine Placental Perfusion Model of Preeclampsia on Fetal Cardiac Maturation and Mitochondrial Function.
  54. Selenomethionine Counteracts T-2 Toxin-Induced Liver Injury by Mitigating Oxidative Stress Damage Through the Enhancement of Antioxidant Enzymes.
  55. SLC39A13 Regulates Heart Function via Mitochondrial Iron Homeostasis Maintenance.
  56. Dysregulation of Mitochondrial Function in Cancer Cells.
  57. Gestational zearalenone causes fetal intrauterine growth restriction partially through deriving ROS-Drp1 mediated placental PANoptosis.
  58. Gentamicin aggravates renal injury by affecting mitochondrial dynamics, altering renal transporters expression, and exacerbating apoptosis.
  59. OPA1 modulates NLRP3 inflammasome activation and microglial-mediated neuroinflammation in neonatal hypoxic-ischemic brain injury.
  60. Reniformin A Suppresses Triple-Negative Breast Cancer Progression by Inducing DRP1-Mediated Mitochondrial Dysfunction and Apoptosis.
  61. Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
  62. Author Correction: The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis.
  63. Absence of Parkin Results in Atrophy of Oxidative Myofibers and Modulation of AKT and MURF1 Signaling in Middle-Aged Male Mice.
  64. Retraction Notice to: SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury.
  65. Author Correction: Molecular machineries and pathways of mitochondrial protein transport.
  66. DIRAS1 Drives Oxaliplatin Resistance in Colorectal Cancer via PHB1-Mediated Mitochondrial Homeostasis.
  67. Mitochondrial quality control in exercise-mitigated muscular atrophy.
  68. Targeting Mitochondrial Quality Control for the Treatment of Triple-Negative Breast Cancer: From Molecular Mechanisms to Precision Therapy.
  69. Mesencephalic Astrocyte-Derived Neurotrophic Factor Binds BAX to Preserve Mitochondrial Homeostasis and Energy Metabolism for Relieving Myocardial Hypertrophy.
  1. Life Sci. 2025 Jul 30. pii: S0024-3205(25)00525-9. [Epub ahead of print] 123890
    Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
    Sarmistha Sarkar, Aindrila Chattopadhyay, Debasish Bandyopadhyay.
      High mortality rates due to cardiovascular diseases (CVDs) fascinate the scientists worldwide in the past few decades to discover potent therapeutic strategies to save the victims. The myocardium being a highly active tissue, mitochondrial homeostasis and mitochondrial quality control system are crucial for maintaining optimal cardiac performance. Mitochondrial quality control mechanism is a finely tuned regulatory network encompassing mitochondrial biogenesis, mitochondrial dynamics and mitophagy and is an integral component of the mitochondrial response to stressor stimuli. Mitochondrial dynamics including the fusion and fission of mitochondrial membranes is regulated by an extensively conserved mechanism comprising a group of mitochondrial membrane proteins belonging to the dynamin family of GTPases. Emerging evidences indicate that defects in mitochondrial fusion or fission are intrinsically correlated with the pathophysiology of CVDs. Mitophagy is a kind of selective autophagy which removes damaged or redundant mitochondria. Experimental findings demonstrated that impairment of mitophagy in cardiomyocytes induces the accumulation of dysfunctional mitochondria, leading to the disruption of cellular homeostasis and consequently precipitating various CVDs. These findings speculate that pharmacological modulation of mitochondrial homeostasis including mitochondrial dynamics and mitophagy may represent a potential therapeutic approach in restoring cardiac physiology. This review summarizes the prevailing insight into the impact of disturbed mitochondrial dynamics and mitophagy in the pathogenesis of CVDs and also delineates the therapeutic potential of several relevant regulatory drugs that target mitochondrial function and quality control in alleviating mitochondrial impairment-related cardiac dysfunction.
    Keywords:  Cardiomyocytes; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.lfs.2025.123890
  2. J Neurophysiol. 2025 Aug 01.
    CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
    Xiaoke Qiu, Shaoda Lai, Yingyi Zhang, Shengtao Huang, Han Li, Junsheng Liu, Yong Huang, Zhinan Zhang.
      The chronic unpredictable mild stress (CUMS) paradigm influences the neuronal count in the dentate gyrus (DG) region of the hippocampus, potentially linking to mitophagy induced by mitochondrial fragmentation. Fission mitochondrial 1 (FIS1)/mitochondrial fission factor (MFF) represents one of the mechanisms regulating mitochondrial fission and autophagy. Herein, we investigated the effects of CUMS on mitophagy and mitochondrial fragmentation in hippocampal DG neurons, along with their modulation of the mitochondrial fission pathway governed by FIS1/MFF. Our results demonstrated that CUMS stress augmented mitophagy in hippocampal DG neurons. Concurrently, it exacerbated the tendency towards mitochondrial fragmentation. The impact on the upstream regulatory pathway of mitochondrial fragmentation manifested as upregulation of FIS1 and downregulation of MFF, resulting in a net loss of mitochondrial content and a subsequent energy deficit. These findings suggest that CUMS stress, by modulating the FIS1/MFF balance, increase mitophagy stemming from mitochondrial fragmentation in hippocampal DG neurons.
    Keywords:  Depression; FIS1; MFF; mitochondria fragmentation; mitophagy
    DOI:  https://doi.org/10.1152/jn.00523.2024
  3. Cell Mol Life Sci. 2025 Jul 29. 82(1): 291
    An emerging role of mitochondrial quality control in bone metabolism: from molecular mechanisms to targeted therapeutic interventions.
    Ziqi Qin, Xiting Zhu, Yifei Shen, Huiling Ling, Ngaifung Ruan, Wushuang Ye, Yang Xu, Xueqi Gan.
      The mitochondrial quality control system is the principal regulatory framework governing mitochondrial quantity, morphology, distribution, and functional integrity. This surveillance and regulatory machinery is essential for preserving cellular homeostasis and determining cellular differentiation. Mitochondria play a central role in maintaining the dynamic equilibrium between osteogenic differentiation and osteoclastic differentiation. Dysregulation of mitochondrial quality control can lead to disrupted mitochondrial homeostasis and functional impairments, disrupting the physiological processes of bone formation and bone resorption. However, comprehensive reviews elucidating the relationship between mitochondrial quality control and bone homeostasis are conspicuously lacking. This review systematically deconstructs the molecular architecture of mitochondrial quality control, elucidating the regulatory mechanism of each part (mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondrial redox) in bone-related cells. In addition, the mitochondrial quality control system in orchestrating cellular physiological activities is summarized to establish its indispensable in governing cellular homeostatic networks. Furthermore, the regulatory roles of the mitochondrial quality control system in bone-related cells and the balance between bone formation and resorption are reviewed. Finally, this review delineates the dysregulation of mitochondrial quality control in bone metabolic diseases and further advances mitochondrial quality control-targeted approaches for restoring mitochondria homeostasis, offering transformative strategies to treat bone metabolic diseases.
    Keywords:  Bone metabolism; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s00018-025-05802-w
  4. Mitochondrion. 2025 Jul 28. pii: S1567-7249(25)00072-8. [Epub ahead of print] 102075
    Role of Prohibitins as Guardians of mitochondrial homeostasis.
    Sabrina Champsi, David A Hood.
      Mitochondria are complex organelles critical to the maintenance of cellular homeostasis. Central to this regulation are Prohibitins (PHBs), a novel set of proteins involved in several mitochondrial quality control pathways, including protein folding, biogenesis, and mitophagy. PHBs mediate various cellular responses including cell survival and myogenesis, suggesting that their roles are intricate and multifaceted. While evidence suggests that PHBs facilitate mitochondrial homeostasis, their exact mechanism of action remains unclear. Elucidating the precise mechanisms driving PHB-mediated adaptations will ultimately enable the development of therapeutic strategies aimed towards the treatment of age-related diseases, characterized by mitochondrial perturbations.
    Keywords:  Aging; Apoptosis; Mitochondria; Mitophagy; Prohibitin
    DOI:  https://doi.org/10.1016/j.mito.2025.102075
  5. Adv Sci (Weinh). 2025 Jul 29. e03408
    SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.
    Liubing Hu, Jianshuang Li, Haolin Guo, Lei Su, Peina Dong, Juan Huang, Yanyan Liu, Xinjie Liu, Zhenhuan Luo, Wei Xiong, Zhenyu Ju, Qinghua Zhou, Hao Wang, Wenjun Wang.
      SUMOylation, a reversible post-translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg-Alzheimer's disease (AD) mice or Aβ1-42 peptide-stimulated cells. Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.
    Keywords:  Mitochondrial protein import; SENP6; SUMOylation; TOM complex; TOM40
    DOI:  https://doi.org/10.1002/advs.202503408
  6. Mol Biol Cell. 2025 Jul 30. mbcE25060271
    Rab14 promotes Parkin mediated mitophagy.
    Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.
      Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-06-0271
  7. Cell Signal. 2025 Jul 29. pii: S0898-6568(25)00447-4. [Epub ahead of print] 112032
    Kindlin-1 promotes mitophagy by inhibiting PINK1 degradation to enhance hepatocellular carcinoma progression and modulates sensitivity to donafenib.
    Huaxing Ma, Guangling Ou, Bibo Wu, Hongwei Ding, Yijie Zhang, Fei Xia, Zixuan Shen, Kunyang Zhao, Chaochun Chen, Long Wu, Jin Lei, Yuan Xu, Xueke Zhao, Kun Cao, Haiyang Li.
      Mitophagy, essential for mitochondrial homeostasis, may affect hepatocellular carcinoma (HCC) progression and drug sensitivity, though its precise role remains unclear. Kindlin-1 is an adhesion protein which can regulate the function of integrins, resulting in an aggressive phenotype in certain solid malignant tumors.This study explored the clinical significance and cellular functions of Kindlin-1 in HCC. The role of Kindlin-1 in HCC progression was assessed, along with its effects on mitophagy and sensitivity to donafenib. Its impact on HCC cell proliferation and metastasis was analyzed using CCK8, colony formation, EdU incorporation, flow cytometry, Immunohistochemistry, Transwell assays, wound healing assays, and subcutaneous tumorigenesis in nude mice. The interactions of Kindlin-1 with other proteins and its main functions and pathways were investigated through RNA sequencing, enrichment analysis, immunohistochemical co-localization, Co-IP and mass spectrometry. Additionally, the effects of Kindlin-1 on PINK1 stability and mitophagy were evaluated, and the impact of Kindlin-1 inhibition on donafenib sensitivity was tested in vitro and in vivo. Kindlin-1 was found to be highly expressed in HCC tissues and correlated with a poor prognosis. Kindlin-1 promotes mitophagy by stabilizing full-length PINK1 and prevents ubiquitin induced degradation of PINK1 by interacting with it, thus promoting HCC cell proliferation. Inhibition of Kindlin-1 expression or mitophagy synergistically enhances the anti-tumor effects of donafenib in vitro and in xenograft mouse models. Our study demonstrates that Kindlin-1 significantly influences HCC progression by regulating mitophagy through the PINK1/Parkin pathway. Inhibiting Kindlin-1 may represent a promising therapeutic strategy to enhance the efficacy of donafenib, thereby providing novel insights into improving treatment outcomes for HCC patients.
    Keywords:  Donafenib; Hepatocellular carcinoma; Kindlin-1; Mitophagy; PTEN-induced putative kinase 1
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112032
  8. J Cell Biochem. 2025 Jul;126(7): e70056
    Comprehensive Insights Into Mitophagy: Mechanisms, Disease Associations, and Therapeutic Implications.
    Min Tang, Ikram Outissint, Yijing Chen, Xun Gong.
      Mitophagy, a selective autophagic process, is critical for maintaining mitochondrial quality and cellular homeostasis. It plays a dual role, facilitating cell survival by removing damaged mitochondria or contributing to programmed cell death in certain conditions. Dysregulation of mitophagy is implicated in various diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancers. This review examines the key regulatory mechanisms of mitophagy, focusing on pathways such as the PINK1-Parkin, BNIP3/NIX, and FUNDC1 pathways, alongside emerging modulators. Notably, mitophagy is frequently associated with various cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis. Primarily, mitophagy functions as a protective mechanism rather than a direct trigger of cell death. It may be connected to cell death when its capacity is overwhelmed rather than actively promoting the process. For instance, impaired mitophagy exacerbates neurodegeneration in Parkinson's and Alzheimer's diseases, while its activation protects against ischemic injury in cardiovascular diseases. In cancer, mitophagy is paradoxical, as it either inhibits tumor growth or promotes survival under stress. Therapeutic interventions targeting mitophagy, including small-molecule modulators, show promise in preclinical studies; however, they require further clinical validation. Advancements in imaging techniques, single-cell omics, and high-throughput screenings are anticipated to deepen our understanding of mitophagy dynamics and therapeutic potential. This review highlights mitophagy as a pivotal target for treating diseases associated with mitochondrial dysfunction, providing insights into innovative therapeutic strategies.
    Keywords:  cell death pathways; metabolic syndromes; mitophagy; neurodegenerative disorders; therapeutic strategies
    DOI:  https://doi.org/10.1002/jcb.70056
  9. Immunotargets Ther. 2025 ;14 773-786
    Mitophagy: A Potential Therapeutic Target for Tuberculosis Immunotherapy.
    Siyu Gao, Zeliang Yang, Jiajia Yu, Fuzhen Zhang, Shenjie Tang, Yu Pang.
      Mitophagy serves as a cytoprotective mechanism that is essential for eliminating dysfunctional or superfluous mitochondria, thereby fine-tuning mitochondrial quantity and maintaining cellular homeostasis. Recent studies underscore the critical role of mitophagy in determining the fate and function of host cells infected by Mycobacterium tuberculosis. The successful pathogen strategically integrates into the host's mitochondrial network, manipulating processes such as apoptosis, metabolic reprogramming, mitochondrial fusion and fission, and reactive oxygen species production. Therefore, understanding those mechanisms is critical for the advancements of host-directed therapies against tuberculosis. This study offers a comprehensive overview of the interplay between Mycobacterium tuberculosis and mitophagy, emphasizing the associated signaling pathways and potential therapeutic targets involved in mitophagy in Mycobacterium tuberculosis infection. Activating mitophagy in infected host cells represents a promising avenue for improving therapeutic outcomes against tuberculosis. This review aims to summarize potential research direction for agents targeting induction of mitophagy. Notably, evidence suggests that BNIP3/NIX-mediated mitophagy may serve as a potential therapeutic target.
