bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–09–28
seventy papers selected by
Gavin McStay, Liverpool John Moores University
  1. The Impacts of Dengue Virus Infection on Mitochondrial Functions and Dynamics.
  2. Regulation of mitochondrial dynamics in cardiomyocytes: implications for cardiac health and disease.
  3. Tirzepatide enhances liver structural integrity by promoting mitochondrial dynamics and mitophagy via PINK1/PRKN and SIRT3/NRF2 pathways in an obese-diabetic-menopausal mouse model.
  4. Activation of AMPK/OPA1 pathway alleviates traumatic brain damage by regulating mitophagy.
  5. Oleuropein Modulates Mitophagy and Metabolism in Cardiomyocyte Via the PINK1/Parkin Signaling Pathway.
  6. NLRX1 orchestrates neuronal mitophagy in Alzheimer's Disease: a mechanistic exploration.
  7. PINK1 functions in mitophagy and mitochondrial homeostasis during mice oocyte maturation.
  8. The Role of Mitochondrial Dysfunction and Dynamics in Hypertensive Heart Disease: Mechanisms and Recent Advances.
  9. Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
  10. The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
  11. Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
  12. Recovery of SIRT3-SOD2 Axis and Mitophagy by Short-Term Calorie Restriction in Old Rat Soleus Skeletal Muscle.
  13. Mono(2-ethylhexyl) Phthalate Disrupts Mitochondrial Function, Dynamics and Biogenesis in Human Trophoblast Cells at Human Exposure Range Concentrations.
  14. Mapping and visualization of global research progress on mitophagy in osteoarthritis: A bibliometric analysis (2008-2024).
  15. Rucaparib induces mitochondrial fragmentation and apoptosis in prostate cancer cells by targeting Drp1.
  16. Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
  17. GCN5L1 Aggravates Postherpetic Neuralgia Through Regulating Microglial Mitochondrial Fission-Fusion Homeostasis.
  18. Ketamine Induces Mitochondrial Fission and Dysfunction in Cervical Cancer Cells via RhoA-Dependent DRP-1 Activation.
  19. Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.
  20. Cavidine alleviates paclitaxel-induced peripheral neuropathy by promoting mitochondrial autophagy through inhibiting PKM2-mediated histone lactylation.
  21. The regulatory role of the Notch signaling pathway in mitophagy and macrophage-mediated elimination of Mycobacterium bovis bacillus Calmette-Guérin.
  22. A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.
  23. Aflatoxin B1 Induces Pyroptosis and Apoptosis in Renal Cells by Mediating Mitophagy Dysfunction and Mitochondrial Pore Formation.
  24. Protective Mechanism of Broad Bean Extract on Parkinson's Disease Model Cells.
  25. Deferoxamine improves intervertebral disc degeneration by activating HIF-1α/BNIP3-mediated mitophagy and inhibiting ferroptosis.
  26. Chronic inhibition of cGMP-specific phosphodiesterase 5 attenuates myocardial hypertrophy by promoting mitophagy in cardiomyocytes.
  27. Fragmented futures: ROCK1 drives mitochondrial fission and muscle loss in CKD.
  28. LRRc17-RANKL pathway regulates mitophagy and contributes to atrial remodeling in diabetes.
  29. Cell death fate switching through organelle-precision thermal control over mitochondrial dynamics.
  30. Mechanisms of mitochondrial autophagy-mediated crosstalk between ferroptosis and cuproptosis in lung cancer.
  31. ZNRF2 integrates ubiquitination-driven ferroptosis and mitochondrial quality control in renal ischemia-reperfusion injury.
  32. Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis.
  33. Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice.
  34. Isolation of functional lysosomes from skeletal muscle.
  35. Stigmasterol improves diabetic retinopathy by inhibiting VAMP7-mediated autophagy/mitophagy.
  36. Identification of biomarkers associated with mitophagy in bladder cancer.
  37. Microglial Autophagy and Mitophagy in Ischemic Stroke: From Dual Roles to Therapeutic Modulation.
  38. Inhibition of Astrocyte Reactivity by Mdivi-1 After Status Epilepticus in Rats Exacerbates Microglia-Mediated Neuroinflammation and Impairs Limbic-Cortical Glucose Metabolism.
  39. Activation of the α7 nicotinic acetylcholine receptor mitigates cognitive deficits in mice with sepsis-associated encephalopathy by inhibiting microglial pyroptosis.
  40. The Role of the Beclin1 Complex in Rab9-Dependent Alternative Autophagy.
  41. Nor1 and Mitophagy: An Insight into Sertoli Cell Function Regulating Spermatogenesis Using a Transgenic Rat Model.
  42. Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
  43. Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
  44. Sanggenol L Enhances Temozolomide Drug Sensitivity by Inhibiting Mitophagy and Inducing Apoptosis Through the Regulation of the TRIM16-OPTN Axis in Glioblastoma.
  45. TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
  46. Genomic-Encoded Mitovirus RdRp Is Required for Embryo Development and Maintaining Mitochondrial Dynamics in Arabidopsis.
  47. Involvement of autophagy and mitophagy modulation in the protective effect of melatonin against BPS-induced ovarian toxicity.
  48. IRS2/FOXO1 mitigates osteoarthritis by regulating chondrocyte autophagy and mitochondrial function.
  49. Portacaval anastomosis promotes fragmentation of mitochondrial network in the cerebellum of male rats.
  50. Corrigendum to "UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice" [Immunobiology 230(5) (2025) 153108].
  51. Okanin Attenuates Mitochondrial Dysfunction and Apoptosis in UVA-Induced HaCaT Cells by Mitophagy Through SIRT3 Pathway.
  52. Pseudostellaria heterophylla polysaccharides attenuate diabetic lower limb ischemia via CYP2E1-mediated mitochondrial homeostasis and PANoptosis regulation.
  53. Selective Senolysis of 5FU-Induced CRC Senescent Cells by Piceatannol Through Mitochondrial Depolarization and AIF-Dependent Apoptosis.
  54. Selenomethionine alleviates LPS-induced septic kidney injury by regulating mitochondrial dynamics changes.
  55. Cardioprotective mechanisms of Jiangfu Decoction against myocardial ischemia may involve regulation of the AMPK/PINK1/Parkin mitochondrial autophagy pathway.
  56. Hyperoside alleviates myocardial ischemia-reperfusion injury in heart transplantation by promoting mitochondrial fusion via activating the Stat3-Tom70-Opa1 pathway.
  57. The Emerging Role of Mitochondrial Dysfunction in Thyroid Cancer: Mediating Tumor Progression, Drug Resistance, and Reshaping of the Immune Microenvironment.
  58. Gibberellic acid induced oxidative stress, mitochondrial division/fusion imbalance, and autophagy in the ovary of Carassius auratus.
  59. Targeting FDX1 with Icaritin Attenuates Neuronal Cuproptosis by Reconciling Mitochondrial Fission-Fusion Dynamics and Bioenergetic Homeostasis.
  60. FUNDC1 Promoted Ferroptosis via JNK Pathway in Cigarette Smoking-Induced Chronic Obstructive Pulmonary Disease.
  61. Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
  62. Rebuilding Mitochondrial Homeostasis and Inhibiting Ferroptosis: Therapeutic Mechanisms and Prospects for Spinal Cord Injury.
  63. Mitochondria-Localized Nestin Protects Mesenchymal Stem Cells from Senescence by Maintaining Cristae Structure and Function.
  64. Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review.
  65. Mitochondrial adaptations and regulation of OPA1 and PERK in Tibetan sheep myocardium under high altitude conditions.
  66. Formoterol promotes mitochondrial biogenesis, improves liver regeneration, and suppresses liver injury and inflammation after liver resection in mice with endotoxemia.
  67. Inhibitory Infrared Light Attenuates Mitochondrial Hyperactivity and Accelerates Restoration of Mitochondrial Homeostasis in an Oxygen-Glucose Deprivation/Reoxygenation Model.
  68. Hypoxia reverses the early anti-inflammatory microglial response to the β-amyloid peptide: mitochondrial involvement and beneficial roles of melatonin and naringenin.
  69. Erastin-induced multi-pathway cell death in endometriosis: a mechanistic and translational narrative review.
  70. Macromolecular Crowding in Mitochondria.
  1. Int J Mol Sci. 2025 Sep 15. pii: 8968. [Epub ahead of print]26(18):
    The Impacts of Dengue Virus Infection on Mitochondrial Functions and Dynamics.
    Showkot Ahmed, Réka Dorottya Varga, Jinsung Yang.
      Dengue virus (DENV) is a mosquito-borne flavivirus responsible for a significant global disease burden, especially in tropical and subtropical regions. DENV critically manipulates host cell mitochondria to ensure its replication and survival. The clinical manifestations are well-studied and how dengue infection significantly alters the mitochondrial dynamics, and the subsequent functional cellular homeostasis has been unveiled. This review discusses the strategies by which DENV alters mitochondrial functions and dynamics. It particularly focuses on the virus-induced suppression of mitochondrial quality control mechanisms like mitophagy. Moreover, the dichotomous role of mitophagy in supporting DENV replication is highlighted. By incorporating recent studies about DENV-host interactions at the mitochondrial interface, mitochondria, as regulators and targets in dengue pathogenesis, are suggested as possible molecular targets for therapeutic intervention.
    Keywords:  biogenesis; cellular homeostasis; dengue virus; mitochondria; mitochondrial bioenergetics; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3390/ijms26188968
  2. Front Cell Dev Biol. 2025 ;13 1652683
    Regulation of mitochondrial dynamics in cardiomyocytes: implications for cardiac health and disease.
    Tengxu Zhang, Ziwei Li, Ying Xu, Chaoqun Xu, Hao Wang, Tao Rui.
      Mitochondrial dynamics, involving fission and fusion, are vital for maintaining mitochondrial quality, shape, and function in heart cells. This review explores how key regulators-Dynamin-related protein 1 (Drp1), mitofusins 1 and 2 (Mfn1/2), and Optic Atrophy 1 (OPA1)-control these processes in the heart. Drp1 facilitates fission, while Mfn1/2 and OPA1 mediate outer and inner membrane fusion. Their activities are finely tuned by modifications, gene regulation, and stress pathways. Disruptions in these dynamics can impair functions like energy production, calcium balance, ROS management, and mitophagy, contributing to heart diseases. Abnormal fission and fusion are also linked to conditions such as sepsis, ischemia/reperfusion injury, and diabetic cardiomyopathy. This review aims to offer a thorough analysis of recent advancements in the understanding of dysregulated mitochondrial dynamics and their contribution to cardiac pathology. Additionally, it evaluates emerging therapeutic strategies that target the balance between mitochondrial division and fusion. We posit that precise modulation of the activities of Drp1, Mfn1/2, and OPA1 presents significant potential for the treatment of cardiac diseases. However, achieving tissue specificity and temporal control remains a critical challenge for clinical translation.
    Keywords:  DRP1; I/R injury; MFN2; Mfn1; OPA1; diabetic cardiomyopathy; mitochondrial dynamics; sepsis
    DOI:  https://doi.org/10.3389/fcell.2025.1652683
  3. Tissue Cell. 2025 Sep 17. pii: S0040-8166(25)00428-8. [Epub ahead of print]98 103146
    Tirzepatide enhances liver structural integrity by promoting mitochondrial dynamics and mitophagy via PINK1/PRKN and SIRT3/NRF2 pathways in an obese-diabetic-menopausal mouse model.
    Ilitch A Marcondes-de-Castro, Thatiany S Marinho, Marcia B Aguila, Carlos A Mandarim-de-Lacerda.
      The effects on hepatic mitochondrial structure, mitophagy, and cellular homeostasis were investigated when treated with Tirzepatide (Tzp), a dual GIP/GLP-1 receptor agonist, in a mouse model combining obesity, type 2 diabetes, and menopause-conditions that collectively exacerbate metabolic dysfunction-associated steatotic liver disease (MASLD). Female C57BL/6 mice were fed either a control or high-fat, high-sucrose diet for 12 weeks, and half underwent bilateral ovariectomy to simulate menopause. Tzp was administered daily for four weeks. Liver tissue was evaluated for ultrastructural alterations, gene expression, and protein profiles. Untreated obese-diabetic and obese-diabetic-ovariectomized mice exhibited hepatocellular fat accumulation, mitochondrial swelling, and disorganized cristae, indicative of metabolic and oxidative stress. In contrast, Tzp-treated mice displayed preserved hepatic architecture and intact mitochondrial morphology. Tzp significantly downregulated autophagy genes (Ulk3, Atg5, Atg7) and key mitophagy regulators (PINK1, PRKN), reestablishing mitochondrial balance, primarily through the modulation of mitophagy and enhanced organelle stability. Simultaneously, it upregulated mitochondrial biogenesis markers (Ppargc1a, Tfam), antioxidant enzymes (SOD2, GR, GPX, CAT), and redox modulators (Sirt3, Nrf2), while normalizing oxidative stress-related genes (Nos1, Nox1). Tzp also mitigated endoplasmic reticulum (ER) stress by downregulating Atf4, Ddit3, and Gadd45 and rebalanced mitochondrial dynamics through the suppression of fission markers (Dnml1, Fis1) and the restoration of fusion mediators (Mfn1, Mfn2). Three-way ANOVA confirmed Tzp's broad regulatory effects on hepatic gene expression, while principal component analysis revealed clear transcriptional separation between treated and untreated groups. In conclusion, these findings demonstrate that Tzp preserves liver ultrastructure and restores mitochondrial dynamics, supporting its therapeutic potential in MASLD and hormone-related metabolic disorders.
    Keywords:  Autophagy; GLP-1; MASLD; Mitochondrial function; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tice.2025.103146
  4. Acta Cir Bras. 2025 ;pii: S0102-86502025000100245. [Epub ahead of print]40 e406925
    Activation of AMPK/OPA1 pathway alleviates traumatic brain damage by regulating mitophagy.
    Hao Wei, Jiushan Liao, Wei Gao, Xiangzhong He.
       PURPOSE: Mitophagy is an important process in brain damage, and the precise impact on a traumatic brain injury (TBI) model remains unclear. AMP-activated protein kinase (AMPK) regulates mitochondrial homeostasis and mitophagy, which are closely related to the remission of early brain injury. This study sought to explore the mechanism behind AMPK/optic atrophy 1 (OPA1) pathway in TBI via experimental verifications.
    METHODS: TBI mouse model induced by weight-drop method was applied in this study. Neurological function tests, Nissl staining, TUNEL staining, and transmission electron microscopy were undertaken to assess the effects of mitophagy on the TBI model. Levels of apoptosis-related factors and mitophagy-related indicators were detected to further reveal the molecular regulatory mechanism of mitophagy in TBI.
    RESULTS: Activation of mitophagy (MK-8722 or rapamycin treatment) reduced the severity of brain damage and mitigated neurological function deficits following TBI. MK-8722 treatment reduced neuronal apoptosis, improved neuronal mitophagy, effectively inhibited the expression of proteins Bcl-2 and Bax, and increased the expression of proteins Parkin, PINK1 and OPA1. Besides, MK-8722 improved TBI through accelerating the AMPK/OPA1 pathway, resulting in increase of mitophagy.
    CONCLUSION: This study is the first to pinpoint the AMPK/OPA1 pathway's involvement in TBI and the mechanism of mitophagy, thereby providing a good foundation for future experimental studies.
    DOI:  https://doi.org/10.1590/acb406925
  5. Drug Dev Res. 2025 Nov;86(7): e70171
    Oleuropein Modulates Mitophagy and Metabolism in Cardiomyocyte Via the PINK1/Parkin Signaling Pathway.
    Hao Ling, Chunli Song.
      ‌Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress and regulating mitochondrial quality control via the PINK1/Parkin pathway. In vitro, H9C2 cardiomyocytes exposed to H₂O₂-induced oxidative stress were treated with OLEU (0-200 μM), and analyses included cell viability, ROS, SOD, MDA, ΔΨm, ATP, PINK1/Parkin expression and detection of Mitophagic Flux. In vivo, myocardial infarction (MI) was induced in SD rats via coronary ligation, followed by OLEU administration, with assessments of cardiac function, histopathology, and mitophagy using echocardiography, electron microscopy, immunohistochemistry and immunofluorescence. Results showed that OLEU (≤200 μM) dose-dependently restored cell viability, reduced ROS, and normalized SOD/MDA (p < 0.05), while mitigating ΔΨm collapse and ATP depletion, indicating enhanced mitochondrial bioenergetics. OLEU upregulated PINK1/Parkin, promoting mitophagic clearance of damaged mitochondria, and metabolomic analysis revealed modulation of arginine/proline and lipid pathways. In MI rats, OLEU attenuated ROS, preserved myocardial structure, and improved cardiac function, supported by elevated mitophagy in electron microscopy. These findings demonstrate that OLEU protects cardiomyocytes by suppressing oxidative stress, stabilizing mitochondrial integrity, and activating PINK1/Parkin-mediated mitophagy, highlighting its therapeutic potential for myocardial injury and mitochondrial dysfunction.
    Keywords:  mitochondrial damage; mitophagy; oleuropein; oxidative stress
    DOI:  https://doi.org/10.1002/ddr.70171
  6. Neurol Res. 2025 Sep 26. 1-14
    NLRX1 orchestrates neuronal mitophagy in Alzheimer's Disease: a mechanistic exploration.
    Baoying Qiu, Jiajun He, Shu Li, Qiaoling Wang, Wenhua Feng, Xiaotong Yu, Yuanyuan Jia, Shuyu Liu, Dijin Jiao, Ling Xie.
       BACKGROUND: Mitophagy dysfunction in Alzheimer's Disease (AD) accelerates disease progression, highlighting the need for novel therapeutic targets. Although Nucleotide oligomerization domain - like receptor X1 (NLRX1) regulates mitophagy, its role in AD remains unclear. This study aimed to elucidate NLRX1's function in AD - associated mitophagy and its therapeutic potential.
    METHODS: APP/PS1 transgenic mice and N2A - SW cells were used to establish AD models. Behavioral assays evaluated cognitive function in APP/PS1 mice, while transmission electron microscopy examined mitochondrial morphology. ELISA measured β - amyloid (Aβ)1-42 levels, and RT - qPCR and Western blot analyzed NLRX1 and mitophagy - related proteins after manipulating NLRX1 expression.
    RESULTS: APP/PS1 mice had cognitive impairment, elevated Aβ1-42, and abnormal mitochondrial morphology, with reduced NLRX1 expression. NLRX1 - RNAi worsened mitochondrial function, increased Aβ1-42 and mitochondrial ROS, decreased the LC3B - II/I ratio, and upregulated Cyt - C, HSP60, and TIM23, while NLRX1 overexpression alleviated these effects. Co-immunoprecipitation confirmed NLRX1's interaction with key mitophagy protein.
    CONCLUSION: NLRX1 is a key regulator of neuronal mitophagy in AD, and its downregulation impairs mitophagy, suggesting it as a potential therapeutic target.
    Keywords:  Alzheimer’s disease; Cyt-c; HSP60; LC3B; NLRX1; TIM23; mitophagy
    DOI:  https://doi.org/10.1080/01616412.2025.2566230
  7. Cell Biosci. 2025 Sep 26. 15(1): 126
    PINK1 functions in mitophagy and mitochondrial homeostasis during mice oocyte maturation.
    Shiwei Wang, Xuan Wu, Mengmeng Zhang, Yixiao Zhu, Yajun Guo, Shuang Song, Shenming Zeng.
       BACKGROUND: As a serine/threonine kinase, PINK1 (PTEN-induced putative kinase 1) is widely expressed in mammalian tissues and cells, especially in the female reproductive system. However, its role in meiotic oocytes remains obscure. Here, we report that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis.
    RESULTS: In the present study, we found that PINK1 protein levels in aged oocytes showed a substantial increase. Importantly, we revealed that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis. This leads to inadequate mitochondrial redistribution, an elevated reactive oxygen species (ROS) level, severely disrupted spindle/chromosome organization, and abnormal mitophagy. Furthermore, we noted that elevated Pink1 expression significantly compromises the developmental ability of the mouse early embryo. In addition, we revealed that RAB8A activity is a key factor for PINK1-mediated mitophagy in old oocytes and active guanosine triphosphate (GTP)-bound state RAB8A could partially rescue the quality of aged oocytes by promoting the formation of autolysosome.
    CONCLUSIONS: Collectively, our data display critical functions for PINK1 in meiotic progression and mitochondrial homeostasis in murine oocytes, and RAB8A activity is required for PINK1-mediated mitophagy in senescent oocytes.
    Keywords:  Mitochondrial homeostasis; Mitophagy; Oocyte; PINK1; RAB8A
    DOI:  https://doi.org/10.1186/s13578-025-01460-4
  8. Biology (Basel). 2025 Sep 08. pii: 1212. [Epub ahead of print]14(9):
    The Role of Mitochondrial Dysfunction and Dynamics in Hypertensive Heart Disease: Mechanisms and Recent Advances.
    Bislom C Mweene, Hanzooma Hatwiko, Joreen P Povia, Sepiso K Masenga.
      Hypertensive heart disease (HHD) is characterized by pressure overload-induced cardiac remodeling, in which mitochondrial dysfunction has emerged as a central contributor to pathophysiology. Mitochondria occupy roughly one-third of the volume of a cardiomyocyte and serve as the primary source of ATP for the constantly active heart, while also regulating calcium homeostasis, redox balance, and apoptotic signaling. Chronic hypertension imposes energetic and oxidative stress on cardiomyocytes, disrupting mitochondrial structure and function. Key mitochondrial quality control processes including organelle fusion-fission dynamics, biogenesis, and mitophagy become dysregulated in HHD, leading to impaired energy production and heightened cell injury. This unstructured review discusses the physiological roles of mitochondria in cardiac muscle and examines how altered mitochondrial dynamics contribute to hypertensive cardiac damage. We detail mechanisms of mitochondrial dysfunction in HHD, such as excessive fission, cristae disruption, and oxidative stress, and how these changes are exacerbated by aging. Age-related mitochondrial remodeling such as loss of cristae and decreased organelle volume may synergistically worsen hypertensive cardiac injury. We further integrate findings from recent studies in animal and human models, including advanced three-dimensional ultrastructural analyses and molecular investigations that illuminate new aspects of mitochondrial network organization, the mitochondrial contact site and cristae organizing system (MICOS), cristae maintenance complex, and quality control pathways in HHD. Understanding mitochondrial dysfunction in HHD reveals potential therapeutic avenues targeting mitochondrial quality and dynamics to preserve cardiac function in hypertension.
    Keywords:  aging; fission; fusion; hypertensive heart disease; left ventricular hypertrophy; metabolic reprogramming; mitochondrial dysfunction; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/biology14091212
  9. Annu Rev Virol. 2025 Sep;12(1): 157-178
    Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
    Théo Defresne, Rodolphe Suspène, Jean-Pierre Vartanian.
      Mitochondria play a vital role in cellular metabolism, energy production, and immune signaling, making them key targets for viral manipulation. Viruses exploit mitochondrial functions to enhance replication and evade immune responses. They also disrupt mitochondrial dynamics by altering fission/fusion balance and modulating mitophagy, which is essential for mitochondrial quality control. Additionally, they reprogram mitochondrial metabolism, affecting pathways such as oxidative phosphorylation and glycolysis to support replication. Viruses regulate apoptosis, either inhibiting or activating mitochondria-mediated apoptosis to prolong host cell survival or facilitate viral spread. Viral infections also induce oxidative stress through reactive oxygen species generation, affecting cellular integrity. Furthermore, viruses manipulate mitochondrial antiviral immunity by degrading mitochondrial antiviral signaling protein and triggering the release of mitochondrial DNA, modulating immune responses. Understanding these interactions offers valuable insights into viral pathogenesis and presents therapeutic opportunities. Targeting mitochondrial dysfunction and enhancing antiviral immunity could provide new strategies to mitigate viral damage and enhance cellular resilience.
    Keywords:  antiviral immunity; metabolic pathways; mitochondria; mitochondrial dynamics; oxidative stress; virus
    DOI:  https://doi.org/10.1146/annurev-virology-092623-090901
  10. J Biol Chem. 2025 Sep 18. pii: S0021-9258(25)02591-8. [Epub ahead of print] 110739
    The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
    Wei-Hua Chu, Yu-Shan Lin, Jing Guo, Wann-Neng Jane, Wong-Jing Wang, Yu-Yang Lin, Pei-Han Liu, Po-Yu Huang, Wei-Chung Chiang.
      PINK1/Parkin-mediated mitophagy is a major homeostatic mechanism by which cells selectively remove damaged, depolarized mitochondria. A signature event in this form of mitophagy is the rupture of the mitochondrial outer membrane (OMM), a process required for the proper disposal of the damaged, depolarized mitochondria. The OMM rupture results in the topological exposure of mitochondrial inner membrane (IMM) mitophagy receptors, which are recognized by autophagy machinery, thus promoting the turnover of the depolarized mitochondria. However, due to the lack of efficient tools to measure OMM rupture, our mechanistic understanding of this process has been limited. In this study, we identified ANKRD13A as a novel mitophagy factor that interacts with multiple mitochondrial proteins and re-localizes to the depolarized mitochondria. ANKRD13A promotes PINK1/Parkin-mediated mitophagy by recruiting Valosin-containing protein (VCP), an AAA-ATPase that functions to remodel protein complexes or membranes via the extraction of protein substrates. Through the development of a novel biosensor that fluorescently marks the sites of OMM rupture, we visualized the OMM rupture events in cellulo and revealed that VCP and its recruitment factors, including ANKRD13A, are required for the rupture of OMM. This finding demonstrated that VCP-dependent remodeling of OMM during PINK1/Parkin-mediated mitophagy is a key driving force behind the OMM rupture. Furthermore, our newly developed biosensor represents an effective, reliable method to detect OMM rupture during PINK1/Parkin-mediated mitophagy, and it is valuable for future mechanistic investigation of this process.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110739
  11. Life Sci. 2025 Sep 23. pii: S0024-3205(25)00631-9. [Epub ahead of print] 123995
    Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
    Paola Zanfardino, Alessandro Amati, Stefano Doccini, Francesco Girolamo, Apollonia Tullo, Giovanna Longo, Filippo M Santorelli, Vittoria Petruzzella.
       AIMS: Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is a rare autosomal recessive neuropathy caused by biallelic MTMR5/SBF1 variants, which encode a catalytically inactive myotubularin involved in phosphoinositide metabolism and autophagy regulation. This study investigates the impact of MTMR5/SBF1 dysfunction on autophagy and mitophagy in patient-derived fibroblasts and examines the relationship between protein aggregates and autophagic machinery.