    Keywords:  Mycobacterium tuberculosis; immunotherapy; mitophagy; tuberculosis
    DOI:  https://doi.org/10.2147/ITT.S518628
  10. J Biochem Mol Toxicol. 2025 Aug;39(8): e70416
    Protection of Dipsacoside B Against Cerebral Ischemia/Reperfusion Injury via Activating PINK1/Parkin-Mediated Mitophagy.
    Guozheng Sun, Chao Chang, Chengbin Guo.
      Cerebral ischemia-reperfusion (CI/R) is a complex process that frequently results in neuronal oxidative stress and apoptosis. Dipsacoside B (DB) possesses antimicrobial and detoxifying properties and can improve mitochondrial function. Nevertheless, the potential neuroprotective effects of DB in stroke remain uncertain. This investigation aims to elucidate the impact of DB on CI/R, as well as its underlying regulatory mechanism. In our study, results showed that DB lessened the decrease in cell viability and increase in LDH release in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated HT22 cells. DB attenuated OGD/R-tempted oxidative stress, apoptosis, and mitochondrial dysfunction. DB enhanced mitophagy in HT22 cells following OGD/R treatment by enhancing the levels of LC3-II/LC3-I, PINK1, and Parkin. Blocking of mitophagy by mdivi-1 or silencing PINK1 abolished the protective effect of DB against OGD/R-induced oxidative stress damage and mitochondrial dysfunction in HT22 cells was found to be dependent on the activation of PINK1/Parkin-mediated mitophagy, as evidenced by the loss of protection when mitophagy was blocked by mdivi-1 or PINK1 silencing. Additionally, the neuroprotective effects of DB were confirmed in the middle cerebral artery occlusion mouse model, indicated by alleviation of oxidative stress, apoptosis, and mitochondrial dysfunction. In conclusion, DB attenuated OGD/R-tempted oxidative stress, apoptosis, and mitochondrial dysfunction in HT22 hippocampal neurons by activating PINK1/Parkin-mediated mitophagy.
    Keywords:  Dipsacoside B; cerebral ischemia‐reperfusion injury; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1002/jbt.70416
  11. Chem Biol Interact. 2025 Jul 26. pii: S0009-2797(25)00306-0. [Epub ahead of print]420 111676
    Atrazine-induced hippocampal neurotoxicity: Involvement of Drp1-mediated mitochondrial fission.
    Jingran Yang, Ling Qi, Cheng Zhang, Ruirui Ding, Haoran Bi, Peng Li, Zhipeng Qi, Qiao Niu, Weiyi Song, Jianan Li.
      The widespread use of atrazine (ATR), a commonly applied herbicide, has raised growing concerns about its neurotoxic effects. However, the underlying molecular mechanisms remain poorly understood. In this study, we demonstrate that ATR disrupts hippocampal function by inducing Drp1-mediated mitochondrial fission. Using both in vivo and in vitro tests, we show that ATR exposure leads to mitochondrial swelling, cristae loss, and fragmentation in hippocampal neurons, correlating with impaired spatial learning and memory. ATR significantly increases Ser616-Drp1 phosphorylation, promoting excessive mitochondrial fission and exacerbating neuronal damage. In contrast, the Drp1 inhibitor Mdivi-1 effectively restores mitochondrial integrity, mitigates mitochondrial membrane potential loss, and alleviates neurotoxicity. Interestingly, ATR exposure results in a non-linear response in the expression of mitochondrial regulatory genes, suggesting complex dose-dependent effects. These findings provide novel insights into the role of mitochondrial dysfunction in ATR-induced cognitive impairment and underscore the importance of Drp1-mediated fission in herbicide neurotoxicity. Our study highlights the need for further investigation into the long-term effects of ATR exposure and suggests that targeting mitochondrial dynamics may offer a promising therapeutic strategy for ATR-induced neuronal dysfunction.
    Keywords:  Atrazine; Drp1; Hippocampus; Mitochondrial dynamics; Mitochondrial fission
    DOI:  https://doi.org/10.1016/j.cbi.2025.111676
  12. Cell Death Discov. 2025 Jul 29. 11(1): 349
    ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
    Mudassar Ali, Anjali, Koyeli Mapa.
      Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.
    DOI:  https://doi.org/10.1038/s41420-025-02638-y
  13. Neurochem Res. 2025 Jul 28. 50(4): 251
    Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.
    Qian Yu, Li Li, Shuyi Yu, Jialin Han, Qian Cheng, Zhikang Cui, Hang Chen, Ming Li, Zhiming Lu.
      Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive neurodegeneration and a variety of cognitive deficits. Of note, mitochondrial malfunctions occur early in the disease's development. Mitophagy impairment leads to the build-up of damaged mitochondria inside the cells, causing malfunction and eventual death of the cells. This review summarizes the mechanisms linking mitochondrial damage and autophagy dysregulation to AD and highlights potential therapeutic opportunities. We summarize how mitochondrial dysfunction contributes to AD, including defects in mitochondrial biogenesis, impaired dynamics, the impact of AD-related protein aggregates on mitochondrial integrity, and defective axonal transport. We also explore the roles of mitophagy in AD, including its function in the removal of harmed proteins and organelles. Finally, we highlight the therapeutic strategies for the treatment of AD, targeting molecular components involved in mitochondrial damage and autophagy dysregulation in AD, i.e., antioxidants, mitochondrial modulators, and mitophagy enhancers.
    Keywords:  Alzheimer’s disease; Aβ; Mitochondrial dysfunction; Mitophagy; p-tau
    DOI:  https://doi.org/10.1007/s11064-025-04490-z
  14. Acta Biomater. 2025 Jul 28. pii: S1742-7061(25)00557-4. [Epub ahead of print]
    Nanotechnology-targeted modulation of mitophagy in cancer therapy: Progress and challenges.
    Hongyu Yang, Chang Peng, Hanjie Sun, Sen Mu, Aiyang Tong, Siqi Wang, Dongkai Wang, Ji Li.
      The clinical efficacy of current cancer treatments remains insufficient, creating an urgent need to identify new therapeutic targets and combine them with traditional treatment methods. Mitophagy, a crucial mechanism for the intracellular clearance of damaged mitochondria, has shown tremendous potential in cancer therapy. However, accurately and effectively regulating mitophagy remains a significant challenge. In some years, nanoparticle-based drug delivery systems have attracted considerable attention due to their high targeting ability and deep tissue penetration. Therefore, applying nanotechnology to regulate mitophagy may offer new therapeutic strategies for cancer treatment. This review provides a comprehensive overview of the recent advances in the targeted regulation of mitophagy using nanotechnology, including the use of nanoparticle carriers alone or in combination with other cancer therapies. Additionally, we discuss the development of mitophagy, the relevant signaling pathways, the relationship between mitophagy and cancer, drugs that modulate mitophagy, and methods for detecting mitophagy. Finally, we explore the prospects and challenges of using nanotechnology to target and regulate mitophagy in cancer therapy. STATEMENT OF SIGNIFICANCE: This review underscores the therapeutic relevance of mitophagy in cancer, focusing on its selective role in mitochondrial quality control and tumor regulation. Given the challenges in precise mitophagy modulation, we highlight the emergence of nanotechnology based delivery systems as a promising solution. The review covers mitophagy mechanisms, associated pathways, detection techniques, mitophagy modu lating agents, and nanoparticle strategies- both standalone and combinatorial. It further discusses translational opportunities and technical barriers, offering a concise, integrative perspective on how nanomedicine can enable targeted mitophagy interventio n for improved cancer therapy.
    Keywords:  Cancer treatment; Mitophagy; Nano-delivery strategy; Nanomaterials
    DOI:  https://doi.org/10.1016/j.actbio.2025.07.059
  15. Neuroreport. 2025 Sep 03. 36(13): 760-766
    MCTR1 alleviates remifentanil-induced hyperalgesia by regulating mitochondrial fission protein DRP1 in rats.
    Lijun Gu, Linyao Chen, Yanan Wang, Linglin Gao, Jianwen Ye, Zixuan Xu, Zijun Zhou, Jiehao Sun.
       OBJECTIVE: This study aimed to investigate whether Maresin conjugates in tissue regeneration-1 (MCTR1) can alleviate remifentanil-induced hyperalgesia (RIH) by modulating the mitochondrial fission protein dynamin-related protein 1 (DRP1).
    METHODS: Pain behavioral tests were conducted 24 h before remifentanil infusion and at 4, 8, and 24 h postinfusion. The expression of DRP1 and NR2B was assessed by Western Blot (WB). Additionally, intrathecal injections of MCTR1 were administered to evaluate the effects on RIH development and progression. Behavioral tests were conducted, meanwhile, the levels of DRP1, NR2B in the spinal cord, superoxide, including malondialdehyde (MDA), glutathione, and reactive oxygen species (ROS) in the spinal dorsal horn were measured. Mitochondrial numbers were counted via transmission electron-microscopy.
    RESULTS: After remifentanil administration, rats exhibited mechanical allodynia and thermal hyperalgesia, along with an increase in spinal levels of DRP1 and NR2B. However, MCTR1-treated rats showed alleviation of remifentanil-induced mechanical and thermal hyperalgesia, accompanied by reduced NR2B expression. Notably, MCTR1 treatment also led to decreased DRP1 expression and mitochondrial fission, as well as reduced MDA content and ROS production.
    CONCLUSION: MCTR1 exerts a preventive effect on RIH by modulating NR2B activity through the DRP1-mitochondrial-ROS pathway.
    Keywords:  Maresin conjugates in tissue regeneration-1; dynamin-related protein 1; hyperalgesia; mitochondria; reactive oxygen species; remifentanil
    DOI:  https://doi.org/10.1097/WNR.0000000000002198
  16. FASEB J. 2025 Aug 15. 39(15): e70882
    PDE4D Regulates Mitochondrial Homeostasis and Adult Hippocampal Neurogenesis via the cAMP/CREB Signaling Pathway in Chronic Stress-Induced Depressive-Like Behavior.
    Wei Zhao, Ziqi Wang, Xiaofei Chen, Shuang Zhao, Fangjiao Zong, Hanting Zhang.
      Phosphodiesterase 4D (PDE4D), a major enzyme responsible for cAMP degradation in the hippocampus, has been implicated in mood regulation. Although PDE4D inhibition exerts antidepressant effects, the underlying mechanisms remain poorly understood. Here, we explored the role of PDE4D in chronic stress-induced depressive-like behaviors, mitochondrial dysfunction, and impaired adult hippocampal neurogenesis (AHN). Using a chronic restraint stress (CRS) model, we found that PDE4D expression was significantly upregulated in the hippocampal dentate gyrus (DG) of CRS mice, leading to suppressed CREB signaling, mitochondrial dysfunction, and impaired AHN. PDE4D knockout (PDE4D-KO) restored mitochondrial quality by enhancing mitochondrial biogenesis, normalizing mitophagy, and improving oxidative phosphorylation (OXPHOS) via the nucleus and mitochondria cAMP/CREB signaling, ultimately promoting AHN and alleviating depression-like symptoms. These findings define PDE4D as a key regulator of mitochondrial homeostasis and AHN, suggesting that targeting PDE4D in the hippocampal DG may represent a novel treatment mechanism for depression.
    Keywords:  adult hippocampal neurogenesis; chronic stress; depression; mitochondrion; pde4d
    DOI:  https://doi.org/10.1096/fj.202501537R
  17. Oncogene. 2025 Jul 25.
    RFX2-BNIP3 axis-driven adaptive mitophagy promotes resistance to ACK1-targeted therapy in non-small cell lung cancer.
    Kui Cao, Shenshui Wei, Tianjiao Ma, Xiaolong Zou, Hongxue Meng, Xinxin Yang, Mengdi Lu, Yuning Wang, Xiangrong He, Jianqun Ma, Jinhong Zhu.
      Activated Cdc42-associated kinase 1 (ACK1) is an oncogenic non-receptor kinase that promotes tumor cell survival and impairs T-cell activation. Targeting ACK1 has great promise in cancer control. However, tumor adaptive responses that may limit the anticancer efficacy of ACK1 inhibition (ACK1i) remain unclear. We found that ACK1i treatment triggered the PINK1/PARKIN-mediated adaptive mitophagy by upregulating the mitophagy receptor BNIP3. Mass/Spectrometry and co-immunoprecipitation (Co-IP) results indicated that ACK1 interacted with transcription factor regulatory factor X 2 (RFX2) through its MHR domain, and competitively inhibits RFX2 ubiquitination via the E3 ubiquitin ligase MIB1. Conversely, ACK1i facilitates MIB1-mediated RFX2 ubiquitination and degradation. Moreover, we observed that RFX2 is a transcriptional suppressor of BNIP3 using luciferase reporter gene assays and chromatin immunoprecipitation (ChIP). Overall, ACK1i treatment causes RFX2 instability and thereby diminishes RFX2's suppressive effects on BNIP3 transcription, leading to BNIP3 accumulation and the activation of mitophagy pathways. This adaptive mitophagy allows NSCLC cells to survive under ACK1 inhibition, potentially reducing the efficacy of ACK1i. ACK1i combined with mitophagy-inhibiting agents may attain a more accomplished response in NSCLC. In conclusion, ACK1i induced mitophagy through the release of RFX2 inhibition on BNIP3 transcription, thereby driving adaptive resistance. Inhibiting mitophagy sensitizes NSCLC to ACK1i.
    DOI:  https://doi.org/10.1038/s41388-025-03502-0
  18. Eur J Pharmacol. 2025 Jul 23. pii: S0014-2999(25)00735-6. [Epub ahead of print]1004 177981
    Repositioning of a nutraceutical, scoparone, in the management of MK-801-induced schizophrenia-like behavior in Mice: An insight into SIRT1/PGC-1α/TFAM pathway.