    MATERIALS AND METHODS: Fibroblasts from a CMT4B3 patient with compound heterozygous MTMR5/SBF1 mutations were compared with a healthy control. Autophagic flux was analyzed via LC3B and SQSTM1; mitophagy was assessed through PINK1 and PRKN recruitment and by quantifying mitophagosomes and autolysosomes under mitochondrial stress. Protein aggregates were visualized using Proteostat and tested for colocalisation with autophagic structures.
    KEY FINDINGS: CMT4B3 fibroblasts showed normal basal macroautophagy but failed to increase autophagy in response to mitochondrial stress or protein aggregates. Conversely, mitophagy was strongly activated via the PINK1-PRKN pathway.
    SIGNIFICANCE: These results reveal an uncoupling between mitophagy and macroautophagy, indicating that MTMR5/SBF1 mutations modify autophagic selectivity. Our findings provide new mechanistic insights into the pathogenesis of CMT4B3 and highlight the value of patient-derived fibroblasts for studying selective autophagy defects.
    Keywords:  CMT4B3; Charcot-Marie-Tooth disease; Macroautophagy; PINK1–PRKN pathway; Phosphoinositide metabolism; Proteasome
    DOI:  https://doi.org/10.1016/j.lfs.2025.123995
  12. Antioxidants (Basel). 2025 Sep 17. pii: 1125. [Epub ahead of print]14(9):
    Recovery of SIRT3-SOD2 Axis and Mitophagy by Short-Term Calorie Restriction in Old Rat Soleus Skeletal Muscle.
    Rosa Di Lorenzo, Anna Picca, Guglielmina Chimienti, Christiaan Leeuwenburgh, Vito Pesce, Angela Maria Serena Lezza.
      Age-related mitochondrial dysfunction is involved in the progressive loss of mass and strength of skeletal muscle with aging. The effects of a short-term calorie restriction (ST-CR) were assessed in the oxidative skeletal soleus muscle (Sol) from 27-month-old rats and compared with those of a CR in combination with resveratrol (RSV) (ST-CR + RSV). PGC-1α and PRXIII proteins showed a marked decrease in both ST-CR and ST-CR + RSV rats. The SIRT3 protein presented a very relevant increase in both ST groups. ST-CR and ST-CR + RSV elicited a marked increase in SOD2 protein amount and activity. ST-CR and ST-CR + RSV led to recovery of the SIRT3-SOD2 axis as a fast/early response. ST-CR and ST-CR + RSV did not affect the MFN2 protein, whereas both treatments induced a relevant increase in DRP1 protein. ST-CR and ST-CR + RSV induced a decrease in Parkin protein, suggestive of rescued mitophagy, leading to the elimination of dysfunctional mitochondria. Such a response likely enhanced the fission-mediated elimination of mitochondria, supported by the marked increase in DRP1. MtDNA copy number and TFAM protein were not changed by any ST treatment. The mtDNA oxidative damage level was strongly increased by both ST treatments. All the effects elicited by ST-CR and ST-CR + RSV were specific to the oxidative type fibers.
    Keywords:  aging; caloric restriction; mitochondrial biogenesis; mitophagy; rat soleus skeletal muscle; resveratrol
    DOI:  https://doi.org/10.3390/antiox14091125
  13. Toxics. 2025 Sep 11. pii: 770. [Epub ahead of print]13(9):
    Mono(2-ethylhexyl) Phthalate Disrupts Mitochondrial Function, Dynamics and Biogenesis in Human Trophoblast Cells at Human Exposure Range Concentrations.
    Luis Daniel Martínez-Razo, Nadia Alejandra Rivero-Segura, Ericka Karol Pamela Almeida-Aguirre, Ismael Mancilla-Herrera, Ruth Rincón-Heredia, Alejandra Martínez-Ibarra, Marco Cerbón.
      Mono(2-ethylhexyl) phthalate (MEHP), a bioactive metabolite of di(2-ethylhexyl) phthalate (DEHP), has been detected in the placenta and urine of pregnant women and is linked to adverse pregnancy outcomes. However, its effects on mitochondrial homeostasis in trophoblast cells remain incompletely understood. This study examined the impact of MEHP (0.5-200 µM) on mitochondrial function, dynamics, and biogenesis in human HTR-8/SVneo trophoblast cells. MEHP (≥5 µM) reduced MTT conversion without compromising membrane integrity, suggesting early metabolic or redox imbalance. A dose-dependent loss of mitochondrial membrane potential was observed, with increased reactive oxygen species (ROS) generation only at 200 µM. MEHP modulated the expression of mitochondrial dynamics genes, with a more pronounced mitofusin 1 (MFN1) induction at low doses and increased mitochondrial DNA content, suggesting a compensatory response to mild stress. Conversely, high doses more strongly induced fission and mitochondrial 1 (FIS1) expression, suggesting mitochondrial fragmentation. Both concentrations induced the expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2), while sirtuin 1 (SIRT1) expression and activity declined progressively with dose. These results demonstrate that MEHP disrupts mitochondrial homeostasis in trophoblast cells at concentrations spanning the estimated human exposure range. The dose-dependent effects, from adaptive responses to overt dysfunction, may help explain the associations between MEHP exposure and placental pathology observed in epidemiological studies.
    Keywords:  MEHP; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; trophoblast
    DOI:  https://doi.org/10.3390/toxics13090770
  14. Medicine (Baltimore). 2025 Sep 19. 104(38): e44421
    Mapping and visualization of global research progress on mitophagy in osteoarthritis: A bibliometric analysis (2008-2024).
    Liping Wang, Dengyan Bai, Xin Ma, Guan Wang, Zhangbin Luo.
       BACKGROUND: This study aimed to provide a thorough overview of research hotspots in mitophagy in osteoarthritis through a bibliometric analysis approach.
    METHODS: A comprehensive literature search was conducted on the Web of Science Core Collection on September 9, 2024. Key metrics were calculated using Microsoft Excel 2019, and bibliometric analysis and visualization were performed with VOSviewer 1.6.20, CiteSpace 6.3.R1, and R 4.3.3.
    RESULTS: The analysis covered 259 articles published between 2008 and 2024, involving 1679 authors from 924 institutions across 41 countries, indicating growing interest in mitophagy research related to osteoarthritis. Wenzhou Medical University emerged as the most prolific institution with 25 articles. The journal Osteoarthritis and Cartilage was a leading venue, showing high citation metrics and an impact factor of 7.2. The most cited article was "Pesticides and human chronic diseases: Evidence, mechanisms, and perspectives" from Toxicology and Applied Pharmacology. The keyword "apoptosis" was the most frequently used, along with significant terms like "oxidative stress" and "mitochondrial dysfunction." Keyword burst analysis indicated intensified focus on "mammalian target of rapamycin" and "cell death."
    CONCLUSION: This bibliometric analysis highlights a growing interest in mitophagy in osteoarthritis research, emphasizing its potential as a therapeutic target and signaling future advancements in this field.
    Keywords:  bibliometrics analysis; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.1097/MD.0000000000044421
  15. Invest New Drugs. 2025 Sep 21.
    Rucaparib induces mitochondrial fragmentation and apoptosis in prostate cancer cells by targeting Drp1.
    Xiaodong Lu, Yishu Lin, Hao Tang, Zhigang Chen, Kewei Tang.
      Mitochondrial dynamics, particularly the balance between fission and fusion, are critical in regulating cellular metabolism, apoptosis, and cancer progression. Dysregulation of this balance contributes to tumor survival and therapeutic resistance in castration-resistant prostate cancer (CRPC). Rucaparib, a clinically approved poly (ADP-ribose) polymerase (PARP) inhibitor, is primarily known for its role in DNA damage repair; however, its impact on mitochondrial function remains largely unexplored. In this study, we demonstrate that Rucaparib induces significant cytotoxicity and apoptosis in PC-3 CRPC cells in a time- and concentration-dependent manner, characterized by increased Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 activation. Mechanistically, Rucaparib disrupts mitochondrial integrity by reducing mitochondrial membrane potential (MMP), inhibiting Complex IV activity, and depleting ATP levels. Confocal imaging and biochemical assays reveal that Rucaparib triggers mitochondrial fragmentation by promoting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and enhancing its translocation to mitochondria. This process is accompanied by elevated intracellular Ca2+ levels and activation of calcium/calmodulin-dependent protein kinase II (CaMKII), suggesting a Ca2⁺/CaMKII/Drp1 signaling axis. Importantly, pharmacological inhibition of CaMKII with KN-93 reverses Drp1 mitochondrial translocation, restores mitochondrial morphology, and partially rescues ATP production, confirming the functional role of CaMKII in Rucaparib-induced mitochondrial dysfunction. These findings uncover a previously unrecognized mechanism of Rucaparib action beyond DNA repair inhibition, highlighting its ability to target mitochondrial dynamics and bioenergetics through Ca2+/CaMKII/Drp1 signaling. Our results provide new insights into the multifaceted anticancer mechanisms of Rucaparib and suggest that modulation of mitochondrial fission may offer a promising therapeutic avenue for CRPC.
    Keywords:  ATP; Castration-resistant prostate cancer (CRPC); Drp1; Mitochondrial dynamics; Rucaparib
    DOI:  https://doi.org/10.1007/s10637-025-01586-9
  16. Mol Ther. 2025 Sep 23. pii: S1525-0016(25)00766-X. [Epub ahead of print]
    Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
    Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo.
      Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.09.037
  17. J Cell Mol Med. 2025 Sep;29(18): e70861
    GCN5L1 Aggravates Postherpetic Neuralgia Through Regulating Microglial Mitochondrial Fission-Fusion Homeostasis.
    Wang Li, Xin Cao, Shenghan Wang, Xuedong Jin, Hongqian Wang.
      Postherpetic neuralgia (PHN) is a debilitating chronic pain condition following varicella-zoster virus (VZV) reactivation, characterised by persistent neuroinflammation. However, the intracellular mechanisms that drive microglial activation and sustained pain sensitisation remain poorly understood. Due to mice having no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well-established PHN mice model. Here, we identified GCN5L1, a mitochondrial acetylation modulator, as a critical regulator of microglial mitochondrial dynamics and a key contributor to PHN pathogenesis. We found that GCN5L1 was markedly upregulated in the spinal dorsal horn after PHN, particularly located in microglia. Microglial Gcn5l1 deficiency attenuated HSV-1-induced neuroinflammatory responses and alleviated mechanical allodynia, whereas Gcn5l1 overexpression exacerbated neuroinflammatory responses both in vivo and in vitro. Mechanistically, GCN5L1 promoted mitochondrial fission and impaired oxidative metabolism by enhancing DRP1 acetylation, without altering the expression of canonical fission-fusion regulators. Restoration of mitochondrial fission using MFI8 intrathecally reversed the anti-inflammatory and analgesic effects of Gcn5l1 deficiency, confirming that GCN5L1 mediated pain sensitisation through mitochondrial fission-fusion in PHN. Finally, inhibiting GCN5L1 by AAV-shGCN5L1 intrathecally suppressed neuroinflammation and mechanical allodynia in PHN mice. These findings uncovered that GCN5L1 aggravated neuroinflammation and PHN through regulating microglial mitochondrial fission-fusion homeostasis, offering new insights and potential feasibility in clinical translation for PHN management.
    Keywords:  GCN5L1; microglia; mitochondrial fission–fusion; neuroinflammation; postherpetic neuralgia
    DOI:  https://doi.org/10.1111/jcmm.70861
  18. J Biochem Mol Toxicol. 2025 Oct;39(10): e70500
    Ketamine Induces Mitochondrial Fission and Dysfunction in Cervical Cancer Cells via RhoA-Dependent DRP-1 Activation.
    Yanfang Zhou, Guangming Chen, Ye Zhu.
      Mitochondrial fragmentation, which is closely linked to mitochondrial dysfunction, has emerged as a critical treatment target for cervical cancer. Ketamine, a well-known anesthetic, has shown potential in cancer therapy by inducing cytotoxicity, impairing mitochondrial function, and promoting apoptosis in tumor cells. Notably, the regulatory role of ketamine in mitochondrial network dynamics remains unexplored in current scientific literature. In this study, we demonstrated that ketamine exerts significant cytotoxic effects on C33A cervical cancer cells, as evidenced by dose-dependent increases in γ-glutamyl transpeptidase (GGT) levels and lactate dehydrogenase (LDH) release, accompanied by a corresponding reduction in cell viability. At 100 μM, ketamine induces mitochondrial dysfunction, characterized by decreased Complex IV activity, mitochondrial membrane potential (MMP), and ATP production, along with mitochondrial fragmentation. Mechanistically, ketamine upregulates mitochondrial p-Drp1 levels without altering total DRP-1 and enhances the expression of CaMK II and RhoA, but not Rac1/Cdc42. Inhibition of RhoA, but not CaMK II, attenuates ketamine-induced mitochondrial DRP-1 activation, fragmentation, and dysfunction, suggesting that RhoA is a key mediator. These findings highlight ketamine's potential as a therapeutic agent targeting mitochondrial dynamics in cervical cancer.
    Keywords:  Cervical Cancer; Drp1; Ketamine; Mitochondrial fragmentation; RhoA
    DOI:  https://doi.org/10.1002/jbt.70500
  19. Biomolecules. 2025 Aug 29. pii: 1252. [Epub ahead of print]15(9):
    Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.
    Davide Steffan, Camilla Pezzini, Martina Esposito, Anais Franco-Romero.
      Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.
    Keywords:  CNS; aging; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/biom15091252
  20. Free Radic Biol Med. 2025 Sep 24. pii: S0891-5849(25)01006-8. [Epub ahead of print]
    Cavidine alleviates paclitaxel-induced peripheral neuropathy by promoting mitochondrial autophagy through inhibiting PKM2-mediated histone lactylation.
    Zhenhui Luo, Zicen Fang, Xiaomin Cheng, Shuqi Shi, Cao Di, Peikun He, Haiqiang Wu, Chuanming Wang, Wuping Sun.
       BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of chemotherapy, with limited therapeutic options due to unclear mechanisms. Cavidine (CAV), a natural alkaloid, has been shown to possess both anti-inflammatory and neuroprotective properties. However, further research is required to elucidate its role in CIPN and the underlying mechanisms by which it exerts its effects.
    PURPOSE: To examine the therapeutic efficacy of CAV in relation to CIPN, with a view to elucidating its underlying mechanism, which is associated with mitophagy and PKM2-mediated histone lactylation.
    METHODS: The post-CAV treatment assessment included the evaluation of mechanical allodynia, thermal hyperalgesia, and footpad immunofluorescence. To identify the regulated pathways of CAV, RNA-seq and lactate metabolomics were performed. The evaluation of mitophagy was conducted through the utilization of immunofluorescence, along with transmission electron microscopy. In addition, the analysis of histone lactylation at H3K18la was undertaken. The use of molecular docking and biolayer interferometry assay confirmed the interactions between CAV-PKM2.
    RESULTS: CAV significantly alleviated both mechanical and thermal pain, as well as peripheral nerve injury, in mice suffering from CIPN. Mechanistically, CAV suppressed PKM2 activity, reducing lactate accumulation and histone H3K18 lactylation. This inhibition promoted mitochondrial autophagy, evidenced by decreased LC3B-II, upregulated PINK1/Parkin, and reduced p62, and promoted the integration of autophagosomes and lysosomes. Molecular docking and biolayer interferometry assay demonstrated high-affinity binding between CAV and the allosteric site of PKM2.
    CONCLUSION: CAV alleviates CIPN by enhancing mitophagy via inhibition of PKM2-driven histone lactylation, thus providing a novel therapeutic strategy for CIPN.
    Keywords:  CIPN; Cavidine; PKM2; histone lactylation; mitophagy; paclitaxel
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.049
  21. BMC Infect Dis. 2025 Sep 26. 25(1): 1141
    The regulatory role of the Notch signaling pathway in mitophagy and macrophage-mediated elimination of Mycobacterium bovis bacillus Calmette-Guérin.
    Yiwei Zhao, Qifeng Li.
       BACKGROUND: The Notch signaling pathway plays a critical role in maintaining immune responses. This study examined the regulatory effect of the Notch signaling pathway on mitophagy and macrophage function in response to Mycobacterium bovis Bacillus Calmette-Guérin (BCG) infection.
    METHODS: RAW264.7 cells with stable Notch-1 knockdown were divided into three groups: control, siRNA Notch-1, and siRNA Notch-1 + valinomycin. Following BCG infection, we measured reactive oxygen species (ROS) levels, the expression of Notch signaling and mitophagy-related genes, cytokines, and BCG colony count.
    RESULTS: RAW264.7 cells infected with 1919-siRNA lentivirus exhibited significantly decreased expression of Notch-1, indicating stable Notch-1 knockdown. Following BCG infection, the expression of Notch-1 decreased in the siRNA Notch-1 group and the siRNA Notch-1 + valinomycin group compared to the control group. Moreover, the expression levels of JAG1, autophagy markers (Beclin 1 and LC3), and mitophagy markers (Drp-1 and Nix) were significantly increased in the siRNA Notch-1 + valinomycin group. Additionally, the ROS level showed a significant increase in the siRNA Notch-1 group, which was further augmented after treatment with mitophagy inducer valinomycin. The BCG clearance rate decreased in the siRNA Notch-1 group but increased after treatment with valinomycin. IL-6 levels were significantly elevated in the siRNA Notch-1 group and further increased in the siRNA Notch-1 + valinomycin group. However, TNF-α levels significantly increased in the siRNA Notch-1 group and decreased significantly in the siRNA Notch-1 + valinomycin group.
    CONCLUSION: The Notch signaling pathway inhibits mitophagy and macrophage-mediated elimination of BCG.
    Keywords:  BCG infection; Mitophagy; Mitophagy inducers; Notch signaling pathway
    DOI:  https://doi.org/10.1186/s12879-025-11552-8
  22. Biomolecules. 2025 Aug 26. pii: 1230. [Epub ahead of print]15(9):
    A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.
    Alessia Nasca, Alessia Catania, Andrea Legati, Rossella Izzo, Carola D'onofrio, Teresa Ciavattini, Eleonora Lamantea, Costanza Lamperti, Daniele Ghezzi.
      Mitochondrial network dynamics, encompassing processes like fission, fusion, and mitophagy, are crucial for mitochondrial function and overall cellular health. Dysregulation of these processes has been linked to various human diseases. Particularly, pathogenic variants in the gene DNM1L can lead to a broad range of clinical phenotypes, ranging from isolated optic atrophy to severe neurological conditions. DNM1L encodes DRP1 (dynamin-1-like protein), which is a key player in mitochondrial and peroxisomal fission. This study describes two twin sisters with a de novo heterozygous variant in DNM1L, due to possible paternal germline mosaicism identified through clinical exome sequencing. The two twins showed a variable clinical presentation, including paraparesis and optic neuropathy. Functional studies of patient-derived fibroblasts revealed altered mitochondrial and peroxisomal morphology, along with dysregulated DNM1L transcript levels, indicating the deleterious effect of the variant. These findings allowed us to reclassify the identified variant from a variant of uncertain significance to a likely pathogenic variant. Our report provides insight into the phenotypic spectrum of DNM1L-related disorders and highlights the need to combine genetic and functional analyses to accurately diagnose rare mitochondrial diseases.
    Keywords:  DNM1L; mitochondrial and peroxisomes fission; mitochondrial disorders; mitochondrial dynamics; variant reclassification
    DOI:  https://doi.org/10.3390/biom15091230
  23. J Agric Food Chem. 2025 Sep 25.
    Aflatoxin B1 Induces Pyroptosis and Apoptosis in Renal Cells by Mediating Mitophagy Dysfunction and Mitochondrial Pore Formation.
    Xinyu Yao, Min Gao, Jing Lu, Xuming Deng, Shuang Guan.
      Aflatoxin B1 (AFB1), a potent mycotoxin, induces nephrotoxicity through previously unrecognized crosstalk between pyroptosis and apoptosis. Using in vivo and in vitro renal injury models, we demonstrate that AFB1 impairs mitophagy, leading to an excessive level of reactive oxygen species (ROS) accumulation. This ROS surge triggers lysosomal membrane permeabilization (LMP) and cathepsin B (CTSB)-dependent activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, initiating caspase-1-mediated pyroptosis via gasdermin D N-terminal (GSDMD-N) pore formation. Importantly, AFB1 also induces cardiolipin translocation to the mitochondrial outer membrane, where pyroptosis-derived GSDMD-N is recruited to form mitochondrial pores. This results in cytochrome c (Cyt-c) release and activation of a caspase-dependent noncanonical apoptotic cascade distinct from the classical apoptotic pathway. These findings establish GSDMD-N-mediated mitochondrial damage as a molecular bridge linking pyroptosis to apoptosis in AFB1 nephrotoxicity and highlight GSDMD-N inhibition as a promising therapeutic strategy. Given AFB1's persistence and bioaccumulation in the food chain, these mechanistic insights provide a molecular basis for developing targeted interventions to mitigate its health risks in agricultural production and food safety.
    Keywords:  aflatoxin B1; apoptosis; mitophagy; nephrotoxicity; pyroptosis
    DOI:  https://doi.org/10.1021/acs.jafc.5c07992
  24. Foods. 2025 Sep 18. pii: 3244. [Epub ahead of print]14(18):
    Protective Mechanism of Broad Bean Extract on Parkinson's Disease Model Cells.
    Xuhao Chen, Qiang Gao, Tingting Li, Jiajia Zhao, Yujiao Liu, Xuejun Wang, Mingcong Fan, Haifeng Qian, Yan Li, Li Wang.
      Broad beans, natural sources of L-DOPA and bioactive phenolics show promise for Parkinson's disease intervention. This study investigated broad bean extracts' protective mechanisms against PD pathogenesis. Among screened varieties, QC25 extract exhibited optimal protection in MPP+-injured PC12 cells, improving viability, reducing LDH release, and mitigating cell cycle arrest. QC25 extract rescued mitochondrial dysfunction by suppressing ROS, restoring membrane potential, normalizing Ca2+ homeostasis, and recovering ATP synthesis. Metabolomics identified glycerophospholipid metabolism as the core protective pathway, mediating mitochondrial membrane stabilization. QC25 extract further activated PINK1/Parkin-mediated mitophagy, upregulating PINK1 and Parkin expression. Crucially, 6-gingerol-uniquely detected in QC25 extract-synergized with L-DOPA, enhancing cell viability and amplifying mitophagy through complementary mitochondrial repair mechanisms. These findings demonstrate QC25 broad bean variety exerts' protective effects on PD model cells by regulating mitochondrial function and mitophagy, and its unique component 6-gingerol synergizes with L-DOPA to strengthen these effects. This study provides a theoretical basis for the development of QC25 as a functional food ingredient for neurological health maintenance.
    Keywords:  6-gingerol; Parkinson’s disease; broad bean; levodopa; synergistic effect
    DOI:  https://doi.org/10.3390/foods14183244
  25. Int Immunopharmacol. 2025 Sep 20. pii: S1567-5769(25)01574-7. [Epub ahead of print]166 115583
    Deferoxamine improves intervertebral disc degeneration by activating HIF-1α/BNIP3-mediated mitophagy and inhibiting ferroptosis.
    Heran Wang, Zimo Zhou, Tong Wu, Zheng Fan, Zhuoru Jin, Yuxiao Cao, Chenhao Huangfu, Yulin Wang, Xiaodong Liu, Da Liu.
       BACKGROUND: Intervertebral disc degeneration (IVDD), a major cause of low back pain, is characterized by cartilage endplate (CEP) degeneration, extracellular matrix (ECM) degradation, and oxidative stress. Deferoxamine (DFO), an iron chelator, demonstrates efficacy in treating iron-overload disorders.
    OBJECTIVE: This study aimed to systematically investigate the role and molecular mechanisms of DFO in IVDD and ferroptosis.
    METHODS: We employed bioinformatics analysis, in vitro cell models, and an in vivo mouse IVDD model.
    RESULTS: Bioinformatics identified 65 common targets for DFO and IVDD, implicating mitochondrial function regulation, oxidative stress response, and the HIF-1α signaling pathway. In vitro, 100 μM DFO restored tert-butyl hydroperoxide (TBHP)-induced suppression of superoxide dismutase (SOD) activity, enhanced COL2 and SOX9 expression, and suppressed MMP3, COL10, and RUNX2 expression, mitigating calcification. In vivo, 100 mg/kg/day for 12 weeks DFO alleviated IVDD pathology in the IVDD model. DFO promoted mitochondrial autophagy (mitophagy) via the HIF-1α/BNIP3 axis, reduced malondialdehyde (MDA) levels, and increased glutathione (GSH) and GPX4 expression. Mechanistic studies confirmed that DFO inhibits ferroptosis and CEP degeneration by activating HIF-1α/BNIP3-mediated mitophagy.
    CONCLUSION: DFO ameliorates CEP degeneration in IVDD by targeting oxidative stress, ferroptosis, and mitochondrial dysfunction. Its protective effects are mediated through multi-targeted mechanisms, prominently involving the activation of HIF-1α/BNIP3-mediated mitophagy to suppress ferroptosis. These findings highlight DFO as a promising therapeutic strategy for IVDD and ferroptosis-related pathologies.
    Keywords:  Deferoxamine; Ferroptosis; HIF-1α/BNIP3; Intervertebral disc degeneration; Mitophagy
    DOI:  https://doi.org/10.1016/j.intimp.2025.115583
  26. Biochem Pharmacol. 2025 Sep 24. pii: S0006-2952(25)00631-8. [Epub ahead of print] 117366
    Chronic inhibition of cGMP-specific phosphodiesterase 5 attenuates myocardial hypertrophy by promoting mitophagy in cardiomyocytes.
    Xuedi Zhang, Yeding Song, Haitao Mai, Wenbin Feng, Jinlin Sun, Zhenggang Zhao, Sujin Zhou, Allan Zijian Zhao, Yunping Mu, Fanghong Li.