    Mostafa A Rabie, Wagih H Marcus, Mohamed A Sadek, Hassan A Ruby, Khloud A F Emam, Barbara Budzynska, Krystyna Skalicka-Wożniak, Rabab H Sayed, Lamiaa A Ahmed, Nesrine S El Sayed.
      Schizophrenia is a prevalent neurodevelopmental psychiatric disorder that remains inadequately managed by current treatments, highlighting the urgent need for new pharmacotherapeutic approaches. Nutraceuticals have gained attention due to their favorable safety and multifaceted pharmacological benefits. Among these, scoparone exhibits a well-documented neuropsychopharmacological profile; however, its potential therapeutic effects on schizophrenia remain unclear and warrant further investigation. Consequently, this study aimed to evaluate the influence of scoparone treatment on MK-801-induced schizophrenia-like behaviors in C57BL/6 mice. C57BL/6 mice were injected with MK-801 (0.6 mg/kg/day, i.p.) for 7 consecutive days to induce schizophrenia. Mice were treated with scoparone (25 mg/kg/day, i.p.) 2 h after the MK-801 administration. Interestingly, scoparone attenuated MK-801-induced positive, negative, and cognitive symptoms of schizophrenia, as demonstrated in behavioral tests. Furthermore, it hindered MK-801-induced histopathological changes in the hippocampus. Importantly, the biochemical analysis shed light on the ability of scoparone to activate the neuroprotective silent mating type information regulation 2 homolog 1/peroxisome proliferator-activated receptor-γ coactivator-1-α/mitochondrial transcription factor A (SIRT1/PGC-1α/TFAM) signaling pathway, thereby regulating mitochondrial homeostasis. Concisely, PGC-1α activation hinders dynamin-related protein 1 (Drp1) levels, restricting mitochondrial fission. Conversely, it augments the fusion of adjacent mitochondria by boosting Mitofusin 2 (MFN2) and protein optic atrophy 1 (OPA1) levels. Moreover, it enhanced mitophagy for selective removal of damaged mitochondria. In conclusion, this study underscores scoparone's beneficial effect in MK-801-induced schizophrenia-like behaviors via SIRT1 activation, which manipulates multiple axes involved in the pathophysiology of schizophrenia.
    Keywords:  Coumarin derivative; MK-801; Mitochondria; SIRT1; Schizophrenia; Scoparone
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177981
  19. J Gastroenterol Hepatol. 2025 Jul 31.
    Targeting DRP1Ser637 Phosphorylation Alleviates Acidic Bile Salt-Induced NF-κB Activation via Mitochondrial Protection.
    Yanqing Yang, Zhenghui Zhu, Xinyan Li, Qinghua Li, Hong Zhu.
       BACKGROUND AND AIMS: The role of mitochondrial dynamics in gastroesophageal reflux disease (GERD) remains unclear. We investigated how bile acid-induced mitochondrial dysfunction triggers mucosal inflammation and explored therapeutic targets.
    METHODS: Esophageal mucosal biopsies from 12 GERD patients and 12 controls underwent RNA-seq. Human esophageal epithelial cells (HEEC) were treated with acidic bile salts (ABS, pH 5.5). Mitochondrial morphology (TOMM20 immunofluorescence), function (TMRM/MitoSOX staining), and DRP1 post-translational modifications (non-reducing Western blot) were analyzed. DRP1 knockdown (shRNA) and pharmacological inhibition (H-89) were used to validate mechanisms.
    RESULTS: RNA-seq revealed enrichment of mitochondrial fission and NF-κB pathways in GERD patients. ABS exposure in HEEC increased DRP1 Ser637 phosphorylation, inducing mitochondrial fragmentation, membrane potential loss, and mtROS overproduction. Paradoxically, DRP1 knockdown exacerbated mitochondrial damage and amplified NF-κB activation. H-89 suppressed DRP1 Ser637 phosphorylation, restored mitochondrial function, and attenuated IL-6/IL-8 secretion. This effect was abolished in DRP1-knockdown cells.
    CONCLUSIONS: ABS-induced DRP1 Ser637 phosphorylation drives mitochondrial fragmentation and mtROS-dependent NF-κB activation in GERD. DRP1-mediated fission paradoxically limits mucosal damage by enabling quality control. Targeting DRP1 phosphorylation may offer a novel therapeutic strategy to break the mitochondrial-inflammation vicious cycle in GERD.
    DOI:  https://doi.org/10.1111/jgh.70056
  20. J Mol Histol. 2025 Jul 31. 56(4): 248
    Myrtenol ameliorates ulcerative colitis by modulating ANXA1/PINK1/Parkin-mediated mitophagy.
    Yimin Li, Xiaobing Gong, Yinghua Peng, Yadang Kuang, Jiaxuan Huang, Mengli Zheng, Leilei Zhan, Jiewen Liang, Weiyi Guo.
      Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by recurrent and intermittent episodes of inflammation. (-)-Myrtenol (MYR) has been shown to exhibit anti-inflammatory, antioxidant, and gastroprotective properties; however, its therapeutic potential in UC remains unexplored. In this study, we established in vitro UC models using lipopolysaccharide (LPS)-induced Caco-2 cells and in vivo models using dextran sulfate sodium (DSS)-induced mice to investigate the effects of MYR on UC. Our findings demonstrated that MYR protected Caco-2 cells from LPS-induced apoptosis and restored mitochondrial function by activating mitophagy. Mechanistically, MYR exerted its protective effects by upregulating ANXA1 expression in LPS-challenged Caco-2 cells, which subsequently activated the PINK1/Parkin pathway. Consistent with these in vitro results, experiments in the DSS-induced mouse model revealed that MYR alleviated UC symptoms and mitigated mitochondrial damage through the regulation of the ANXA1/PINK1/Parkin pathway-mediated mitophagy. In conclusion, MYR reduced apoptosis in LPS-induced Caco-2 cells and ameliorated UC symptoms in DSS-induced mice by enhancing mitophagy and alleviating mitochondrial dysfunction via the ANXA1/PINK1/Parkin pathway.
    Keywords:  ANXA1; MYR; Mitophagy; PINK1/Parkin pathway; UC
    DOI:  https://doi.org/10.1007/s10735-025-10486-4
  21. Nat Struct Mol Biol. 2025 Jul 25.
    A structural switch reveals how to disarm USP30 and unlock mitophagy.
    Julia C Fitzgerald, Anja Bremm.
      
    DOI:  https://doi.org/10.1038/s41594-025-01640-3
  22. Nutrients. 2025 Jul 10. pii: 2290. [Epub ahead of print]17(14):
    Effect of Peanut Shell Extract and Luteolin on Gut Microbiota and High-Fat Diet-Induced Sequelae of the Inflammatory Continuum in a Metabolic Syndrome-like Murine Model.
    Hemalata Deshmukh, Roberto Mendóza, Julianna M Santos, Sathish Sivaprakasam, Moamen M Elmassry, Jonathan M Miranda, Patrick Q Pham, Zarek Driver, Matthew Bender, Jannette M Dufour, Chwan-Li Shen.
      Background: Metabolic syndrome (MetS) is characterized by chronic inflammation, oxidative stress, and mitochondrial dysfunction. MetS is associated with increased intestinal permeability and dysbiosis. The objective of this study was to investigate the effects of peanut shell extract (PSE) and luteolin (LUT) on the kidneys, colon, and ileum in a MetS-like murine model. Methods: Thirty-six male Slc6a14y/- mice were divided into four groups: low-fat diet (LFD), high-fat diet (HFD), HFD + 200 mg PSE/kg BW (PSE, p.o.), and HFD + 100 mg LUT/kg BW (LUT, p.o.) for 4 months. Outcome measures included glucose homeostasis, intestinal permeability, gut microbiome composition, and mRNA gene expression of mitochondrial homeostasis and inflammation/oxidative stress in the kidneys, colon, and ileum. Results: HFD resulted in glucose dysregulation with hyperglycemia and insulin resistance. PSE and LUT improved insulin tolerance and beta-cell function. PSE and LUT mitigated HFD-increased serum lipopolysaccharide-binding protein concentration. Perturbations in the gut microbiome were associated with HFD, and PSE or LUT reversed some of these changes. Specifically, Phocaeicola vulgatus was depleted by HFD and reverted by PSE or LUT. Relative to the LFD group, the HFD group (1) upregulated mitochondrial fusion (MFN1, MFN2, OPA1), mitophagy (TLR4, PINK1, LC3B), and inflammation (NFκB, TNFα, IL6), and (2) downregulated mitochondrial fission (FIS1, DRP1), biosynthesis (PGC1α, NRF1, NRF2, TFAM), electron transport chain (complex I), and antioxidant enzyme (SOD1) in the kidneys, colon, and ileum. Conclusions: PSE and LUT reversed such HFD-induced changes in the aforementioned gene expression levels.
    Keywords:  bioactive compounds; colon; diabetes; ileum; kidney; luteolin; mice; microbiome; mitochondria; tissues
    DOI:  https://doi.org/10.3390/nu17142290
  23. Int Immunopharmacol. 2025 Jul 25. pii: S1567-5769(25)01270-6. [Epub ahead of print]163 115280
    S100A9 inhibition ameliorates HFpEF by modulating mitochondrial fission and oxidative stress.
    Moran Wang, Bowen Ren, Xiaofan Wu, Junyi Guo, Yu Cao, Lintong Men, Wei Shi, Cuntai Zhang, Li Lin, Jiagao Lv, Sheng Li, Shengqi Huo.
      Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and myocardial stiffness, with limited treatment options due to the unclear molecular mechanisms underlying the disease. In this study, we investigate the role of S100A9, an inflammatory mediator, in regulating mitochondrial dynamics in HFpEF. Using "two-hit" (high-fat diet and L-NAME) and db/db mouse models, we show that S100A9 is significantly elevated in both cardiac tissue and serum, correlating with impaired diastolic function, cardiac hypertrophy, and increased oxidative stress. Inhibition of S100A9 with Paquinimod (PAQ) improved diastolic function, reduced cardiac hypertrophy, and decreased S100A9-positive macrophage infiltration, while preventing M1 macrophage polarization. In vitro, S100A9 secreted by palmitic acid-stimulated RAW 264.7 macrophages promoted mitochondrial fission in AC16 cardiomyocytes by increasing p-Drp1 and Fis1 expression, similar to the effects observed with recombinant S100A9. Excessive mitochondrial fission, regulated by S100A9, is a key factor in HFpEF progression. Transcriptomic analysis revealed significant upregulation of pyruvate dehydrogenase kinase 4 (PDK4) in HFpEF mice. Mechanistically, S100A9 induced PDK4 expression via SPI1-mediated transcription, exacerbating oxidative stress and mitochondrial fragmentation. PAQ treatment or silencing PDK4/SPI1 in AC16 cells reversed these effects, restoring ATP levels and stabilizing mitochondrial membrane potential. Cardiomyocyte-specific PDK4 knockdown in vivo further ameliorated HFpEF progression without affecting systolic function. These findings highlight S100A9 inhibition as a promising therapeutic strategy for HFpEF by targeting mitochondrial dysfunction through the S100A9/SPI1/PDK4 axis.
    Keywords:  Heart failure with preserved ejection fraction; Mitochondrial fission; Oxidative stress; PDK4; S100A9
    DOI:  https://doi.org/10.1016/j.intimp.2025.115280
  24. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2511890122
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like lipid transporter densities connected to mitophagic phagophores. A subpopulation of ATP synthases relocalized from cristae to the inner boundary membrane. The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by subtomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation being enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    Keywords:  autophagy; cryo-ET; mitochondria; mitophagy; prohibitin
    DOI:  https://doi.org/10.1073/pnas.2511890122
  25. Commun Biol. 2025 Aug 01. 8(1): 1141
    HEP14 treatment improves ovarian function in aged mice through mitophagy enhancement and oxidative stress reduction.
    Liming Gui, Jiajia Sun, Qin Zhong, Kan Liu, Qili Sun, Yingtong Di, Helen Picton, Bin Tang, Xiaojiang Hao, Changzhong Li.
      Ovarian aging profoundly impacts reproductive health and accelerates the overall aging process, yet the development of effective therapeutic strategies remains a formidable challenge. In this study, we report the rejuvenating effects of HEP14, a natural activator of protein kinase C (PKC) pathway, on aged ovarian function by inducing mitophagy and effectively clearing reactive oxygen species. To ensure controlled and sustained delivery of HEP14 in vivo, we develop HEP14-loaded PLGA microspheres. Transcriptomic analysis reveals a significant overlap between the transcriptional profiles of HEP14-treated aged ovaries and those of adult ovaries, suggesting molecular rejuvenation process closely associated to HEP14-induced mitophagy. Histopathological evaluations further substantiate these findings, showing that HEP14 enhances mitophagy, exhibits antioxidative properties and promotes follicular regeneration. Consequently, ovarian endocrine function in aged mice is substantially restored. Using transmission electron microscopy, confocal microscopy, and western blot analysis alongside pharmocological inhibitors and PKC-specific siRNA, in vitro studies further demonstrate the restorative effect of HEP14 on mitophagy, leading to improved mitochondrial function and subsequent alleviation of oxidative stress in senescent ovarian granulosa cells. This effect is mediated through the activation of the PKC-ERK1/2 pathway, which plays an pivotal role in the action mechanism in HEP14. These discoveries offer new therapeutic hope for ovarian aging.
    DOI:  https://doi.org/10.1038/s42003-025-08576-w
  26. Chem Biol Interact. 2025 Jul 26. pii: S0009-2797(25)00296-0. [Epub ahead of print]420 111666
    Evidence of biological aging through mitochondrial DNA damage and dysregulation of mitophagy-related genes in veterans with delayed sulfur mustard toxicity.
    Maryam-Sadat Kalantar, Mohammad-Reza Vaez-Mahdavi, Leila Nasiri, Hossein Hassanpour, Sussan Kaboudanian-Ardestani.