      Cardiac hypertrophy is a pathological adaptive response to chronic hemodynamic stress or injury, which may progress irreversibly to heart failure if left untreated. The objective of the study was to investigate whether inhibition of phosphodiesterase 5 can induce mitophagy to alleviate pathological cardiac hypertrophy. Sildenafil (Sif) effectively alleviates isoproterenol-induced cardiac hypertrophy in vivo by decreasing left ventricular wall thickness, reducing cardiac interstitial fibrosis, and improving cardiac functional parameters. Additionally, Sif protects against cardiomyocyte hypertrophy in vitro by lowering atrial natriuretic peptide levels and cardiomyocyte cross-sectional area. It also enhances mitochondrial function through the activation of PTEN-induced putative kinase-1 (PINK1)/Parkin-mediated mitophagy. Importantly, the autophagy inhibitor chloroquine abolished Sif-induced mitophagy and cardioprotection, thereby confirming the essential role of autophagic flux. Furthermore, the protective effects of Sif were reversed by the protein kinase G (PKG) inhibitor KT5823, indicating a dependence on the cyclic GMP (cGMP)-PKG signaling pathway. Altogether, Sif enhances mitophagy and maintain mitochondrial integrity by activating the PINK1/Parkin pathway through the cGMP-PKG signaling cascade, highlighting its potential to protect the myocardium perioperatively.
    Keywords:  Cardiac hypertrophy; Mitophagy; Phosphodiesterase 5; Sildenafil; cGMP-PKG
    DOI:  https://doi.org/10.1016/j.bcp.2025.117366
  27. Kidney Int. 2025 Oct;pii: S0085-2538(25)00578-2. [Epub ahead of print]108(4): 529-532
    Fragmented futures: ROCK1 drives mitochondrial fission and muscle loss in CKD.
    Mia Y Kawaida, Terence E Ryan.
      Patients with chronic kidney disease (CKD) experience skeletal muscle wasting that leads to weakness and negatively impacts quality of life. Decreases in mitochondrial health and function have long been associated with skeletal muscle wasting in CKD, yet mechanisms linking mitochondrial alterations to muscle atrophy are lacking. In this issue, Si et al. present experimental work in mice with CKD linking Rho-associated protein kinase-1 activation to increased mitochondrial fission, oxidative stress, and atrophy. They also investigate therapeutic strategies to alter this mitochondria-muscle atrophy axis to promote better outcomes in CKD.
    DOI:  https://doi.org/10.1016/j.kint.2025.07.012
  28. Cell Signal. 2025 Sep 18. pii: S0898-6568(25)00563-7. [Epub ahead of print]136 112148
    LRRc17-RANKL pathway regulates mitophagy and contributes to atrial remodeling in diabetes.
    Lu Zhou, Daiqi Liu, Qiankun Bao, Zandong Zhou, Ziheng Jia, Xinyi Gao, Wenhua Song, Gary Tse, Gregory Y H Lip, Tong Liu, Qingmiao Shao.
       BACKGROUND: Impaired autophagy and mitochondrial dysfunction are significant causes of atrial remodeling, increasing the risk of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). Both LRRc17 and RANKL proteins are involved in the autophagic mechanism. Nevertheless, there is limited understanding of the mechanisms how LRRc17 and RANKL regulate mitophagy to facilitate atrial remodeling under diabetic conditions.
    METHODS: Echocardiography, intracardiac programmed electrical stimulation, and epicardial electrical activation mapping were used to identify atrial remodeling. Mitophagy was identified by western blot analysis and immunofluorescence techniques. The regulatory relationship between LRRc17 and RANKL was validated using lentiviral transfection and siRNA knockdown. This work employed AAV9-cTNT-RANKL vectors to overexpress RANKL in the myocardium of diabetic mice for determining its specific involvement.
    RESULTS: Significant atrial remodeling caused by diabetes was characterized by enlarged atrium, increased fibrotic interstitial deposits, and abnormal electrical conduction. In diabetic atrial tissue, the level of LRRc17 protein was downregulated and RANKL protein expression was elevated. The negative regulatory function of LRRc17 on RANKL in atrial myocytes was elucidated using HL-1 cells. Overexpression of RANKL highlighted its critical role in causing mitochondrial malfunction. And the administration of the RANKL antagonist, denosumab, markedly improved the compromised mitophagy.
    CONCLUSION: In atrial myocytes, mitophagy is mediated by the LRRc17-RANKL pathway. Diabetes induced atrial remodeling may worsen due to the overexpression of RANKL brought on by the decrease in LRRc17. The LRRc17-RANKL pathway may be a therapy option for diabetic atrial remodeling by improving mitochondrial function.
    Keywords:  Atrial fibrillation; Diabetic atrial remodeling; LRRc17; Mitophagy; RANKL
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112148
  29. J Colloid Interface Sci. 2025 Sep 20. pii: S0021-9797(25)02443-9. [Epub ahead of print]703(Pt 1): 139051
    Cell death fate switching through organelle-precision thermal control over mitochondrial dynamics.
    Huiyue Zhao, Jingjing Chen, Qing Lin, Sile Shen, Yuanfeng Ye, Da Huo.
      Organelle-precision photothermal therapy (OPTT) is widely used for disease treatment with fewer side effects, but its potential to manipulate organelle dynamics is not fully understood. This study investigates how OPTT-induced PANoptotic cell death regulates inter-mitochondrial behaviors using gold nanorods. We show that localized heat stress prompts initial mitochondrial network fusion followed by hyper-fission, disrupting homeostasis and increasing sensitivity to chemotherapeutics. Both non-specific and mitochondria-targeted OPTT were analyzed, revealing the importance of mitochondrial dynamics in determining cell fate. Our results indicate that modulating these dynamics can control cell death and immune responses, highlighting the promise of nanotherapeutic approaches for enhancing cancer therapies.
    Keywords:  Bio-interface; Gold nanomaterials; Mito-dynamics; Nanomedicine; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.jcis.2025.139051
  30. Tissue Cell. 2025 Sep 18. pii: S0040-8166(25)00430-6. [Epub ahead of print]98 103148
    Mechanisms of mitochondrial autophagy-mediated crosstalk between ferroptosis and cuproptosis in lung cancer.
    Lang Jiang, Zhijun Shen.
      Globally, lung cancer has an extremely high morbidity and fatality rate among malignant tumors. Studies on the mechanisms of cell death have yielded fresh concepts and treatment approaches for lung cancer in recent years. As a crucial mitochondrial quality control mechanism, mitochondrial autophagy is strongly related to new forms of cell death, ferroptosis and cuproptosis, and it is crucial for the development, progression, management, and outcomes of lung cancer. In order to provide a theoretical foundation and possible therapeutic targets for precision lung cancer treatment, this review provides an overview of the molecular mechanisms of mitochondrial autophagy, ferroptosis, and cuproptosis as well as how these mechanisms of action interact with one another in lung cancer.
    Keywords:  Crosstalk mechanisms; Cuproptosis; Ferroptosis; Lung cancer; Mitochondrial autophagy
    DOI:  https://doi.org/10.1016/j.tice.2025.103148
  31. Biomed Pharmacother. 2025 Sep 22. pii: S0753-3322(25)00778-4. [Epub ahead of print]192 118584
    ZNRF2 integrates ubiquitination-driven ferroptosis and mitochondrial quality control in renal ischemia-reperfusion injury.
    Kangyu Wang, Yun Deng, Changhong Xu, Rui Yan, Hao Wang, Yalong Zhang, Jiangwei Man, Li Yang.
      Renal ischemia-reperfusion injury (RIRI) is characterized by a surge of oxidative stress, lipid peroxidation, and mitochondrial dysfunction, leading to ferroptotic tubular cell death and renal impairment. Recent findings implicate ZNRF2, a RING-type E3 ubiquitin ligase localized to the endo‑lysosomal membrane, as a central regulator that integrates ubiquitin-mediated signaling, ferroptosis susceptibility, and mitochondrial quality control (MQC) pathways. In this review, we synthesize current evidence on ZNRF2's structural features, ubiquitination targets (e.g., GPX4, SLC7A11, NCOA4), and its modulation of key MQC processes-DRP1-driven mitochondrial fission, PINK1-Parkin-mediated mitophagy, and lysosomal clearance via mTORC1/TFEB axis. We propose a temporal model aligning ischemia and reperfusion phases with specific redox and cell-death events, and highlight testable hypotheses such as ZNRF2's control over GPX4 stability or ferritinophagy dynamics. Moreover, we discuss therapeutic perspectives, including pharmacological modulators of ZNRF2 activity (small‑molecule stabilizers, PROTACs), and timing-based intervention windows. This integrated mechanistic framework advances understanding of RIRI pathogenesis and opens avenues for novel redox-targeted therapeutic strategies.
    Keywords:  Ferroptosis; Mitochondrial quality control; Renal ischemia–reperfusion injury; Ubiquitination
    DOI:  https://doi.org/10.1016/j.biopha.2025.118584
  32. Antioxidants (Basel). 2025 Aug 28. pii: 1058. [Epub ahead of print]14(9):
    Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis.
    Gi Cheol Park, Soo-Young Bang, Ji Min Kim, Sung-Chan Shin, Yong-Il Cheon, Hanaro Park, Sunghwan Suh, Jung Hwan Cho, Eui-Suk Sung, Minhyung Lee, Jin-Choon Lee, Byung-Joo Lee.
      Salivary gland dysfunction is a common but underexplored complication of menopause that contributes to oral dryness, dysphagia, and increased risk of infection. Although ferroptosis, a form of regulated necrotic cell death driven by iron-dependent lipid peroxidation, has recently been implicated in postmenopausal tissue degeneration, its regulatory mechanisms in salivary glands remain unclear. In this study, we investigated the roles of mitochondrial dysfunction and mitophagy in driving ferroptosis-induced salivary gland injury in an ovariectomized (OVX) rat model of estrogen deficiency. OVX rats exhibited elevated markers of oxidative stress, lipid accumulation, and iron overload, and suppression of GPX4 activity in the salivary glands, consistent with ferroptotic activation. These changes were accompanied by impaired mitochondrial dynamics (MFN1 and OPA1), decreased expression of mitochondrial antioxidant regulators (PGC-1α, SOD, and catalase), and upregulation of mitophagy-related genes (PINK1, ULK1, Rab9, and LC3B), as well as LAMP, a lysosomal marker involved in autophagosome-lysosome fusion, while ferritinophagy (NCOA4) remained unchanged. Early administration of ferrostatin-1 effectively suppressed these pathological changes, preserving both glandular structure and function, as evidenced by the restored AQP5 and AMY2A expression. Collectively, our findings reveal that ferroptosis in estrogen-deficient salivary glands is regulated by mitochondrial instability and aberrant mitophagy, and ferrostatin-1 mitigates this cascade through multi-level mitochondrial protection. These results highlight ferrostatin-1 as a promising preventive agent against menopause-associated salivary gland dysfunction, with broader implications for organ-specific ferroptosis modulation.
    Keywords:  ferroptosis; menopause; mitochondria; mitophagy; salivary gland dysfunction
    DOI:  https://doi.org/10.3390/antiox14091058
  33. Mol Metab. 2025 Sep 22. pii: S2212-8778(25)00163-2. [Epub ahead of print] 102256
    Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice.
    Lorenzo Da Dalt, Francesca Fantini, Giulia Giancane, Annalisa Moregola, Silvia Roda, Monika Svecla, Silvia Pedretti, Giovanni Battista Vingiani, Jiangming Sun, Andreas Edsfeldt, Isabel Goncalves, Patrizia Uboldi, Elena Donetti, Andrea Baragetti, Nico Mitro, Luca Scorrano, Giuseppe Danilo Norata.
       AIMS: Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascular cell plasticity. OPA1, a key regulator of inner mitochondrial membrane fusion, has been implicated in metabolic remodeling and cellular stress responses. We therefore investigated whether modulation of OPA1 expression affects lipid homeostasis and plaque formation in LDL receptor-deficient (LDLR KO) mice and in human carotid atherosclerosis.
    METHODS: OPA1TG/LDLR KO and OPA1ΔHep /LDLR KO were fed with a Western-type diet (WTD) for 12 weeks. The development of atherosclerosis was compared to that of LDLR KO mice. In humans, the impact of OPA1 was investigated in asymptomatic and symptomatic subjects from the Carotid Plaque Imaging Project (CPIP) biobank.
    RESULTS: OPA1TG/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1TG/LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression also resulted in an altered vascular smooth muscle cell (VSMC) cellular metabolism and differentiation, promoting a shift from a contractile/synthetic phenotype toward a more proliferative and metabolically active state. Concordantly, the deletion of OPA1 in hepatocytes improved systemic lipoprotein metabolism protecting from atherosclerosis. Concordantly in humans, plaque OPA1 mRNA levels are associated with metabolic and smooth muscle cell related pathways.
    CONCLUSION: Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism and vascular smooth muscle cell biology.
    Keywords:  Atherosclerosis; Lipoprotein; Liver; OPA1; VSMCs
    DOI:  https://doi.org/10.1016/j.molmet.2025.102256
  34. Am J Physiol Cell Physiol. 2025 Sep 22.
    Isolation of functional lysosomes from skeletal muscle.
    Thulasi Mahendran, Anastasiya Kuznyetsova, Neushaw Moradi, David A Hood.