      Sulfur mustard (SM) is a potent alkylating agent known to cause long-term health effects, including accelerated aging. This study investigated mitochondrial dysfunction as a key mechanism underlying biological aging in 142 SM-exposed veterans (25 years post-exposure) and 54 matched controls. The SM-exposed veterans were stratified into subgroups (asymptom, mild, and severe) based on clinical criteria and lung function tests. Using buffy coat-derived leukocytes, we assessed mitochondrial DNA (mtDNA) copy number and damage frequency of long/short mtDNA fragments, and mitophagy-related gene expression (PINK1, PRKN, DRP1, FIS1). Demographic variables (age, marital status, income, smoking status, education) did not differ significantly between SM-exposed and control groups, ensuring comparability. Results showed no significant differences in mtDNA copy number between groups; however, mtDNA damage frequency was significantly elevated in the severe exposure subgroup. Gene expression analysis revealed significantly increased mRNA levels of PINK1, PRKN, DRP1, and FIS1 in SM-exposed veterans compared to controls, with the highest expression observed in the severe and mild subgroups, while PINK1 expression showed no significant subgroup differences. These findings demonstrate that SM exposure induces persistent mitochondrial dysfunction through cumulative mtDNA damage, dysregulated mitophagy signaling, and aberrant fission activation. While preserved mtDNA copy numbers suggest adaptive biogenesis, the severity-dependent patterns in fission genes and mtDNA lesions establish mitochondrial impairment as a central pathway in SM-related aging.
    Keywords:  Biological ageing; Gene expression; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1016/j.cbi.2025.111666
  27. J Cell Sci. 2025 Jul 30. pii: jcs.263680. [Epub ahead of print]
    Mitochondrial protein aggregates recruit key chaperones and are sequestered in a fission/fusion-dependent process.
    Laura Ruland, Marc Sylvester, Lydia Maus, Hannes Beckert, Wolfgang Voos.
      The potential proteotoxicity of mitochondrial aggregates in yeast cells is reduced by a sequestration of affected polypeptides into a mitochondrial protein quality control compartment (IMiQ). Based on the expression of an aggregation-prone protein in the mitochondrial matrix, we determined the effect of organelle dynamics on aggregate sequestration. Fusion deficient cells were unable to accumulate the aggregates in the IMiQ, resulting in a stress-sensitive phenotype. In contrast, fission deficient cells could not separate the aggregate from the mitochondrial network. In these mitochondria, the aggregates were neutralized by the formation of a shell formed by mitochondrial chaperones. We also performed quantitative mass spectrometry to analyse the mitochondrial proteome and the extent of co-aggregation of mitochondrial proteins. While only minor changes of the total proteome were detected in response to aggregate accumulation, we found a recruitment of proteins of the respiratory chain complexes and of the protein quality control system (PQC). In particular members of the Hsp70 chaperone family were prominently associated with the aggregate. We conclude that this chaperone-dependent neutralization prevents a major co-aggregation of endogenous mitochondrial proteins.
    Keywords:  Cell biology; Chaperone; Hsp70; Mitochondria; Protein aggregation; Proteostasis; Yeast
    DOI:  https://doi.org/10.1242/jcs.263680
  28. Ecotoxicol Environ Saf. 2025 Jul 24. pii: S0147-6513(25)01074-7. [Epub ahead of print]302 118729
    NQO1 antagonizes PM2.5-induced apoptosis of Sertoli cells by activating the UPRmt pathway.
    Cao Wang, Qing Xiao, Mingchen Xiao, Yu Chu, Yaya Ai, Zhen Luo, Guangxu Zhou, Kaiyi Mao, Bin Liu.
      The mechanism by which NQO1 antagonizes PM2.5-induced apoptosis in Sertoli cells through activation of the mitochondrial unfolded protein response (UPRmt) was investigated. A reproductive toxicity model was established using TM4 cells exposed to PM2.5 (50 μg/mL, 24 h). Transcriptome sequencing and bioinformatics analysis identified NQO1 as the target gene, playing a key role in redox regulation and apoptosis. Phenotypic analysis showed that PM2.5 exposure significantly increased intracellular ROS levels (P < 0.01), induced structural disintegration of mitochondrial cristae (as observed by TEM), and activated apoptosis pathways. Overexpression of NQO1 effectively mitigated these effects. The mechanistic analysis demonstrated that NQO1 overexpression significantly upregulated UPRmt-related proteins (HSP60, ATF5, and CLPP) (P < 0.05), increased SOD activity, and reduced MDA levels (P < 0.01). On the other hand, NQO1 knockout led to mitochondrial membrane potential loss and Cytochrome C release via UPRmt inhibition (P < 0.01), resulting in an increased Bax/Bcl-2 ratio and enhanced apoptosis. Overall, these findings suggest that the NQO1-UPRmt axis protects against PM2.5-induced germ cell damage by maintaining mitochondrial protein homeostasis and redox balance. This study identifies potential therapeutic targets for male infertility associated with environmental pollutants.
    Keywords:  Apoptosis; Mitochondrial Unfolded Protein Response (UPR(mt)); NQO1; PM2.5; Sertoli cells
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118729
  29. Cell Mol Biol Lett. 2025 Jul 28. 30(1): 94
    Perspectives on mitochondrial dysfunction in the regeneration of aging skeletal muscle.
    Kai Wang, Mailin Gan, Yuhang Lei, Tianci Liao, Jiaxin Li, Lili Niu, Ye Zhao, Lei Chen, Yan Wang, Li Zhu, Linyuan Shen.
      As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults. A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.
    Keywords:  Aging; Mitochondrial dynamics; Mitophagy; Oxidative stress; Skeletal muscle regeneration
    DOI:  https://doi.org/10.1186/s11658-025-00771-1
  30. Cell Mol Biol (Noisy-le-grand). 2025 Jul 30. 71(7): 1-7
    Modern methods of detecting mitophagy.
    Alexander V Blagov, Andrey Y Vinokurov, Vasily N Sukhorukov, Anton Y Postnov, Elizaveta M Pleshko, Alexander N Orekhov.
      Inhibition of mitophagy is one of the signs of chronic disease pathogenesis. Detection and measurement of mitophagy levels under in vitro and in vivo models provide a better understanding of the role of mitophagy disorder in disease development and serve as prerequisites for creating a clinically applicable system test. The development of such a system is potentially feasible, but taking into account a number of factors that will be discussed in detail in this article. Here it is considered the main models of mitophagy-based test systems and an analysis is carried out showing their advantages and disadvantages. The future potential for the development of mitophagy-based diagnostic test systems is also discussed here.
    DOI:  https://doi.org/10.14715/cmb/2025.71.7.1
  31. World J Clin Oncol. 2025 Jul 24. 16(7): 107788
    Unleashing the potential of ferroptosis, autophagy, and mitochondrial dynamics as emerging modalities in cancer treatment.
    Tanha Ashok Rana, Akhilesh Prajapati.
      New approaches in cancer treatment are increasingly emphasizing innovative biological processes such as ferroptosis, autophagy, and mitochondrial dynamics. Ferroptosis, characterized by iron-dependent lipid peroxidation, has emerged as a promising strategy for targeting aggressive and metastatic cancers including those of the lung, breast, prostate, pancreas, and colorectal regions. Autophagy, a cellular degradation mechanism, plays a dual role in cancer-it can inhibit tumor development by clearing damaged cellular components or, paradoxically, support tumor growth under stressful conditions. Mitochondrial dynamics, encompassing the continuous processes of fission and fusion, are often disrupted in various types of human cancers, leading to altered metabolism, therapy resistance, and metastasis. These disruptions make them favorable targets for innovative treatments. This review highlights ferroptosis as a novel form of cell death, focusing on its biological pathways and connections with mitochondrial dysfunction and autophagy. Understanding the interplay among these three mechanisms in the complex biology of cancer could provide a more comprehensive and effective approach to cancer therapy.
    Keywords:  Autophagy; Cancer treatment; Ferroptosis; Mitochondrial dynamics; Regulated cell death
    DOI:  https://doi.org/10.5306/wjco.v16.i7.107788
  32. Adv Sci (Weinh). 2025 Jul 30. e14282
    PTPN2 Inhibition Disrupts Mitochondrial Renewal and Blocks TFRC-Mediated Mitophagy to Exert Anti-Tumor Activities in ALK-Positive Anaplastic Large Cell Lymphoma.
    Wei-Ting Wang, Zi-Wen Duan, Tong-Yao Xing, Wei Hua, Kai-Xing Du, Chun-Yu Shang, Yi-Fan Wu, Li Wang, Jian-Yong Li, Rui Gao, Jin-Hua Liang, Wei Xu.
      Anaplastic large cell lymphoma (ALCL) is a heterogeneous subtype of T-cell lymphoma usually driven by genetic alterations affecting the anaplastic lymphoma kinase (ALK) gene. Despite the relatively favorable prognosis of ALK-positive (ALK+) ALCL, approximately 30-40% of patients experience relapses or disease progression. This work identifies protein tyrosine phosphatase PTPN2 as a critical gene essential for the growth and survival of ALK+ ALCL by CRISPR/Cas9 editing. PTPN2 depletion can significantly suppress tumor cell proliferation, induce apoptosis, and provoke cell cycle arrest. Mechanistically, PTPN2 negatively regulates transferrin receptor (TFRC) expression to promote mitochondrial renewal via PTEN induced kinase 1 (PINK1)-PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitophagy. The process functions independently of ferroptosis. Interestingly, TFRC is directly regulated by the transcription factor hypoxia-inducible factor 1 alpha (HIF1A) in its promoter. Notably, an orally bioavailable potent PTPN2/N1 active-site inhibitor ABBV-CLS-484 (AC484) demonstrates significant therapeutic potential against ALK+ ALCL by disturbing mitochondrial renewal and blocking TFRC-mediated PINK1-PRKN-dependent mitophagy to exert anti-tumor activities, providing critical insights into the selection of targeted treatment strategies for ALK+ ALCL patients and a strong rationale for advancing AC484 into clinical trials.
    Keywords:  ABBV‐CLS‐484; ALK‐positive anaplastic large cell lymphoma; PTPN2; TFRC; mitophagy
    DOI:  https://doi.org/10.1002/advs.202414282
  33. Sci Rep. 2025 Jul 26. 15(1): 27273
    Mitophagy related gene signature for prognosis and therapeutic evaluation in KIRC.
    Dengyi Duan, Yangyang Guo, Jianmin Li, Zhengyang Li, Guoping Xu, Yuanjie Niu, Yang Zhao.
      This study conducted a comprehensive investigation of the prognostic significance and immunological features associated with mitophagy-related gene signatures in clear cell renal cell carcinoma (KIRC). Our primary aim was to establish an optimized predictive model for precise prognosis stratification and treatment response prediction in KIRC patients. Through LASSO Cox regression analysis, we systematically identified mitophagy-related genes (MRGs) and implemented them to develop a prognostic risk stratification model. The model's reliability was rigorously validated using both internal cohorts and independent external datasets. We subsequently constructed a clinically applicable nomogram by integrating the risk score with established prognostic indicators and relevant clinical parameters, thereby enabling multidimensional risk evaluation. Notably, tumor microenvironment characterization revealed enhanced immunotherapeutic responsiveness in high-risk patients, highlighting potential clinical utility for treatment selection. Complementary in vitro functional assays demonstrated that METTL24 overexpression significantly suppressed KIRC cell proliferation and migration capacity. Collectively, our mitophagy-related gene signature represents a novel prognostic biomarker with substantial clinical relevance, offering valuable insights for personalized therapeutic strategies in KIRC management. These findings not only advance our understanding of KIRC pathogenesis but also provide a framework for developing precision medicine approaches to optimize clinical outcomes.
    Keywords:  Immune microenvironment; Immunotherapy; Mitophagy; Prognostic model; Renal clear cell carcinoma
    DOI:  https://doi.org/10.1038/s41598-025-10798-1
  34. Cardiol Res Pract. 2025 ;2025 7778063
    Exercise-Based Cardiac Rehabilitation Improves Left Ventricular Dysfunction, Mitophagy, and Oxidative Stress Postmyocardial Infarction.
    Changyong Wu, Haojie Li, Shuangfeng Zhao, Jiang Liu, Ruijie Li, Huang Sun, Suli Bao, Menghan Li, Yunzhu Peng.
      Aim: Left ventricular dysfunction, disturbed mitophagy, and persistent oxidative stress after myocardial infarction (MI) are critical drivers of myocardial injury and cardiac remodeling. Exercise-based cardiac rehabilitation (CR) is a cornerstone of post-MI treatment and management, yet its mechanistic effects on myocardial repair remain incompletely elucidated. This study aimed to the effect of exercise-based CR on the left ventricular dysfunction, mitophagy, and oxidative stress post-MI. Methods: Mendelian randomization analysis elucidated causal relationship between six physical activities and MI. Subsequently, 70 MI patients were randomized to control or exercise-based CR groups (moderate-to-vigorous physical activity intensity, 3 days/week, 10-50 min/day, 12 weeks); left ventricular function, cardiopulmonary function, and SF-36 quality of life scale were assessed pre-/postintervention using standardized protocols. Additionally, 21 rats were allocated to Sham, MI, or MI + treadmill running groups (high-intensity interval exercise training, 5 days/week, 30-50 min/day, 10-25 m/min, 4 weeks); left ventricular function, mitophagy, and oxidative stress were detected postintervention. Results: Genetically predicted moderate-to-vigorous intensity physical activity was significantly associated with lower risk of MI (IVW OR = 0.66, 95% CI: 0.54-0.81), with no causal links for other activities. Critically, clinical and animal studies demonstrated that exercise-based CR improved left ventricular systolic function (LVEF) after MI. Four-week exercise in MI rats enhanced mitophagy levels (LC3, FUNDC1, PINK1, and Parkin) and attenuated oxidative injury (MDA, GSH, SOD2, and GPX4) post-MI. Additionally, exercise-based CR also improved cardiopulmonary function (peak VO2/kg, peakVO2/pred%, and MET) in patients with MI and ameliorated mitochondrial damage in MI rats. However, GLS, secondary cardiopulmonary parameters (Wmax, HRR1min, peakVO2/HR, and peakVO2/HRpred%), and SF-36 (PCS and MCS) showed no significant changes, which may be associated with shorter duration of exercise intervention. Conclusion: Exercise-based CR significantly ameliorated left ventricular dysfunction, enhanced mitophagy levels, and attenuated oxidative stress post-MI, establishing its role in critical pathological mechanisms. Future studies should validate long-term sustainability of exercise-based CR and explore the interaction mechanism between mitophagy and oxidative stress in cardiac remodeling, providing personalized and precise exercise protocols for people at high risk of exercise.