      Lysosomes are membrane-bound organelles responsible for the degradation of damaged or dysfunctional cellular components, including mitochondria. Their acidic internal environment and the presence of an array of hydrolytic enzymes facilitate the efficient breakdown of macromolecules such as proteins, lipids, and nucleic acids. Mitochondria play a critical role in maintaining skeletal muscle homeostasis to meet the energy demands under physiological and pathological conditions. Mitochondrial quality control within skeletal muscle during processes such as exercise, disuse, and injury is regulated by mitophagy, where dysfunctional mitochondria are targeted for lysosomal degradation. The limited understanding of quality control mechanisms in skeletal muscle necessitates the need for isolating intact lysosomes to assess organelle integrity and the degradative functions of hydrolytic enzymes. Although several methods exist for lysosome isolation, the complex structure of skeletal muscle makes it challenging to obtain relatively pure and functional lysosomes due to the high abundance of contractile proteins. Here we describe a method to isolate functional lysosomes from small amounts of mouse skeletal muscle tissue, preserving membrane integrity. We also describe functional assays that allow direct evaluation of lysosomal enzymatic activity and we provide data indicating reduced lysosomal degradative activity in lysosomes from aging muscle. We hope that this protocol provides a valuable tool to advance our understanding of lysosomal biology in skeletal muscle, supporting investigations into lysosome-related dysfunction in aging, disease, and exercise adaptations.
    Keywords:  differential centrifugation; lysosomal enzymes; mitochondria; mitophagy; proteolysis
    DOI:  https://doi.org/10.1152/ajpcell.00471.2025
  35. Biochem Biophys Res Commun. 2025 Sep 14. pii: S0006-291X(25)01369-5. [Epub ahead of print]785 152653
    Stigmasterol improves diabetic retinopathy by inhibiting VAMP7-mediated autophagy/mitophagy.
    Qin Wang, Peiran Zhang, Fengtao Ji, Yongrong Li, Peirong Lu.
      Diabetic retinopathy (DR) is a disease derived from diabetes, which brings great trouble to patients' lives. Stigmasterol has demonstrated beneficial effects in the management of diabetes; however, its influence on DR and the underlying mechanisms remain to be elucidated. Here, we cultured high-glucose (HG)-induced ARPE-19 cells and constructed a DR mice model, which were subsequently treated with stigmasterol. The function and mechanism of stigmasterol on HG-damaged cells were evaluated in vivo and in vitro models. The results showed that 10 μM stigmasterol effectively alleviated the HG-induced cell damage, as evidenced by the significant suppression of ROS levels and the protein expression of pro-apoptosis BAX, the enhancement of protein expression of anti-apoptosis BCL2. The increase in the pro-autophagy protein LC3B and the decrease in the anti-autophagy protein induced by HG were reversed by stigmasterol. Additionally, the co-localization of TOMM20 and LC3B enhanced by HG indicated the occurrence of mitophagy, while mitophagy was inhibited by stigmasterol. RNA-seq revealed that stigmasterol mediates differential gene enrichment in autophagy/mitophagy-related GO terms, while also resulting in a reduction of the autophagy/mitophagy-related gene VAMP7. The over-expression of VAMP7 diminished the effective benefits of stigmasterol in HG-induced cells. In vivo, Stigmasterol effectively reduced blood glucose levels and alleviated retinal damage in DR mice. The decreased expression of VAMP7 and LC3 in the retina of the DR mice with stigmasterol treatment were detected by immunohistochemistry. These results reveal that stigmasterol alleviates DR by inhibiting VAMP7-mediated autophagy/mitophagy. Our findings provide new insights into the treatment and drug development of DR.
    Keywords:  Apoptosis; Autophagy and mitophagy; Diabetic retinopathy; Stigmasterol; VAMP7
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152653
  36. Sci Rep. 2025 Sep 26. 15(1): 33272
    Identification of biomarkers associated with mitophagy in bladder cancer.
    Xianbin Huang, Yanqiu Meng, Jielong Song, Yizi Zhu, Jian Li, Yan Xi, Xiaodong Peng, Yaoyi Xiong.
      Bladder cancer (BLCA) is the most prevalent malignant tumor of the urinary system. Mitophagy is a selective form of autophagy that occurs within the mitochondria. The goal of this study was to determine mitophagy-related biomarkers associated with BLCA and to explore their underlying molecular mechanisms. CTSK, MTERF3, SRC, and CSNK2B were identified as biomarkers. A risk model classified BLCA patients into high-risk group (HRG) and low-risk group (LRG), with HRG patients exhibiting lower survival probabilities. The "chemical carcinogenesis-DNA adducts" and "cytokine-cytokine receptor interaction" signaling pathway were closely associated with HRG and LRG. TP53 had the highest mutation frequencies in the HRG and LRG, respectively. The two groups exhibited significant differences in 14 immune cells, including M2 macrophages. CTSK exhibited the strongest correlation with the naive B cells. A total of 135 drugs differed in sensitivity between HRG and LRG, including KU.55933. The identified regulatory network included ADAMTSL4-AS1-hsa-miR-149-5p-SRC. Expression analysis showed that CTSK was significantly downregulated in the BLCA group, while MTERF3, SRC, and CSNK2B were significantly upregulated. In conclusion, CTSK, MTERF3, SRC, and CSNK2B laid the foundation for targeted therapy in the treatment of BLCA.
    Keywords:  Biomarkers; Bladder cancer; Mitophagy; Risk model
    DOI:  https://doi.org/10.1038/s41598-025-18820-2
  37. Biology (Basel). 2025 Sep 15. pii: 1269. [Epub ahead of print]14(9):
    Microglial Autophagy and Mitophagy in Ischemic Stroke: From Dual Roles to Therapeutic Modulation.
    Juan Wu, Jiaxin Liu, Yanwen Li, Fang Du, Weijia Li, Karuppiah Thilakavathy, Jonathan Chee Woei Lim, Zhong Sun, Juqing Deng.
      Ischemic stroke induces complex neuroinflammatory cascades, where microglial autophagy and mitophagy serve dual roles in both injury amplification and tissue repair. This scoping review synthesized current evidence on their regulatory mechanisms and therapeutic implications. Literature was identified via PubMed and Embase, yielding 79 records, from which 39 original research articles and 13 review papers were included after eligibility screening. Search terms included "microglia," "autophagy," and "ischemic stroke." Protective autophagy was frequently associated with AMPK activation, mTOR inhibition, and mitophagy pathways such as PINK1/Parkin and BNIP3/NIX, facilitating mitochondrial clearance, M2 polarization, and anti-inflammatory signaling. Therapeutic agents such as rapamycin, Tat-Beclin 1, and Urolithin A consistently demonstrated neuroprotection in preclinical stroke models. In contrast, excessive or prolonged autophagic activation was linked to inflammasome amplification, oxidative stress, and phagoptosis. Limited human studies reported associations between elevated serum ATG5 levels or ATG7 polymorphisms and worse clinical outcomes, suggesting preliminary translational relevance. These findings support the potential of phase-specific modulation of microglial autophagy as a therapeutic avenue for stroke, although further validation in human models and development of autophagy biomarkers are needed for clinical application.
    Keywords:  M1/M2 polarization; PINK1/Parkin; autophagy; inflammasome; ischemic stroke; microglia; mitophagy; neuroinflammation
    DOI:  https://doi.org/10.3390/biology14091269
  38. Biomolecules. 2025 Aug 27. pii: 1242. [Epub ahead of print]15(9):
    Inhibition of Astrocyte Reactivity by Mdivi-1 After Status Epilepticus in Rats Exacerbates Microglia-Mediated Neuroinflammation and Impairs Limbic-Cortical Glucose Metabolism.
    Francisca Gómez-Oliver, Rubén Fernández de la Rosa, Mirjam Brackhan, Pablo Bascuñana, Miguel Ángel Pozo, Luis García-García.
      The lithium-pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp1, for its ability to modulate astrocytic mitochondrial dynamics and for its reported preventive neuroprotective properties. Mdivi-1 was administered shortly after SE onset, and we assessed brain glucose metabolism using [18F]FDG PET, alongside histological markers of neurodegeneration, astrocyte reactivity, and microglial activation, at 3 days post-SE. As expected, SE induced widespread brain hypometabolism measured by a VOI analysis, hippocampal neurodegeneration, and glial activation. Post-SE Mdivi-1 administration reduced hippocampal astrogliosis but neither conferred neuroprotection nor rescued glucose metabolism. On the contrary, Mdivi-1 exacerbated limbic-cortical hypometabolism when evaluated by SPM and normalized to whole brain tracer uptake and microglia-mediated neuroinflammation. These findings challenge the assumption that early astrocyte inhibition confers neuroprotection. Furthermore, early suppression of astrocyte reactivity after the damage has occurred may shift the neuroinflammatory response toward maladaptive microglial activation. Thus, while Mdivi-1 holds promise as a preventive neuroprotective agent, its use post-SE may have unintended adverse effects on the brain's response to SE.
    Keywords:  2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG); Mdivi-1; astrocyte; hypometabolism; lithium–pilocarpine model; microglia; neuroinflammation; positron emission tomography (PET); status epilepticus
    DOI:  https://doi.org/10.3390/biom15091242
  39. World J Emerg Med. 2025 Sep 01. 16(5): 438-446
    Activation of the α7 nicotinic acetylcholine receptor mitigates cognitive deficits in mice with sepsis-associated encephalopathy by inhibiting microglial pyroptosis.
    Qiaosheng Wang, Qiong Luo, Zhiwei Su, Yan Xu, Liangshan Peng, Yin Wen, Hongke Zeng, Hongguang Ding.
       BACKGROUND: While the α7 nicotinic acetylcholine receptor (α7 nAChR) is implicated in sepsis-associated encephalopathy (SAE), its pathophysiological contributions require further investigation.
    METHODS: SAE was induced in mice via cecal ligation and puncture (CLP), and microglia were treated with lipopolysaccharide (LPS). PHA-543613 (an α7 nAChR agonist) was used to activate α7 nAChR. To study the role of α7 nAChR in mitophagy and pyroptosis, caspase-1-deficient mice and PTEN-induced kinase 1 (PINK1) small interfering RNA (siRNA) were used. Cognitive function, cerebral oxygen extraction ratio (CERO2), and brain tissue oxygen pressure (PbtO2) were measured. Blood-brain barrier (BBB) integrity was evaluated via Evan's blue staining. Mitophagy, pyroptosis, and cytokine levels were analyzed via Western blotting and immunofluorescence.
    RESULTS: CLP or LPS treatment significantly down-regulated α7 nAChR protein expression in microglia. The administration of PHA-543613 to activate α7 nAChR not only restored its expression post-sepsis, but also notably decreased BBB permeability and mitigated cognitive deficits. Both α7 nAChR activation and caspase-1 knockout effectively suppressed microglial pyroptosis. The activation of α7 nAChR also promoted mitophagy in microglia. This led to an amelioration of brain tissue hypoxia, as shown by elevated PbtO2 and reduced CERO2 levels. The suppression of microglial pyroptosis by α7 nAChR was counteracted when mitophagy was inhibited through the siRNA-mediated silencing of PINK1.
    CONCLUSION: The activation of α7 nAChR reduces pyroptosis by enhancing microglial mitophagy, thereby mitigating SAE.
    Keywords:  Mitophagy; Pyroptosis; Sepsis-associated encephalopathy; α7 nicotinic acetylcholine receptor
    DOI:  https://doi.org/10.5847/wjem.j.1920-8642.2025.099
  40. Int J Mol Sci. 2025 Sep 19. pii: 9151. [Epub ahead of print]26(18):
    The Role of the Beclin1 Complex in Rab9-Dependent Alternative Autophagy.
    Sohyeon Baek, Yunha Jo, Jihoon Nah.
      Autophagy is a conserved catabolic pathway that degrades intracellular cargo through the lysosomal system. Canonically, this process is orchestrated by the autophagy-related (Atg)5-Atg7 conjugation system, which facilitates the formation of microtubule-associated protein 1 light chain 3 (LC3)-decorated double-membrane vesicles known as autophagosomes. However, accumulating evidence has revealed the existence of an Atg5-Atg7-independent, alternative autophagy pathway that still relies on upstream regulators such as the unc-51 like autophagy activating kinase 1 (Ulk1) kinase and the Beclin1 complex. In this review, we provide a comprehensive overview of the role of the Beclin1 complex in canonical autophagy and highlight its emerging importance in alternative autophagy. Notably, the recent identification of transmembrane protein 9 (TMEM9) as a lysosomal protein that interacts with Beclin1 to promote member RAS oncogene family 9 (Rab9)-dependent autophagosome formation has significantly advanced our understanding of alternative autophagy regulation. Furthermore, this Ulk1-Rab9-Beclin1-dependent mitophagy has been shown to mediate to mitochondrial quality control in the heart, thereby contributing to cardioprotection under ischemic and metabolic stress conditions. We further examine how the Beclin1 complex functions as a central scaffold in both canonical and alternative autophagy, with a focus on its modulation by novel factors such as TMEM9 and the potential therapeutic implications of these regulatory mechanisms.
    Keywords:  Beclin1 complex; Rab9; TMEM9; WD-repeat protein, phosphoinositide interacting (Wipis); alternative autophagy; heart diseases
    DOI:  https://doi.org/10.3390/ijms26189151
  41. Int J Mol Sci. 2025 Sep 20. pii: 9209. [Epub ahead of print]26(18):
    Nor1 and Mitophagy: An Insight into Sertoli Cell Function Regulating Spermatogenesis Using a Transgenic Rat Model.
    Bhola Shankar Pradhan, Deepyaman Das, Hironmoy Sarkar, Indrashis Bhattacharya, Neerja Wadhwa, Subeer S Majumdar.