    Keywords:  cardiac fibrosis; cardiac rehabilitation; exercise training; mitophagy; myocardial infarction; oxidative stress
    DOI:  https://doi.org/10.1155/crp/7778063
  35. J Hematol Oncol. 2025 Aug 01. 18(1): 78
    Mitophagy's impacts on cancer and neurodegenerative diseases: implications for future therapies.
    Jason Huang, Vincent Truong Pham, Shaozi Fu, Gang Huang, Ya-Guang Liu, Lei Zheng.
      Substantial evidence supports an inverse relationship between cancer and neurodegenerative diseases (NDDs), but few studies investigate the biological mechanisms underlying this phenomenon. While previous explanations-such as inflammation, reactive oxygen species (ROS), genetic mutations, and cell death-remain significant, they ultimately converge on mitophagy. This review identifies mitophagy as a pivotal factor in the development of both cancer and NDDs, while also evaluating specific mechanisms and processes to clarify how mitophagy connects these opposing disease trajectories. By examining these factors, we aim to uncover the underlying mechanisms that explain the inverse relationship between cancer and NDDs, which will help develop therapeutic strategies that target common factors for both conditions.
    Keywords:  Calcium; Cancer; Cell death; Inflammation; Mitochondrial dysfunction; Mitophagy; Mutations; Neurodegenerative diseases; ROS; Therapeutics
    DOI:  https://doi.org/10.1186/s13045-025-01727-w
  36. Mol Biol Cell. 2025 Jul 30. mbcE25010033
    Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
    Sara Wong, Katherine R Bertram, Sai Sangeetha Balasubramaniam, Nidhi Raghuram, Thomas Knight, J Alan Maschek, James E Cox, Adam L Hughes.
      Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0033
  37. J Mol Histol. 2025 Jul 31. 56(4): 245
    The effect of USP17 knockdown on autophagic ferroptosis in gastric cancer by regulating the BNIP3-NCOA4-FTH1 axis.
    Jintao Tang, Lebin Yang, Xiongying Chen, Kai Yin, Chunyun Wang.
      
    Keywords:  BNIP3; FTH1; Ferroptosis; Gastric cancer; Mitophagy; NCOA4; Ubiquitin-specific protease 17
    DOI:  https://doi.org/10.1007/s10735-025-10526-z
  38. Mol Neurobiol. 2025 Aug 01.
    Semaglutide Mitigates Ischemic Brain Injury by Inhibiting Ferroptosis via Modulation of FoXO1 and DRP1 Pathways.
    Weihua Wang, Meng Pang, Yifeng Zhang, Shuai Hou, Yulei Xia, Youkui Shi, Xiaojun Zhang, Yanqiang Wang.
      Multiple pathogenic processes contribute to cerebral ischemia-reperfusion injury (CIRI); however, their relative importance and sequence remain unclear, warranting further investigation. Although our previous studies showed that inhibiting ferroptosis mitigates brain damage after ischemic stroke, the crosstalk among intracellular pathways remains poorly understood. The protective effects of semaglutide, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in ischemic stroke have yet to be fully elucidated. In this study, bioinformatics analysis was conducted to predict the potential therapeutic mechanisms of semaglutide in CIRI, highlighting the involvement of the FoXO1-autophagy pathway and mitochondrial dynamics. A rat's middle cerebral artery occlusion/reperfusion (MCAO/R) model was established to validate these predictions. Histopathological examination demonstrated that semaglutide alleviated pathological damage and reduced neuronal apoptosis. Using Western blotting, RT-PCR, immunofluorescence, and ELISA, we assessed key markers-GLP-1R, FoXO1, Beclin1, DRP1, Mfn2, ATP, and ROS-in the ischemic penumbra. The results showed that semaglutide inhibited autophagy (Beclin1), suppressed mitochondrial fission (DRP1), promoted mitochondrial fusion (Mfn2), and improved mitochondrial function, as reflected by increased ATP production and reduced ROS levels. Furthermore, we investigated the involvement of FoXO1 and mitochondrial function in the regulation of ferroptosis. The findings suggest that semaglutide inhibits ferroptosis by activating GLP-1R, thereby modulating the intracellular FoXO1/GPX4 and DRP1/ACSL4 signaling pathways. In summary, semaglutide acts through GLP-1R to regulate FoXO1-mediated autophagy, mitochondrial dynamics, and ferroptosis, as well as to modulate DRP1-dependent mitochondrial fission and ferroptosis. Together, these mechanisms account for its protective effects against ischemic stroke.
    Keywords:  Cerebral ischemia/reperfusion injury; DRP1; Ferroptosis; FoXO1; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s12035-025-05253-1
  39. Biology (Basel). 2025 Jul 20. pii: 893. [Epub ahead of print]14(7):
    Protective Effects of N-Acetylcysteine in Alleviating Cocaine-Mediated Microglial Activation and Neuroinflammation.
    Uma Maheswari Deshetty, Abiola Oladapo, Yazhini Mohankumar, Elias Horanieh, Shilpa Buch, Palsamy Periyasamy.
      Cocaine misuse induces microglial activation and neuroinflammation, contributing to neurodegeneration and behavioral impairments. Prior studies have shown that cocaine induces mitochondrial dysfunction, dysregulated mitophagy, and lysosomal impairment in microglia. Here, we investigated the therapeutic potential of N-acetylcysteine (NAC) in mitigating cocaine-induced microglial activation and neuroinflammation. Mouse primary microglial cells (MPMs) were pretreated with NAC (5 mM) for 1 h prior to cocaine exposure (10 µM, 24 h) and analyzed for markers of microglial activation, mitophagy, and lysosomal integrity using Western blot, Seahorse assays, lysosomal pH, and membrane potential measurements. In vivo, C57BL/6N mice received NAC (200 mg/kg, i.p.) 1 h before daily cocaine injections (20 mg/kg, i.p.) for 7 days. Behavioral assays (open field, novel object recognition) and brain biomarker analyses (frontal cortex, hippocampus) were performed. Cocaine exposure elevated CD11b, mitophagy markers (PINK1, PARK, and DLP1), and autophagy proteins (Beclin1, and p62), while impairing mitochondrial and lysosomal functions. NAC pretreatment restored mitochondrial and lysosomal function, reduced reactive oxygen species, and normalized protein expression. In vivo, NAC also alleviated cocaine-induced microglial activation and behavioral deficits. These findings highlight NAC as a promising therapeutic agent to counteract cocaine-mediated neuroinflammation and neurotoxicity.
    Keywords:  N-acetylcysteine; autophagy; cocaine; lysosomes; microglial activation; mitophagy; neuroinflammation
    DOI:  https://doi.org/10.3390/biology14070893
  40. Bioorg Chem. 2025 Jul 25. pii: S0045-2068(25)00669-8. [Epub ahead of print]163 108789
    New rhodium(III)-triphenylphosphine complexes with 5-halogenate-8-hydroxyquinoline as ligands: synthesis, characterization, cytotoxicity, and mechanism of action.
    Zhen-Feng Wang, Xiao-Qiong Huang, Run-Chun Wu, Shu-Hua Zhang, Guangzhao Li.
      The incorporation of triphenylphosphine (PPh3) can enhance the antiproliferative activity of complexes. Herein, four Rh(III) complexes GUPT1-GUPT4 were synthesized. GUPT4 exhibited stronger anticancer activity than HGU, cisplatin, and GUPT1-GUPT3 against human non-small cell lung A549 and its cisplatin-resistant A549 cell line (CR-A549), with IC50 values of 6.73 ± 0.41 and 5.11 ± 0.16 μM, respectively. The antiproliferative activity of the four RhIII complexes increased with different 5-substituted ligands in the following order: H (GUPT1) < Br (GUPT2) < Cl (GUPT3) < F (GUPT4). GUPT3 and GUPT4 induce CR-A549 mitochondrial autophagy and ATP blockade, leading to apoptosis. In addition, the inhibition rate of GUPT4 on A549 was 39.1 %, showing potential antitumor efficacy. Thus, GUPT3 and GUPT4 can be considered as promising non-Pt drug candidates for lung cancer treatment.
    Keywords:  5-halogenate-8-hydroxyquinoline; Apoptosis; Mitophagy; Rhodium(III) complexes; Triphenylphosphine
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108789
  41. Nat Cell Biol. 2025 Jul 25.
    Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.
    Elias Adriaenssens, Stefan Schaar, Annan S I Cook, Jan F M Stuke, Justyna Sawa-Makarska, Thanh Ngoc Nguyen, Xuefeng Ren, Martina Schuschnig, Julia Romanov, Grace Khuu, Louise Uoselis, Michael Lazarou, Gerhard Hummer, James H Hurley, Sascha Martens.
      Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, whereas FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with important implications for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41556-025-01712-y
  42. Eur J Pharmacol. 2025 Jul 30. pii: S0014-2999(25)00761-7. [Epub ahead of print] 178007
    The novel effects of the cardiovascular drug ranolazine on the alleviation of age-related cognitive decline and the underlying mechanisms.
    Xiaohua Yue, Shufen Wu, Yiru Yin, Xin Zhao, Enhui Li, Geliang Liu, Xiang Zan, Qi Yu, Peifeng He, Ce Zhang.
      The cognitive decline associated with ageing is the most critical health issue affecting elderly individuals, and there is still a lack of effective interventions available. This study was designed to identify a drug capable of ameliorating age-related cognitive decline and the underlying mechanisms. Utilizing data mining of multisource databases and drug repositioning approaches based on transcriptome similarity, the cardiovascular drug ranolazine (Ran), was identified as a potential candidate with similar effects to those of resveratrol (RSV). Network pharmacology analysis predicted that Ran's effects on cognitive decline through the PI3K/AKT/mTOR signalling pathway. These predictions were subsequently verified using a combination of molecular, cellular, and tissue experiments, animal models of ageing induced by D-galactose, and omics studies. The results revealed that Ran extended the lifespan of Caenorhabditis elegans (C. elegans), improved the head swinging ability of ageing C. elegans, and alleviated mitochondrial membrane potential (MMP) damage in ageing hippocampal neuronal cells (HT22). In ageing rats, Ran not only enhanced spatial memory,exploratory behaviors and motor ability,but also alleviated mitochondrial structural damage in hippocampus and medial prefrontal cortex (mPFC). Notably, Ran alleviated age-related cognitive decline by regulating mitochondrial autophagy in hippocampus and mPFC through the PI3K/AKT/mTOR signalling pathway, rather its conventional mechanism of regulating fatty acid metabolism. In summary, this study reveals Ran's previously unrecognized role in alleviating age-related cognitive decline for the first time. These findings provide new options for the treatment of age-related cognitive decline and broaden the potential clinical applications of Ran.
    Keywords:  PI3K/AKT/mTOR signalling pathway; age-related cognitive decline; drug repurposing; mitochondrial autophagy; ranolazine
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178007
  43. Free Radic Biol Med. 2025 Jul 24. pii: S0891-5849(25)00849-4. [Epub ahead of print]239 155-176
    Treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization via activating mitophagy post-TBI.
    Jie Chen, Tong Zhu, Xixi Yang, Zhuojin Yang, Mengqing Shen, Boyuan Gu, Danmei Wang, Yuxiang Zhang, Mingxia Zhang, Siyu Sun, Jun Yu, Chunxia Yan.
      Moderate-intensity treadmill exercise has emerged as a promising therapeutic intervention for traumatic brain injury (TBI), yet its precise mechanisms remain unclear. Emerging evidence suggests that STING-mediated microglial pyroptosis and polarization might exacerbate TBI-induced pathological damage. Our previous work demonstrated treadmill exercise's inhibitory effects on the STING level, and mitophagy has been recognized as a crucial regulator of STING activity. Therefore, we aimed to test the possibility that treadmill exercise alleviates STING-mediated microglia pyroptosis and polarization partially through activating mitophagy post-TBI. First, we found that TBI-induced pyroptosis primarily occurred in neurons and microglia, along with pro-inflammatory M1 microglial polarization in the injured cortex. Remarkably, treadmill exercise could effectively reverse those pathological changes, demonstrating its anti-pyroptotic and anti-inflammatory potential. Then, we explored the dynamic expression of STING post-TBI, and found a progressively increased trend of STING in neurons, astrocytes, and microglia from 6 h to 35 days after TBI, with the most prominent rise in microglia. Notably, STING knockdown markedly diminished TBI-induced pyroptosis and prompted a shift in microglial polarization from M1 to M2. Furthermore, STING overexpression could partly abolish the treadmill exercise's neuroprotective effects against pyroptosis and inflammation post-TBI, suggesting that the anti-pyroptosis and anti-inflammatory effects of treadmill exercise were partly established via inhibiting the STING pathway. Crucially, pharmacological inhibition of mitophagy using mdivi-1 could partly reverse the treadmill exercise's suppressive effects on STING signaling, establishing mitophagy as the likely regulatory mechanism through which treadmill exercise regulates the STING pathway. To conclude, these findings demonstrated that treadmill exercise ameliorates STING-mediated microglial pyroptosis and M1 polarization, at least partially through enhancing mitophagy following TBI.
    Keywords:  Microglia polarization; Mitophagy; Pyroptosis; Stimulator of interferon genes; Traumatic brain injury; Treadmill exercise
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.034
  44. Commun Biol. 2025 Jul 29. 8(1): 1122
    Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
    Pin-Chao Liao, Tzu-Ying Lin, Catherine A Tsang, Chen-Jing Huang, Katherine Filpo, Istvan Boldogh, Liza A Pon.
      The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.
    DOI:  https://doi.org/10.1038/s42003-025-08549-z
  45. Ageing Res Rev. 2025 Jul 23. pii: S1568-1637(25)00191-6. [Epub ahead of print]111 102845
    Mitochondrial dysfunction in postoperative cognitive dysfunction: From preclinical mechanisms to multimodal diagnostics and precision intervention.
    Fengying Liu, Xiaodong Wu, Zilin Wang, Ao Li, Yuan Luo, Jiangbei Cao.
      Postoperative cognitive dysfunction (POCD) poses a significant clinical challenge with far-reaching implications for patient recovery and long-term quality of life. Growing evidence underscores the central role of mitochondrial dysfunction in the pathogenesis of POCD, uncovering an intricate interplay of molecular mechanisms that influence cognitive function. This study reviews the key mechanistic pathways involving mitochondria: bioenergetic impairment and metabolic irregularities, oxidative stress pathways and neuroinflammation, disruptions in calcium signaling, and deficiencies in mitochondrial quality control mechanisms-including kinetic abnormalities, defective mitophagy, and mitochondrial genetic material damage. Each of these pathways acts as a potential molecular nexus contributing to the cognitive decline in post-surgery, revealing the multifaceted nature of POCD progression. Furthermore, the review synthesizes recent advances in diagnostic and preventive strategies targeting mitochondrial dysfunction, bridging preclinical discoveries with clinical relevance. By delineating the role of mitochondria in the molecular landscape of POCD, this review not only clarifies the disease's pathogenic foundations but also paves the way for future translational research in mitochondria-targeted diagnostics and interventions.
    Keywords:  Energy metabolism; Evaluation and intervention; Inflammation; Mitochondrial dysfunction; Mitochondrial quality control; Postoperative cognitive dysfunction
    DOI:  https://doi.org/10.1016/j.arr.2025.102845
  46. Curr Issues Mol Biol. 2025 Jun 25. pii: 486. [Epub ahead of print]47(7):
    Investigating the Mechanism of Emodin in Rheumatoid Arthritis Through the HIF-1α/NLRP3 Pathway and Mitochondrial Autophagy.
    Dehao Du, Linlan Zhou, Jiayu Tian, Lianying Cheng, Han Zhang, Yifu Tang, Zexuan Qiu, Tingdan Zhang, Xiaofeng Rong.
      In this study, we investigated the inhibitory effects of emodin on pyroptosis in rheumatoid arthritis (RA) synovial cells by modulating the HIF-1α/NLRP3 inflammasome pathway and mitochondrial autophagy. By employing a chemically induced hypoxia model with CoCl2, we established experimental groups including normal control, model group, and emodin-treated groups at different concentrations (5 μM, 10 μM, and 20 μM). We optimized the CoCl2 concentration via CCK-8 assay to ensure cell viability. ELISA, Western blotting, transmission electron microscopy, and immunofluorescence were employed to assess HIF-1α, IL-1β, and IL-18 levels, pyroptosis-related proteins, autophagy markers, and NLRP3 fluorescence intensity. Statistical analysis revealed that increased CoCl2 concentrations led to a significant cell viability reduction (p < 0.05), with 300 μM CoCl2 causing ~50% inhibition at 24 h. Transmission electron microscopy confirmed autophagosome formation in emodin-treated groups, while Western blotting showed dose-dependent downregulation of HIF-1α, NLRP3, BNIP3, and related proteins. Immunofluorescence revealed reduced NLRP3 fluorescence intensity with increasing emodin doses (p < 0.05), alongside dose-dependent cell viability recovery (p < 0.05). Our findings demonstrate that emodin alleviates RA synovitis through dual mechanisms: inhibition of mitochondrial autophagy to regulate the balance between mitochondrial autophagy and pyroptosis, and suppression of HIF-1α/NLRP3-mediated pyroptosis signaling, thereby reducing IL-1β and IL-18 release and inhibiting synovial cell proliferation. This study provides innovative approaches for targeted RA therapy.
    Keywords:  cobalt chloride; emodin; hypoxia; mitochondrial autophagy; pyroptosis; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/cimb47070486
  47. Neuropharmacology. 2025 Jul 26. pii: S0028-3908(25)00310-7. [Epub ahead of print]279 110602
    The mitochondria-targeted hydrogen sulfide donor AP39 reduces cortical stroke volume and improves motor function in a photothrombotic stroke model in mice in a sex-dependent manner.
    Jakub Jurczyk, Zuzanna Guzda, Alicja Skórkowska, Żaneta Broniowska, Małgorzata Piechaczek, Aleksandra Więcek, Emilia Schulze, Angelika Ziaja, Roberta Torregrossa, Matthew Whiteman, Michel Soares Mesquita, Bartosz Pomierny, Lucyna Pomierny-Chamioło.
      Despite many years of research, the treatment for patients affected by ischemic stroke remains very limited and insufficient. Currently, new neuroprotective treatment strategies are being sought to reduce brain tissue damage in the penumbra zone. One of these strategies involves the use of a hydrogen sulfide donor, the compound AP39, which mitochondria-targeted and, in very low concentrations, has shown a favorable action profile in preclinical studies across various disease models. In this study, we evaluated whether the administration of AP39, given 10 min after photothrombotic focal cerebral stroke, affects motor performance in a skilled reaching task in both female and male mice. We also assessed cerebral blood flow using laser speckle contrast analysis, stroke volume via MRI at 24 h, 3 days, and 6 days post-stroke, as well as the expression of mitochondrial proteins TOMM20, COX4, PINK1 and Parkin as markers of mitophagy in cells. Our results showed significant improvement in motor function, increased blood flow and noticeably lower stroke volume, and TOMM20 and COX4 expression with concomitant upregulation of PINK1 and Parkin expression at day 6 in men treated with AP39 after focal cortical stroke. In females, the beneficial effect was limited, with only a slight reduction in stroke volume observed, without any impact on skilled task performance. These results indicate that AP39 has neuroprotective potential, but it is sex dependent.
    Keywords:  AP39; MRI imaging; Mitophagy; Photothrombotic stroke in mice; Skilled reaching task
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110602
  48. Phytother Res. 2025 Jul 30.
    Targeting Mitochondrial Dysfunction by Natural Products for the Treatment of Diabetic Kidney Disease.
    Jin-Ling Huo, Peipei Li, Qi Feng, Wenjia Fu, Shaokang Pan, Dongwei Liu, Zhang-Suo Liu.
      Diabetic kidney disease (DKD) is one of the most common complications of diabetes and is the primary cause of end-stage renal disease (ESRD). However, due to its complex pathological mechanism, there is a lack of effective targeted drugs for DKD. Natural products, such as Corbrin Capsule, Huang Kui Jiaonang, and uremic clearance granule, which are derived from Chinese herbal medicine, have several advantages and potential in the treatment of various human diseases, especially DKD, and they have become promising treatment strategies for DKD. Recent research has suggested that mitochondrial dysfunction plays a vital role in the progression of DKD, and many natural products have been found to ameliorate or delay DKD by improving mitochondrial function. In this review, we mainly describe mitochondrial dysfunction involved in the progression of DKD and summarize natural products targeting mitochondrial dysfunction through multiple signaling pathways in the treatment of DKD, providing new insights and promising therapeutic targets for DKD.
    Keywords:  DKD; mitochondrial dysfunction; mitophagy; natural products; oxidative stress; therapeutic targets
    DOI:  https://doi.org/10.1002/ptr.70059
  49. Autophagy Rep. 2025 ;4(1): 2529196
    The role of autophagy in the pathogenesis and treatment of multiple sclerosis.
    Giulio Righes, Luana Semenzato, Konstantinos Koutsikos, Veronica Zanato, Paolo Pinton, Carlotta Giorgi, Simone Patergnani.
      Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.
    Keywords:  Multiple sclerosis; autophagy; ferritinophagy; lipophagy; mielinophagy; mitophagy; therapy
    DOI:  https://doi.org/10.1080/27694127.2025.2529196
  50. Cell Signal. 2025 Jul 29. pii: S0898-6568(25)00442-5. [Epub ahead of print]135 112027
    High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway.
    Fadian Ding, Yikun Guo, Han Zhang, Yun Zhong, Denghan Zhang, Qiang Huang, Zhou Zheng, Guozhong Liu, Xiang Zhang, Shangeng Weng.
       PURPOSE: Diabetes mellitus is a critical risk factor for pancreatic cancer, yet its underlying molecular mechanism remains unclear. This study aims to investigate whether high glucose levels promote pancreatic cancer progression, and its molecular mechanism.
    METHODS: Tumor samples were collected from pancreatic cancer patients with diabetes mellitus (DM + PC). Additionally, pancreatic cancer animal models were constructed with diabetes/high glucose feeding and high glucose cell culture medium. The expression of p-AMPK, p-DRP1(Ser616), and mitochondrial fission were evaluated through molecular analysis. The levels of lactic acid, H3K18la, TTK, and BUB1B were also evaluated.
    RESULT: Survival analysis indicated that the clinical DM + PC group exhibited significantly worse overall survival (p < 0.05) and expressed significantly elevated levels of p-DRP1(Ser616) and HSP60 (p < 0.05). In the pancreatic cancer animal model with diabetes mellitus, higher tumor volumes and weights were observed along with elevated levels of p-DRP1(Ser616) and HSP60 (p < 0.05). Additionally, the high-glucose medium promoted proliferation and migration in cell lines (p < 0.05) and led to an increased expression of H3K18la, TTK, and BUB1B in a dose-dependent manner (p < 0.05). High levels of H3K18la, L-lactyl lysine, and TTK/BUB1B were expressed in DM + PC group(p < 0.05).
    CONCLUSION: High glucose increases the expression of p-DRP (Ser616) by inhibiting p-AMPK and subsequently affecting mitochondrial fission and lactic acid levels. This process is likely prompted by lactation levels of histone H3 and the expression of BUB1B and TTK.
    Keywords:  H3K18la/TTK/BUB1B signaling pathway; High glucose; Histone lactylation; Mitochondrial fission; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112027
  51. Antioxidants (Basel). 2025 Jul 17. pii: 876. [Epub ahead of print]14(7):
    A High-Fat Diet Induces Oxidative Stress in OPA1+/- Mouse Cortices: A Critical Double Challenge.
    Camille Champigny, Marlène Botella, Djamaa Atamena, Sébastien Bullich, Corentin Coustham, Bruno Guiard, Pascale Belenguer, Noélie Davezac.
      A high-fat diet (HFD) has significant effects on health, leading to cardiovascular, metabolic, neurodegenerative, and psychiatric conditions and contributing to obesity and type 2 diabetes. Mitochondria, essential for energy production and oxidative metabolism, are adversely affected by a HFD, causing oxidative stress and impaired cellular function. Mutations in the OPA1 (OPtic Atrophy 1) gene, crucial for mitochondrial dynamics and functions, are responsible for dominant optic atrophy (DOA), a mitochondrial neurodegenerative disease associated with increased reactive oxygen species (ROS). The expressivity of DOA is highly variable, even within the same family. This suggests that both modifying genetics and environmental factors could influence the penetrance of the disease. We previously demonstrated that genetic background modulates DOA expressivity and now ask if this is also the case for external cues. We thus explore how OPA1 deficiency interacts with HFD-induced metabolic disturbances, hypothesizing that long-term HFD consumption impairs brain mitochondrial function and disrupts oxidative metabolism. OPA1+/- mice were thus subjected to a HFD for a period of 12 weeks, and ROS levels and the expression of antioxidant genes were evaluated by Western blot and spectrophotometry. Cortices from high-fat diet-fed OPA1+/- mice showed lower aconitase activity than those of their wild-type (WT) litter mates, indicative of an unbalanced increase in mitochondrial ROS. Accordingly, OPA1+/- mice present lower levels of the antioxidant enzyme superoxide dismutase 2 compared to WT mice. Therefore, this study (i) reveals the onset of oxidative stress in brain cortices from OPA1+/- mice challenged with a HFD, (ii) shows that diet is a modifying factor for DOA, and (iii) suggests that food control could be used to moderate the severity of the disease.
    Keywords:  OPA1; antioxidant defenses; cortices; mitochondria; neurodegenerative disease
    DOI:  https://doi.org/10.3390/antiox14070876
  52. Eur J Paediatr Neurol. 2025 Jul 19. pii: S1090-3798(25)00116-3. [Epub ahead of print]58 20-26
    AFG2A-related encephalopathy: Effectiveness of ketogenic diet in epilepsy and mitochondrial dynamics modulation.
    Laia Nou-Fontanet, Uliana Musokhranova, Alia Ramírez Camacho, Verónica Delgadillo Chilavert, Víctor Soto Insuga, Luisa Arrabal Fernández, Itziar Alonso-Colmenero, Alexis Arzimanoglou, Ángeles García Cazorla, Alfonso Oyarzabal, Carmen Fons.
      AFG2A-related encephalopathy (AFG2A-RE) is a neurodevelopmental disorder that may present with drug-resistant epilepsy (DRE). Our aims were: to evaluate the clinical response to a ketogenic diet (KD) in a series of patients with AFG2A-RE and DRE, and to describe the mitochondrial effects in patient's fibroblasts cultured in a KD mimicking medium (KD-MM). This was a collaborative, descriptive, and experimental study involving a total of five patients. The primary outcomes assessed following ketogenic diet (KD) treatment were the percentage of seizure reduction and the parents' global impression of change. Additionally, patient-derived fibroblasts (n = 3) were cultured in a KD-MM to evaluate effects on mitochondrial dynamics and metabolism. The mean age of the patients was 7.9 years, and four were males. All patients presented with developmental and epileptic encephalopathy with DRE, motor impairment, severe intellectual disability, deafness, and microcephaly. In all but one case, the initial epilepsy presentation was infantile epileptic spasms syndrome (IESS), with a mean age at onset of 13.6 months. Four patients received KD treatment for DRE, with seizure reduction rates of 0 %, 30 %, 70 % and 100 %, respectively. Improvement in social interaction improvement was observed in one patient, while improvements in attentional and motor function were noted in two. In vitro studies demonstrated that AFG2A-deficient fibroblasts exhibited altered mitochondrial morphology and dynamics, as well as reduced ATP production and ROS levels. These abnormalities were significantly reversed when the fibroblasts were cultured in KD-MM. In conclusion, this small series of patients with AFG2A-RE showed beneficial effects from KD treatment. Greater seizure control was achieved when the ketogenic diet was initiated during early childhood. These findings are preliminary and validation in multicenter prospective study is required.