      Male infertility is a global health concern, and many cases are idiopathic in nature. The development and differentiation of germ cells (Gcs) are supported by Sertoli cells (Scs). Differentiated Scs support the development of Gcs into sperm, and hence, male fertility. We previously reported on a developmental switch in Scs around 12 days of age onwards in rats. During the process of the differentiation of Scs, the differential expression of mitophagy-related genes and its role in male fertility are poorly understood. To address this gap, we evaluated the microarray dataset GSE48795 to identify 12 mitophagy-related hub genes, including B-Cell Leukemia/Lymphoma 2 (Bcl2) and FBJ murine osteosarcoma viral oncogene homolog (Fos). We identify Neuron-derived orphan receptor 1 (Nor1) as a potential mitophagy-related gene of interest due to its strong regulatory association with two hub genes, Bcl2 and Fos, which were differentially expressed during Sc maturation. To validate this finding, we generated a transgenic rat model with the Sc-specific knockdown of Nor1 during puberty. A functional analysis showed impaired spermatogenesis with reduced fertility in these transgenic rats. Our findings suggest that Nor1 may be an important mitophagy-related gene regulating the function of Scs and thereby regulating male fertility.
    Keywords:  Nor1; Sertoli cell; germ cell; male fertility; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms26189209
  42. J Cell Sci. 2025 Sep 15. pii: jcs263691. [Epub ahead of print]138(18):
    Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
    Mariana Joaquim, Maria-Bianca Bulimaga, Marie A Mohn, Solenn Plouzennec, Leon Osinski, Selver Altin, Esther Mahabir, Arnaud Chevrollier, Mafalda Escobar-Henriques.
      The neuropathy Charcot-Marie-Tooth (CMT) is an incurable disease with a lack of genotype-phenotype correlation. Variants of the mitochondrial protein mitofusin 2 (MFN2), a large GTPase that mediates mitochondrial fusion, are responsible for the subtype CMT type 2A (CMT2A). Interestingly, beyond membrane remodelling, additional roles of MFN2 have been identified, expanding the possibilities to explore its involvement in disease. Here, we investigated how cellular functions of MFN2 are associated with variants present in individuals with CMT2A. Using human cellular models, we observed that cells expressing CMT2A variants display increased endoplasmic reticulum (ER) stress and apoptotic cell death. Increased cleavage of PARP1, caspase 9, caspase 7 and caspase 3, alongside BAX translocation to mitochondria, pointed towards effects on intrinsic apoptosis. Moreover, although disruption of fusion and fission dynamics per se did not correlate with cell death markers, expression of MFN1 or MFN2 alleviated the apoptosis markers of CMT2A variant cell lines. In sum, our results highlight excessive cell death by intrinsic apoptosis as a potential target in CMT2A disease.
    Keywords:  Apoptosis; CMT2A; Cell death; Charcot–Marie–Tooth; Fusion; MFN2; Mitochondria
    DOI:  https://doi.org/10.1242/jcs.263691
  43. Nat Aging. 2025 Sep 24.
    Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
    Gabriele Civiletto, Dario Brunetti, Giulia Lizzo, Kamila Muller, Guillaume E Jacot, Ioanna Daskalaki, Federico Sizzano, Minji Huh, Ivano Di Meo, Maria Nicol Colombo, José L Sanchez-Garcia, Bertrand J Bétrisey, Alix Zollinger, Patricia Lino, Christopher Neal, Anne-Laure Egesipe, Joy Richard, Myriam Chimen, Aurélie Hermant, Benjamin Brinon, Lorane Texari, Sylviane Metairon, Mohammed Adnan Qureshi, Dhaval S Patel, Siva A Vanapalli, Marco Malavolta, Arwen W Gao, Amelia Lalou, Mauro Provinciali, Fiorenza Orlando, Valeria Tiranti, Robert T Brooke, Steve Horvath, Johan Auwerx, Jerome N Feige, Philipp Gut.
      Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.
    DOI:  https://doi.org/10.1038/s43587-025-00957-4
  44. Adv Sci (Weinh). 2025 Sep 24. e02915
    Sanggenol L Enhances Temozolomide Drug Sensitivity by Inhibiting Mitophagy and Inducing Apoptosis Through the Regulation of the TRIM16-OPTN Axis in Glioblastoma.
    Hongbo Chang, Jianbing Hou, Xin Hu, Nana Hou, Minghao Xu, Yi Du, Jingyang Xu, Yongzhao Wang, Zhuohao Xie, Junbo Shi, Yundong Zhang, Hongjuan Cui.
      Glioblastoma (GBM) is the most aggressive and lethal form of glioma, with current standard-of-care treatments including surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). However, therapeutic resistance to TMZ frequently arises, partly attributed to autophagy, as demonstrated by analysis of clinical glioblastoma specimens. Through screening of mulberry metabolites, a bioactive small molecule, Sanggenol L (SL) is identified, which inhibits glioblastoma growth and blocks autophagy flux, thereby markedly enhancing TMZ chemosensitivity when delivered via a liposome-based system. Mechanistically, SL is found to suppress mitophagy by promoting ubiquitin-mediated proteasomal degradation of OPTN. Moreover, the first evidence that SL upregulates TRIM16 expression is presented, which acts as an E3 ubiquitin ligase for OPTN degradation in glioblastoma. TRIM16 depletion or OPTN overexpression partially abrogated SL-induced suppression of autophagy and apoptosis in GBM cells. Collectively, these findings suggest that SL enhances TMZ sensitivity by disrupting autophagy and inducing apoptosis through TRIM16-mediated OPTN degradation.
    Keywords:  OPTN; Sanggenol L; TRIM16; autophagy; glioblastoma; temozolomide
    DOI:  https://doi.org/10.1002/advs.202502915
  45. bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]
    TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
    Alia K Syeda, Shekoufeh Almasi, J Cory Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.
      Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.
    DOI:  https://doi.org/10.1101/2025.09.11.675705
  46. Int J Mol Sci. 2025 Sep 17. pii: 9035. [Epub ahead of print]26(18):
    Genomic-Encoded Mitovirus RdRp Is Required for Embryo Development and Maintaining Mitochondrial Dynamics in Arabidopsis.
    Yadi Gong, Rongqin Chen, Chen Yang, Yingcui Lu, Zhenjie Fu, Ye Feng, Xiaomeng Li, Ling Li, Xiaoyun Li.
      Mitoviral-derived sequences are frequently detected in plant genomes, encoding an RNA-dependent RNA polymerase (RdRp). These sequences share many similarities with mitoviruses that are known to commonly infect plant mitochondria. However, the functional characterization of nuclear-encoded mitoviral-RdRp remains unclear. This study elucidates the critical role of mRdRp (AT2G07749) in maintaining mitochondrial homeostasis and embryo viability, highlighting the dual role of viral-derived genes in plant development and stress response. Phylogenetic analysis reveals that mRdRp shares 96.8% identity with the mitoviral RdRp encoded by mitochondrial-genomes, suggesting that this nuclear mRdRp gene originated from horizontal transfer events following ancestral plant-mitovirus infections. To dissect mRdRp function, we generated a mRdRp knockout mutant via CRISPR-Cas9 or knockdown mutant by RNA interference (RNAi). These mRdRp mutants exhibited severe developmental defects, including dwarfism, embryo lethality, and sterility. Phenotypic assays further showed that mRdRp mutants displayed heightened susceptibility to ABA and rotenone, indicating impaired adaptive capacity to both hormonal and metabolic stress. Loss of mRdRp led to fragmented mitochondrial networks and a significant reduction in mitochondrial abundance in both leaf protoplasts and root meristematic cells. Additionally, mitochondrial-derived small RNA (sRNA) aberrantly accumulated in mRdRp mutants, which potentially disrupts endogenous RNA-silencing pathways that rely on sRNA-mediated gene regulation. Collectively, these results provide mechanistic insights into the function integration of a virus-derived gene into plant cellular networks, advancing our understanding of host-virus coevolution and the role of horizontally transferred viral genes in shaping plant physiology.
    Keywords:  Arabidopsis; RNA-dependent RNA polymerase (RdRp); coevolution; mRdRp; mitovirus
    DOI:  https://doi.org/10.3390/ijms26189035
  47. Reprod Toxicol. 2025 Sep 24. pii: S0890-6238(25)00243-6. [Epub ahead of print] 109072
    Involvement of autophagy and mitophagy modulation in the protective effect of melatonin against BPS-induced ovarian toxicity.
    Lina Chouchene, Kaouthar Kessabi, Lobna Lajmi, Imed Messaoudi.
      Plastics pose a global health risk due to their detrimental effects, with bisphenol S (BPS) being a prominent plasticizer of concern. In this study, we aimed to investigate the effects of BPS exposure on ovarian function in Wistar rats and assess the protective potential of melatonin (MLT), with the goal of elucidating some of the underlying biochemical and molecular mechanisms involved. We first assessed changes in weight parameters and oxidative stress markers, including antioxidant enzymes (SOD and CAT), PSH, and MDA levels. Then, we investigated ovarian function parameters, namely those related to the estrous cycle, ovarian histology, folliculogenesis, and the molecular expression of markers associated with autophagy (LC3, P62, ATG5) and mitophagy (PINK1, PARKIN) processes. Our findings indicate that BPS induces oxidative stress, with increased CAT activity and decreased SOD activity, along with elevated PSH levels, without any effect on lipid peroxidation. Significant ovarian toxicity is also evident, manifested by a decrease in ovarian weight and anomalies related to the estrous cycle, such as irregularities and disruptions in the total duration and the different estrous phases, along with histological alterations in ovarian tissue that result in variations in the number of follicles at different maturation stages. Furthermore, BPS exposure induces an overexpression of LC3, ATG5, P62, PINK1 and PARKIN markers. Conversely, MLT supplementation significantly mitigated these effects, mainly through its ability to improve oxidative status and to modulate autophagy and mitophagy processes, resulting in the restoration of ovarian function parameters and highlighting its protective role against BPS-induced ovarian toxicity.
    Keywords:  Autophagy; Bisphenol S; Estrous cycle; Folliculogenesis; Melatonin; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.reprotox.2025.109072
  48. Mol Med. 2025 Sep 26. 31(1): 293
    IRS2/FOXO1 mitigates osteoarthritis by regulating chondrocyte autophagy and mitochondrial function.
    Chaoren Qin, Kai Chen, Yingchun Sun, Changjiang Wang, Yaohui Yu, Hao Zhu, Guoyou Zou.
       PURPOSE: Osteoarthritis (OA) is a debilitating joint disease with no effective cure. This study investigates the role of Insulin Receptor Substrate 2 (IRS2) in OA and its potential as a therapeutic target.
    METHODS: Transcriptomic analysis of OA-related datasets (GSE178557, GSE169077, GSE64394, GSE57218) was conducted to identify differentially expressed genes (DEGs), with KEGG pathway analysis highlighting the PI3K/AKT pathway. In vivo, the destabilization of the medial meniscus (DMM) OA mouse model was used to assess IRS2 expression through histology, qPCR, and Western blot. IRS2 was overexpressed in primary mouse chondrocytes via adenoviral transfection, with proliferation, apoptosis, and autophagy assessed by EdU, Annexin V/PI staining, and autophagy-related protein analysis. Adenovirus expressing Irs2 was injected intra-articularly into DMM mice, and cartilage integrity was assessed using histology and micro-CT.
    RESULTS: IRS2 expression was significantly reduced in OA cartilage, correlating with PI3K/AKT pathway inhibition. IRS2 overexpression restored AKT activation, FOXO1 phosphorylation, and mitochondrial autophagy. Intra-articular IRS2 injection improved cartilage matrix integrity, reduced MMP13, and alleviated subchondral bone changes in DMM mice.
    CONCLUSION: IRS2 plays a key role in OA pathogenesis and targeting it may provide a promising therapeutic approach for OA.
    Keywords:  FOXO1; IRS2; Mitophagy; Osteoarthritis
    DOI:  https://doi.org/10.1186/s10020-025-01346-8
  49. Metab Brain Dis. 2025 Sep 24. 40(7): 274
    Portacaval anastomosis promotes fragmentation of mitochondrial network in the cerebellum of male rats.
    Mayra López-Cervantes, Andrés Quintanar-Stephano, Rogelio Hérnandez-Pando, Raúl Aguilar-Roblero, Jorge Larriva-Sahd, Olivia Vázquez-Martínez, Gema Martínez-Cabrera, Mauricio Díaz-Muñoz.
      Portacaval anastomosis (PCA) is a model for hypometabolic liver dysfunction. Spongiform neurodegeneration has been detected in the cerebellum of PCA rats 13 weeks after surgery. This report characterizes the damage associated with spongiform degeneration by studying mitochondrial, ultrastructural, and oxidative changes in the molecular, Purkinje, and granular layers of the cerebellar cortex. Morphometry by electron microscopy determined an increase in mitochondrial presence in PCA rats. In parallel, mitochondria displayed smaller size, diminished interconnectivity, and decreased elongation. Fluorescent probes revealed that PCA cerebellar mitochondria showed a reduction in membrane potential (ΔΨ) alongside a rise in superoxide levels. In contrast, the calcium content exhibited variability across the three cerebellar layers. In addition, an elevation of intracellular reactive oxygen species in the cerebellar cortex was detected. The measurement of TBARS, conjugated dienes, and total antioxidant activity confirmed the presence of oxidative stress in the PCA cerebella. The increased number of smaller mitochondria was accompanied by an altered equilibrium between mitochondrial fission and fusion markers in PCA rats: increased FIS1 and p-DRP1, as well as OPA1, but decreased MFN1. Immunohistochemical analyses of these markers indicated that the molecular layer was the most affected in the cerebellum of PCA rats. In conclusion, we characterized the active cerebellar damage associated with dysregulated mitochondrial activity accompanied by an evident pro-oxidative condition. Ultrastructural analysis helped to strengthen the depiction of the mitochondrial and biochemical alterations associated with the spongiform vacuolization observed in the PCA cerebellar cortex, especially within the molecular layer.