    DOI:  https://doi.org/10.1016/j.ejpn.2025.07.007
  53. Am J Physiol Regul Integr Comp Physiol. 2025 Aug 01.
    Sex-specific Impact of Selective Reduced Uterine Placental Perfusion Model of Preeclampsia on Fetal Cardiac Maturation and Mitochondrial Function.
    Paulami Chatterjee, Rebecca Molberg, Raven Kirschenman, Claudia D Holody, Anita Quon, Floor Spaans, Stephane L Bourque, Hélène Lemieux, Sandra T Davidge.
      Preeclampsia is a serious pregnancy complication and increases the risk of cardiovascular disease in offspring later in life. Cardiac development includes maturation of cardiomyocytes, a process that is intricately dependent on proper mitochondrial function. However, it remains unclear whether preeclampsia impairs mitochondrial function and alters cardiac maturation of fetal hearts during late gestation. Herein we induced selective reduced uterine placental perfusion (sRUPP), as a model of preeclampsia in rats, to investigate fetal cardiac myosin heavy chain (MYH) expression, reactive oxygen species (ROS) production, mitochondrial respiration, mitochondrial content and dynamics in male and female fetuses at gestational day (GD) 20 (term = GD 22). Litter size was reduced, while pup reabsorptions were increased in sRUPP compared to Sham controls. In only the male fetuses of sRUPP dams, cardiac MYH7/MYH6 ratio was reduced and MYH6 expression increased. Complex IV activity was elevated in sRUPP male fetuses, with no changes in mitochondrial citrate synthase or ATP synthase activities in either sex. However, ROS production increased in only sRUPP female fetuses. In male fetal hearts, sRUPP increased fusion protein MFN1 expression, tended to decrease fusion protein OPA1 expression, and decreased fission protein FIS1 expression. In contrast, MFN2 and OPA1 were reduced in sRUPP female fetuses. In conclusion, the sRUPP model of preeclampsia affected cardiac maturation and mitochondrial function in late gestation fetuses in a sex-specific manner. As prenatal strategies are being developed to improve pregnancy outcomes, sex-specific fetal effects should be taken into consideration.
    Keywords:  cardiac maturation; fetus; mitochondrial dynamics; preeclampsia; sex differences
    DOI:  https://doi.org/10.1152/ajpregu.00118.2025
  54. Antioxidants (Basel). 2025 Jul 15. pii: 866. [Epub ahead of print]14(7):
    Selenomethionine Counteracts T-2 Toxin-Induced Liver Injury by Mitigating Oxidative Stress Damage Through the Enhancement of Antioxidant Enzymes.
    Yan Wang, Mingxia Zhou, Suisui Gao, Pishun Li, Xiaofeng Zheng, Di Tu, Lingchen Yang.
      T-2 toxin, a highly toxic feed contaminant, poses a significant health risk to both humans and animals, particularly targeting the liver. This study aimed to investigate the protective effects and underlying mechanisms of selenomethionine (SeMet) against T-2-induced liver injury in mice. We pretreated mice with SeMet before exposing them to an acute liver injury model induced by T-2. By assessing indicators related to liver injury, oxidative stress, inflammatory response, and mitochondrial disorder, we found that SeMet mitigated T-2-induced liver damage. Specifically, SeMet upregulated the gene expression and activity of antioxidant enzymes like glutathione peroxidase 1 (GPX1), which consequently reduced reactive oxygen species (ROS), inflammatory cytokines levels, and normalized mitochondrial biogenesis. Conclusively, SeMet effectively alleviated T-2-induced mitochondrial overproduction, inflammatory responses, and oxidative stress damage in hepatocyte primarily by enhancing GPX1 and other antioxidant enzymes, thereby exerting a protective effect on the liver. This study provides theoretical and experimental support for further research and application of SeMet in the livestock industry.
    Keywords:  T-2 toxin; antioxidant enzymes; mitochondrial biogenesis; oxidative stress; selenomethionine
    DOI:  https://doi.org/10.3390/antiox14070866
  55. Circ Res. 2025 Jul 29.
    SLC39A13 Regulates Heart Function via Mitochondrial Iron Homeostasis Maintenance.
    Huihui Li, Xiaoting Wang, Yu Zhang, Yuan Yang, Joe Z Zhang, Bing Zhou.
       BACKGROUND: Iron is a necessary trace element for multiple reactions but is toxic in excess. Its intracellular balance is delicately maintained. We previously found that the loss of SLC39A13 (ZIP13), a newly identified endoplasmic reticulum/Golgi-resident iron transporter, impacted iron homeostasis in multiple tissues. The purpose of this study is to investigate the role of ZIP13 in regulating cardiac functions and the precise mechanism of cardiac injury caused by ZIP13 deficiency.
    METHODS: Cardio-specific knockout of Zip13 (Zip13-CKO), tamoxifen-inducible Zip13 knockout (Zip13-iKO), and systemic (germline) Zip13 knockout mouse model were used to study the effect of Zip13 deletion on cardiac functions. These mice were analyzed for growth, cardiac systolic function, mitochondrial morphology, mitochondrial iron metabolism, and mitochondrial biogenesis and activity. We also generated cardio-specific ferroportin 1 (Fpn1-CKO) and Zip13&Fpn1 (Zip13&Fpn1-CKO) double-knockout mice to compare with Zip13-CKO mice. Mouse embryonic fibroblasts and primary cardiomyocytes were used for in vitro experiments.
    RESULTS: Zip13-CKO mice displayed severe cardiac systolic dysfunctions. The mitochondrial function and morphology were markedly abnormal in Zip13-CKO cardiomyocytes, accompanied by cytosolic iron increase and mitochondrial iron decrease. These were also confirmed in vitro with mouse embryonic fibroblasts and primary cardiomyocytes. Moreover, iron supplementation or overexpressing MFRN1 (mitoferrin 1), a mitochondrial iron importer, could substantially restore the mitochondrial iron homeostasis and function of ZIP13-deficient primary cardiomyocytes, indicating mitochondrial iron dyshomeostasis underlies the observed cardiac abnormality. The Zip13-CKO did not wholly resemble that of Fpn1-CKO, which was associated with elevated cytosolic iron, but no statistically significant change was observed in mitochondrial iron. Zip13&Fpn1-CKO mice presented a more severe heart defect than either single mutant alone, likely due to a further aggravated iron accumulation in the cytosol of cardiomyocytes.
    CONCLUSIONS: We propose that ZIP13 and FPN1 are both required to maintain cardiac functions via overlapping but different manners; FPN1 maintains the cytosolic iron by exporting iron out of the cells, while ZIP13 helps balance the iron equilibrium between the cytosol and the organellar network system, including the mitochondrion. These findings establish the critical role of ZIP13 in maintaining mitochondrial iron homeostasis and activity, enabling cardiomyocytes to perform effectively their essential roles.
    Keywords:  homeostasis; iron; mice; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326201
  56. Int J Mol Sci. 2025 Jul 14. pii: 6750. [Epub ahead of print]26(14):
    Dysregulation of Mitochondrial Function in Cancer Cells.
    Ahmed Mahmoud Ahmed Mahmoud Awad, Norwahidah Abdul Karim.
      In addition to their well-known role in ATP production, mitochondria are vital to cancer cell metabolism due to their involvement in redox regulation, apoptosis, calcium signaling, and biosynthesis. This review explores how cancer cells drive the extensive reprogramming of mitochondrial structure and function, enabling malignant cells to survive hostile microenvironments, evade therapy, and proliferate rapidly. While glycolysis (the Warburg effect) was once thought to be the dominant force behind cancer metabolism, recent updates underscore the pivotal contribution of mitochondrial oxidative phosphorylation (OXPHOS) to tumor development. Cancer cells often exhibit enhanced mitochondrial ATP production, metabolic flexibility, and the ability to switch between energy sources such as glucose, glutamine, and pyruvate. Equally important are changes in mitochondrial morphology and dynamics. Due to disruptions in fusion and fission processes, regulated by proteins like Drp1 and MFN1/2, cancer cells often display fragmented mitochondria, which are linked to increased motility, metastasis, and tumor progression. Moreover, structural mitochondrial alterations not only contribute to drug resistance but may also serve as biomarkers for therapeutic response. Emerging evidence also points to the influence of oncometabolites and retrograde signaling in reshaping mitochondrial behavior under oncogenic stress. Collectively, these insights position mitochondria as central regulators of cancer biology and attractive targets for therapy. By unraveling the molecular mechanisms underlying mitochondrial reprogramming-from energy production to structural remodeling-researchers can identify new approaches to disrupt cancer metabolism and enhance treatment efficacy.
    Keywords:  OXPHOS; bioenergetics; cancer metabolism; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/ijms26146750
  57. Ecotoxicol Environ Saf. 2025 Jul 24. pii: S0147-6513(25)00981-9. [Epub ahead of print]302 118636
    Gestational zearalenone causes fetal intrauterine growth restriction partially through deriving ROS-Drp1 mediated placental PANoptosis.
    Jie Ru Liu, Fang Nan Wu, Shuai Lin, Chen Chen, Yan Liu, Jing Wen Fan, Qiang Hong, Yuan Hua Chen.
      The ubiquity of zearalenone (ZEA) in cereal-based products and the aquatic environment raises growing concerns about health problems to humans and animals. Here, we explored the mechanism by which ZEA exposure during pregnancy induced fetal growth restriction (FGR). Interestingly, both fetal weights and crown-rump length were significant decreases when dams were administrated with ZEA. Consistently, the incidence of FGR is significantly increased in ZEA group in a dose-dependent manner. Moreover, mean placental weight and diameter was significantly reduced in ZEA group, suggesting that poor placental development may be involved in ZEA-induced FGR. The genome-wide expression profiles of mouse placentas were significantly different between two groups by RNA-sequencing. GO and KEGG analysis indicated significant enrichment of these differentially expressed genes in mitochondrial apoptotic signaling pathway, inflammatory cell apoptotic process, necroptosis, and regulation of mitochondrial membrane potential. Further study showed that mitochondrial quality control disorder and PANoptosis plays an important role in ZEA-induced poor placental development. Mdivi-1, an inhibitor of Drp-1, attenuated ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. N-acetylcysteine (NAC), an antioxidant, abolished ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. Importantly, Mdivi-1 and NAC rescued gestational ZEA exposure-induced poor placental development and FGR in mice. Our results indicate that ZEA exposure during pregnancy caused poor placental development and subsequently FGR may be via deriving ROS-Drp1 mediated placental PANoptosis.
    Keywords:  Fetal growth restriction; Mitochondrial quality control disorder; PANoptosis; Placenta; Zearalenone
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118636
  58. Toxicol Lett. 2025 Jul 26. pii: S0378-4274(25)01555-3. [Epub ahead of print]412 55-67
    Gentamicin aggravates renal injury by affecting mitochondrial dynamics, altering renal transporters expression, and exacerbating apoptosis.
    Mingkang Zhang, Yan Zhou, Xiujuan Wang, Yile Li, Xin'an Wu.
      Drug-induced nephrotoxicity has developed as a prevalent trigger in patients with hospital-acquired AKI. Gentamicin, a broad-spectrum bactericidal aminoglycoside antibiotic, is used clinically in synergy with other antibiotics. However, the presence of nephrotoxicity greatly limits their widespread clinical application. The kidney is one of the most energy intensive organs in the body, second to the heart in mitochondrial content and oxygen consumption. In particular, the mitochondria-rich proximal renal tubules are highly susceptible to be damaged by metabolic wastes or exogenous substances, and many studies have considered mitochondrial dysfunction as a targeted therapeutic strategy for the treatment of AKI. In this study, the results of in vitro experiments revealed that gentamicin could damage renal tubular epithelial cells in a dose- or time-dependent manner and resulted in impaired mitochondrial structure, decreased membrane potential, and reactive oxygen species (ROS) accumulation. Moreover, gentamicin aggravated renal injury by altering renal transporters expression, impairing mitochondrial homeostatic balance by affecting the expression of mitochondrial dynamics (e.g., OPA1, Mitofusin1/2, and DRP1), and promoting apoptosis through the Bax/Bcl2-Caspase3 pathway. It is worth noting that changes in serum creatinine or blood urea nitrogen (BUN) levels could not accurately identify early renal injury caused by gentamicin, and the road to finding an early diagnosis of kidney injury is still long. Our study provided a theoretical basis for gentamicin-induced renal injury and also contributed to the clinical application of gentamicin.
    Keywords:  Apoptosis; Gentamicin; Mitochondria; Renal injury; Transporters
    DOI:  https://doi.org/10.1016/j.toxlet.2025.07.1418
  59. J Neuroimmunol. 2025 Jul 22. pii: S0165-5728(25)00182-1. [Epub ahead of print]407 578701
    OPA1 modulates NLRP3 inflammasome activation and microglial-mediated neuroinflammation in neonatal hypoxic-ischemic brain injury.
    Qingchen Lv, Fei Hong, Zhanyuan Sun, Haiyan Shen, Hongyi Lu, Ye Jin, Liming Mao, Lei Song.
       BACKGROUND: Hypoxic-ischemic brain injury (HIBD) represents a primary cause of neurological impairment in neonates and is frequently associated with persistent cognitive and motor deficits. This study explores the regulatory function of optic atrophy 1 (OPA1) in modulating NLRP3 inflammasome-mediated neuroinflammation in a neonatal rat model of hypoxic-ischemic encephalopathy (HIE), and evaluates the impact of the OPA1 inhibitor MYLS22 on neuroinflammatory responses and cerebral injury.
    METHODS: Neonatal rats were subjected to HIBD. Temporal expression patterns of OPA1 and inflammasome-associated proteins were assessed using Western blotting, immunofluorescence, and histopathological analyses. The influence of MYLS22 treatment on neuroinflammatory markers, brain pathology, and cognitive outcomes was also investigated.
    RESULT: HIBD led to a marked reduction in long-form OPA1 (L-OPA1) expression and a concomitant increase in short-form OPA1 (S-OPA1). Activation of the NLRP3 inflammasome peaked between 24 and 48 h post-injury. Treatment with MYLS22 suppressed OPA1 expression in a dose-dependent manner, further enhancing inflammasome activation and aggravating brain injury, characterized by enlarged infarct volumes, increased edema, and impaired cognitive performance. Conversely, in vitro overexpression of L-OPA1 attenuated inflammasome activation and reduced microglial inflammation following ischemia/reperfusion insult, indicating a neuroprotective effect.
    CONCLUSION: These findings demonstrate a pivotal role for OPA1 in controlling neuroinflammation and mitochondrial integrity in the context of HIE. Modulation of OPA1 expression or targeting inflammasome signaling may represent promising therapeutic strategies to alleviate neuroinflammatory injury and improve neurological outcomes in neonates.
    Keywords:  Hypoxic-ischemic encephalopathy (HIE); MYLS22; NLRP3 inflammasome; Neuroinflammation; OPA1
    DOI:  https://doi.org/10.1016/j.jneuroim.2025.578701
  60. Phytother Res. 2025 Jul 27.
    Reniformin A Suppresses Triple-Negative Breast Cancer Progression by Inducing DRP1-Mediated Mitochondrial Dysfunction and Apoptosis.
    Yifei Guan, Lei Liu, Wei Wang, Ran Zheng, Pinghao Lin, Yalin Liu, Siyu Chen, Huiyu Zhu, Xinhui Liu, Hua Huang.
      Reniformin A (RA) is a natural compound extracted from the medicinal herb Isodon excisoides, known for its tumor-suppressive properties in lung cancer. Yet, its effects and mechanisms of action in other cancers, such as triple-negative breast cancer (TNBC), remain unclear. This study aims to investigate the potential effects and underlying molecular mechanisms of RA in TNBC. Here, we demonstrate the significant anti-cancer activity of RA against TNBC, primarily through the induction of mitochondrial dysfunction and intrinsic apoptosis. Molecular docking and in vitro validation revealed that RA interacts directly with DRP1 at two primary binding sites. This interaction promotes the association of DRP1 with BAX, facilitating their translocation to mitochondria, where they trigger mitochondrial permeabilization, leading to the release of cytochrome c and subsequent apoptosis. Additionally, DRP1 is essential for RA-induced apoptosis; disruption of the RA-DRP1 interaction not only impeded the mitochondrial translocation of DRP1 and BAX but also significantly reduced RA's impact on mitochondrial function, apoptosis, and TNBC progression. The inhibition of the RA-DRP1 interaction also compromised the activation of apoptosis and diminished the effectiveness of RA as a chemotherapeutic agent in vivo. Collectively, these findings suggest that Reniformin A significantly inhibits TNBC by inducing DRP1/BAX-mediated apoptosis, offering a promising therapeutic strategy for TNBC treatment.
    Keywords:  BAX; DRP1; Reniformin A; apoptosis; mitochondria
    DOI:  https://doi.org/10.1002/ptr.70034
  61. Cell Rep Med. 2025 Jul 16. pii: S2666-3791(25)00321-0. [Epub ahead of print] 102248
    Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
    Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano.
      Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.
    Keywords:  OPA1; antimiRs; cristae remodeling; disuse myopathies; miR-128-3p; miR-148/152-3p family; microRNAs; mitochondrial myopathies; mitochondrial ultrastructure
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102248
  62. Exp Mol Med. 2025 Jul 25.
    Author Correction: The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis.
    Qian Ding, Xiao-Li Xie, Miao-Miao Wang, Jie Yin, Jin-Mei Tian, Xiao-Yu Jiang, Di Zhang, Jing Han, Yun Bai, Zi-Jin Cui, Hui-Qing Jiang.
      
    DOI:  https://doi.org/10.1038/s12276-025-01515-z
  63. Acta Physiol (Oxf). 2025 Sep;241(9): e70082
    Absence of Parkin Results in Atrophy of Oxidative Myofibers and Modulation of AKT and MURF1 Signaling in Middle-Aged Male Mice.
    Isabela Aparecida Divino, Ana Laura da Vieira-da-Silva, Marcos Vinicius Esteca, Rafael Paschini Tonon, Felipe Oliveira Gomes da Cruz, Renata Rosseto Braga, Eduardo Rochete Ropelle, Paulo Guimarães Gandra, Igor Luchini Baptista.
       AIM: This work aimed to investigate the effects of the loss of Parkin in middle-aged mice skeletal muscle, focusing on different types of myofibers and in the analysis of proteins related to protein synthesis and degradation as well as the analysis of force generation and motor balance.
    METHODS: We used male mice C57BL/6J (WT) and Parkin knockout mice, Parkintm1Shn (Parkin-/-) at 3 and 10 months of age. We used Walking Beam, Open Field, Spider Mice and Maximum Power Tests to assess motor, balance, and endurance functions. We used flexor digitorum brevis (FDB) muscle for force generation analysis, and tibial anterior (TA) and soleus (SOL) muscles were used for biomolecular techniques because of their difference in fiber type. These muscles were used to investigate markers of protein synthesis and degradation, mitochondrial respiration, and myofiber diameter.
    RESULTS: The Absence of Parkin in middle-aged mice leads to a reduction in isometric force generation but maintained overall motor and locomotion abilities, exhibited only minor balance deficits. In the SOL muscle of middle-aged Parkin-/- mice, we observed a reduction of muscle mass and myofiber diameter, also a significant decrease in mitochondrial respiratory capacity and Complex V. In the same group, we observed a reduction in the phosphorylation of AKT and 4E-BP1, and an increase in MURF-1 while Ubiquitin K63 levels decreased. We did not observe relevant differences in the TA muscle.
    CONCLUSION: Our results suggest middle-aged Parkin-/- mice exhibited muscle atrophy and mitochondrial dysfunction primarily in oxidative myofibers before noticeable motor dysfunction occurs.
    Keywords:  E3 ubiquitin ligase; aging; muscle loss; protein synthesis signaling; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.70082
  64. Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102637
    Retraction Notice to: SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury.
    Ying Tan, David Mui, Sam Toan, Pingjun Zhu, Ruibing Li, Hao Zhou.
      [This retracts the article DOI: 10.1016/j.omtn.2020.09.013.].
    DOI:  https://doi.org/10.1016/j.omtn.2025.102637
  65. Nat Rev Mol Cell Biol. 2025 Jul 30.
    Author Correction: Molecular machineries and pathways of mitochondrial protein transport.
    Toshiya Endo, Nils Wiedemann.
      
    DOI:  https://doi.org/10.1038/s41580-025-00885-6
  66. Biology (Basel). 2025 Jul 05. pii: 819. [Epub ahead of print]14(7):
    DIRAS1 Drives Oxaliplatin Resistance in Colorectal Cancer via PHB1-Mediated Mitochondrial Homeostasis.
    Min Long, Qian Ouyang, Jingyi Wen, Xuan Zeng, Zihui Xu, Shangwei Zhong, Changhao Huang, Jun-Li Luo.
       BACKGROUND: Colorectal cancer (CRC) is a prevalent global malignancy with particularly challenging treatment outcomes in advanced stages. Oxaliplatin (OXA) is a frontline chemotherapeutic agent for CRC. However, 15% to 50% of stage III patients experience recurrence due to drug resistance. Elucidating the molecular mechanisms underlying OXA resistance is, therefore, crucial for improving CRC prognosis. The role of DIRAS1, a RAS superfamily member with reported tumor-suppressive functions in various cancers, remains poorly defined in CRC.
    METHODS: The effects of DIRAS1 on CRC cell proliferation and migration were evaluated using MTT, wound healing, and colony formation assays. Stable cell lines with knockdown or overexpression of DIRAS1 and PHB1 were established via plasmid and lentiviral systems. Drug sensitivity to OXA was assessed through cytotoxicity assays and IC50 determination. Clinical relevance was validated through immunohistochemical analysis of CRC tissue samples. Transcriptomic sequencing was performed to explore downstream regulatory mechanisms.
    RESULTS: DIRAS1 expression was positively correlated with OXA resistance and was significantly upregulated following prolonged chemotherapy exposure. Silencing DIRAS1 reduced the IC50 of OXA in vitro and increased tumor sensitivity to OXA in vivo. Transcriptome analysis identified PHB1 as a downstream effector of DIRAS1. Functional studies revealed that PHB1 contributes to chemoresistance by maintaining mitochondrial stability.
    CONCLUSIONS: This study identifies DIRAS1 as a key contributor to OXA resistance in CRC by modulating PHB1 expression and mitochondrial function. Targeting the DIRAS1-PHB1 axis may offer a novel therapeutic strategy to overcome chemoresistance in CRC.
    Keywords:  DIRAS1; PHB1; colorectal cancer; mitochondrial function; oxaliplatin resistance; targeted therapy
    DOI:  https://doi.org/10.3390/biology14070819
  67. Mitochondrion. 2025 Jul 28. pii: S1567-7249(25)00071-6. [Epub ahead of print] 102074
    Mitochondrial quality control in exercise-mitigated muscular atrophy.
    Jingcheng Fan, Xin Wen, Xuemei Duan, Xinyi Zhu, Jianzheng Bai, Tan Zhang.
      Muscle atrophy is a loss of muscle mass, posing a huge burden on patients and society. Increased protein degradation, decreased protein synthesis, inflammatory response, oxidative stress, and mitochondrial dysfunction are risk factors of muscular atrophy. Mitochondrial quality control (MQC) processes maintain mitochondrial health, which is essential to maintain skeletal muscle structural and functional integrity. Of note, it is widely acknowledged that regular exercise induces significant improvements in muscular atrophy. Mechanistically, exercise reinforces mitochondrial function through MQC, as well as mitigate muscular atrophy.. However, the role and molecular mechanism of MQC in exercise-attenuated muscular atrophy have not yet fully elucidated. Here, we review the current knowledge relevant to MQC in the context of muscular atrophy, and focus on MQC in exercise-mediated anti-atrophic effect, which may be conductive to muscular atrophy prevention and therapy through targeting mitochondria.
    Keywords:  Exercise; Mitochondrial quality control; Muscular atrophy
    DOI:  https://doi.org/10.1016/j.mito.2025.102074
  68. Biomolecules. 2025 Jul 05. pii: 970. [Epub ahead of print]15(7):
    Targeting Mitochondrial Quality Control for the Treatment of Triple-Negative Breast Cancer: From Molecular Mechanisms to Precision Therapy.
    Wanjuan Pei, Ling Dai, Mingxiao Li, Sihui Cao, Yili Xiao, Yan Yang, Minghao Ma, Minjie Deng, Yang Mo, Mi Liu.
      Breast cancer is the leading threat to the health of women, with a rising global incidence linked to social and psychological factors. Among its subtypes, triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is highly heterogeneous with early metastasis and a poor prognosis, making it the most challenging subtype. Mounting evidence shows that the mitochondrial quality control (MQC) system is vital for maintaining cellular homeostasis. Dysfunction of the MQC is tied to tumor cell invasiveness, metastasis, and chemoresistance. This paper comprehensively reviews the molecular link between MQC and TNBC development. We focused on how abnormal MQC affects TNBC progression by influencing chemoresistance, immune evasion, metastasis, and cancer stemness. On the basis of current studies, new TNBC treatment strategies targeting key MQC nodes have been proposed. These findings increase the understanding of TNBC pathogenesis and offer a theoretical basis for overcoming treatment challenges, providing new research angles and intervention targets for effective precision therapy for TNBC.
    Keywords:  TNBC; immune evasion; maintenance of stemness; metabolic reprogramming; mitochondrial quality control
    DOI:  https://doi.org/10.3390/biom15070970
  69. Adv Sci (Weinh). 2025 Jul 30. e02835
    Mesencephalic Astrocyte-Derived Neurotrophic Factor Binds BAX to Preserve Mitochondrial Homeostasis and Energy Metabolism for Relieving Myocardial Hypertrophy.
    Dong Wang, Xinru Zhang, Baolong Wang, Haipeng Li, Dongshuo Xu, Yun Yang, Jialu Zhang, Wenbing Wang, Ren Zhang, Xinyu Wang, Yunfeng Cai, Shiyu Cao, Chao Hou, Changhui Wang.
      Myocardial hypertrophy (MH) is a heart disease accompanied by mitochondrial energy disorder and oxidative stress for cardiomyocyte apoptosis. Mesencephalic astrocyte-derived neurotrophic factor (MANF), with anti-inflammation and cytoprotection, is found to be negatively correlated with atrial apoptosis and fibrillation. Here, the effect and mechanism of MANF on MH are studied. Myocardial cell-specific MANF knockout (MKO) mice are constructed to establish transverse aortic constriction (TAC) or angiotensin II (Ang II)-induced MH model. MANF is found to be upregulated by MH and protects cardiomyocytes against TAC or Ang II-induced MH. Mechanistically, through single-cell RNA sequencing and metabolomics analysis, MANF in cardiomyocytes is closely involved in glycolysis-oxidative phosphorylation balance and mitochondrial homeostasis. Furthermore, MANF interacts with pro-apoptotic BAX to inhibit BAX mitochondrial translocation, subsequently decreasing mitochondrial damage, cytochrome c release, and cardiomyocyte death. These results indicate a promising clinical value of MANF for MH treatment, and also preliminarily define MANF's role in mitochondrial energy production and mitochondria-associated apoptosis pathway.
    Keywords:  Bcl2‐associated X protein; cytochrome c; mesencephalic astrocyte‐derived neurotrophic factor; mitochondria; myocardial hypertrophy
    DOI:  https://doi.org/10.1002/advs.202502835
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