    Keywords:  Hepatic encephalopathy; Oxidative stress; Spongiform neurodegeneration; Ultrastructure
    DOI:  https://doi.org/10.1007/s11011-025-01705-8
  50. Immunobiology. 2025 Sep 23. pii: S0171-2985(25)00254-2. [Epub ahead of print] 153120
    Corrigendum to "UMI-77 targets MCL-1 to activate mitophagy and ameliorate periodontitis in mice" [Immunobiology 230(5) (2025) 153108].
    Dalei Sun, Shu Ouyang, Xiaoxuan Xu, Jingjing Yan, Heqian Wang, Chenkai Lan, Wubin Ouyang, Liangjun Zhong, Jun Lin.
      
    DOI:  https://doi.org/10.1016/j.imbio.2025.153120
  51. Antioxidants (Basel). 2025 Aug 23. pii: 1040. [Epub ahead of print]14(9):
    Okanin Attenuates Mitochondrial Dysfunction and Apoptosis in UVA-Induced HaCaT Cells by Mitophagy Through SIRT3 Pathway.
    Fang Lu, Jiangming Zhong, Qi Zhou, Yiwei Yu, Mengdi Liang, Ying Yuan, Aowei Xie, Jin Cheng, Peng Shu, Jiejie Hao.
      As the primary bioactive flavonoid in Coreopsis tinctoria, okanin has emerged as a promising antioxidant compound of substantial pharmacological interest. However, its efficacy against UVA-mediated photoaging remains unexplored. This research investigated the molecular mechanism underlying the photoprotective activity of okanin against UVA-mediated photoaging. Network pharmacology was employed to predict the pharmacological mechanism of Coreopsis tinctoria in skin photoaging, which was then validated through in vivo and in vitro studies. In vitro experiments indicated that treatment with okanin alleviated oxidative damage, apoptosis and mitochondrial dysfunction in HaCaT cells exposed to UVA radiation. In addition, the interaction between okanin and SIRT3 was confirmed using molecular docking, SPR and DARTS assays. However, silencing SIRT3 with siRNA abolished the promoting effects of okanin on mitophagy genes, confirming that okanin protects HaCaT cells against UVA damage through SIRT3 regulation. In in vivo, okanin enhanced the expression of SIRT3 and FOXO3a in dorsal skin, mitigating UV-mediated skin damage. Taken together, our results suggest the protective effects of okanin against UV radiation in both HaCaT cells and mice induced, at least in part, by regulating SIRT3/FOXO3a/PINK1/Parkin signaling pathway. These findings highlight the potential of okanin for use in skin care products aimed at promoting skin repair following UVA exposure.
    Keywords:  apoptosis; mitochondrial dysfunction; mitophagy; okanin; sirtuin 3
    DOI:  https://doi.org/10.3390/antiox14091040
  52. Phytomedicine. 2025 Sep 16. pii: S0944-7113(25)00891-8. [Epub ahead of print]148 157252
    Pseudostellaria heterophylla polysaccharides attenuate diabetic lower limb ischemia via CYP2E1-mediated mitochondrial homeostasis and PANoptosis regulation.
    Yiqiong Wang, Yi Tao, Shujing Zhang, Qiuru Wang, Zheting Liu, Shudong Lin, Yaoting Wang, Yunchao Huang, Ting Zhang, Henry Anselmo Mayala, Wenming He, Hui Shen, Ling Zhang, Hui Chai.
       BACKGROUND: Diabetes mellitus (DM) and its complications pose a significant threat to human health. Diabetes-related lower limb ischemia (DLLI), as a severe complication of diabetic macrovascular disease, presents substantial challenges in clinical management.
    PURPOSE: The pharmacodynamic profile and mode of action of Pseudostellaria heterophylla polysaccharides (PHP) in DLLI treatment constitute the core investigative objectives herein.
    STUDY DESIGN: Using complementary in vivo (DLLI murine model) and in vitro (high glucose (HG)-exposed human umbilical vein endothelial cells (HUVECs)) systems, PHP's bioactivity was systematically profiled.
    METHODS: In vivo: The effects of PHP on blood perfusion, microvessel density, and PANoptosome assembly in the ischemic limbs of DLLI mice were evaluated. In vitro: HUVECs treated with HG were used to assess PHP's regulatory effects on angiogenesis functions (cell migration, proliferation, tube formation), PANoptosome/inflammasome formation, key components of the PANoptotic pathway, reactive oxygen species (ROS/mtROS), mitochondrial homeostasis, and autophagy. Transcriptomic analysis was conducted to identify potential target genes.
    RESULTS: In vivo: PHP significantly improved blood perfusion, increased microvessel density, and modulated PANoptosome assembly in ischemic limbs. In vitro: PHP reversed HG-induced angiogenesis dysfunction, inhibited PANoptosis and oxidative stress, restored mitochondrial function, and enhanced autophagic activity.
    MECHANISM: PHP exerted its effects by targeting cytochrome P450 enzyme CYP2E1 through downregulating its expression, thereby alleviating mitochondrial damage and PANoptosis. Additionally, CYP2E1 downregulation promoted endothelial cell migration.
    CONCLUSION: We pioneered a PANoptosome-centric framework for DLLI, proving that PHP target CYP2E1 to restore mitochondrial homeostasis, inhibit PANoptosis, and drive angiogenesis, thereby offering a novel natural product-derived therapeutic strategy. Collectively, this work establishes PHP as a promising candidate for DLLI treatment through CYP2E1-mediated restoration of mitochondrial homeostasis and PANoptosis suppression.
    Keywords:  CYP2E1; Diabetes-related lower limb ischemia; PANoptosis; Pseudostellaria heterophylla polysaccharides
    DOI:  https://doi.org/10.1016/j.phymed.2025.157252
  53. Int J Mol Sci. 2025 Sep 18. pii: 9134. [Epub ahead of print]26(18):
    Selective Senolysis of 5FU-Induced CRC Senescent Cells by Piceatannol Through Mitochondrial Depolarization and AIF-Dependent Apoptosis.
    Alessia Ambrosino, Deanira Patrone, Claudia Moriello, Sura Hilal Ahmed Al-Sammarraie, Ida Lettiero, Mauro Finicelli, Dario Siniscalco, Nicola Alessio.
      Chemotherapy-induced senescence (CIS) contributes to tumor persistence and relapse. In this study, we investigated the senolytic activity of piceatannol (PCT) in 5-fluorouracil (5FU)-induced senescent colorectal cancer (CRC) cells. Senescence was established in P53-proficient HCT116 cells and normal colon fibroblasts (CCD18Co) following prolonged 5FU exposure, as shown by increased SA-β-gal activity, upregulation of P16, P21, and P53, mitochondrial depolarization, and enhanced oxidative stress. Subsequent PCT treatment selectively induced apoptosis in senescent populations, while non-senescent or p53-mutant, senescence-resistant HT29 cells were minimally affected. This effect was prevented by N-acetylcysteine, indicating a redox-sensitive mechanism. Mechanistically, PCT triggered mitochondrial depolarization and AIF-associated, caspase-independent apoptosis without increasing ROS. Morphological analysis with MitoTracker and quantitative morphometry using Fiji confirmed a fragmented mitochondrial network, characterized by reduced form factor, length, and number per cell. Western blotting revealed downregulation of fusion proteins (MFN1, MFN2), decreased FIS1, stable DRP1, and marked upregulation of the DRP1 adaptor MFF, consistent with suppressed fusion and enhanced fission competence. Together, these findings demonstrate that PCT selectively targets chemotherapy-induced senescent CRC cells through mitochondrial fragmentation and AIF-dependent apoptosis, highlighting its potential as an adjuvant strategy to limit the long-term burden of therapy-induced senescence.
    Keywords:  5-Fluorouracil; Piceatannol; apoptosis; mitochondria; senescence
    DOI:  https://doi.org/10.3390/ijms26189134
  54. Front Pharmacol. 2025 ;16 1606365
    Selenomethionine alleviates LPS-induced septic kidney injury by regulating mitochondrial dynamics changes.
    Xu Zhou, Jiling Zhao, Wusong Cheng, Su Chen, Ya Zhang, Yangang Qu, Xiaohui Hu, Yong Lan, Qimin Tu, Jiaxin Hu, Hongbo Chen.
       Background: Acute kidney injury (AKI) is a prevalent complication of sepsis, where the inflammatory response plays a crucial role. Selenium exhibits anti-inflammatory and antioxidant properties, but its impact on sepsis-induced AKI remains unclear.
    Methods and results: In this study, we used a lipopolysaccharide (LPS)-induced murine model of sepsis-associated acute kidney injury (SA-AKI) in male C57BL/6 mice (8-12 weeks old) to investigate the protective mechanisms of selenomethionine (SeMet). Mice received weekly oral administration of SeMet (0.375 mg/kg) commencing 1 week prior to AKI induction. Our results demonstrated that SeMet treatment significantly attenuated the inflammatory response, reduced oxidative stress, and ameliorated renal pathological damage compared to saline-treated controls. Mechanistic investigations revealed that SeMet modulates altered mitochondrial dynamics and suppresses the NF-κB signaling pathway, thereby promoting macrophage polarization toward the anti-inflammatory M2 phenotype.
    Conclusion: These findings collectively demonstrate that SeMet effectively mitigates inflammation and ameliorates sepsis-induced AKI, suggesting its potential as a therapeutic candidate for SA-AKI prevention and treatment.
    Keywords:  NF-κB; acute kidney injury; lipopolysaccharide; macrophages; mitochondria
    DOI:  https://doi.org/10.3389/fphar.2025.1606365
  55. Histol Histopathol. 2025 Sep 26. 18994
    Cardioprotective mechanisms of Jiangfu Decoction against myocardial ischemia may involve regulation of the AMPK/PINK1/Parkin mitochondrial autophagy pathway.
    Yawei Zhao, Yiwei Hao, Chen Li, Haoying Li, Xue Han, Hefei Wang, Xi Chu, Zhiwei Su, Shijiang Sun.
       BACKGROUND: Jiangfu Decoction (JFD) is a classical traditional herbal medicine used to clinically treat ischemic heart disease (IHD). Nonetheless, the influence of JFD on myocardial ischemia (MI), along with its precise underlying mechanism, is still unclear. The objective of this research was to investigate the potential mechanisms by which JFD exerts cardioprotective effects on MI induced by isoproterenol (ISO).
    METHODS: An acute MI model was established by subcutaneous injection of ISO (85 mg/kg/d). To evaluate alterations in myocardial structure, electrocardiogram recordings and heart histology examinations were employed. The myocardial ultrastructure was observed by transmission electron microscopy (TEM). Using specific kits, the levels and activities of oxidative stress markers as well as inflammatory cytokines were separately assessed. Western blotting was employed to assess the expression levels of proteins related to adenosine monophosphate-activated protein kinase (AMPK), PTEN-induced putative kinase 1 (PINK1), Parkin, Nod-like receptor protein 3 (NLRP3), and Caspase-1.
    RESULTS: The findings show that JFD treatments markedly diminished heart rate, pathological alterations in cardiac tissue, chondriosome injury, and serum concentrations of creatine kinase, creatine kinase-myocardial band, lactate dehydrogenase, malondialdehyde, interleukin-1β, and interleukin-18. Concurrently, these treatments augmented the activation of superoxide dismutase, catalase, and glutathione peroxidase in the serum of animals subjected to ISO treatment. Additionally, JFD also reversed the ISO-induced changes in the levels of AMPK, PINK1, Parkin, NLRP3, and Caspase-1.
    CONCLUSION: JFD exhibits a notable safeguarding influence on MI via a mechanism that involves regulation of the AMPK/PINK1/Parkin mitochondrial autophagy pathway, inhibition of pyroptosis, and reduction of oxidative stress and inflammation.
    DOI:  https://doi.org/10.14670/HH-18-994
  56. Front Pharmacol. 2025 ;16 1566674
    Hyperoside alleviates myocardial ischemia-reperfusion injury in heart transplantation by promoting mitochondrial fusion via activating the Stat3-Tom70-Opa1 pathway.
    Jincheng Hou, Hongwen Lan, Chenghao Li, Zihao Wang, Qiang Zheng, Kan Wang, Tixiusi Xiong, Yixuan Wang, Jiawei Shi, Nianguo Dong.
       Background: Myocardial ischemia-reperfusion injury (IRI) is the major cause of primary graft dysfunction in heart transplantation, which is characterized by mitochondrial dysfunction. Hyperoside is a bioactive compound that has been reported to have pharmacological potential for cardiac and mitochondrial protection. Here, we investigated the protective effect of hyperoside during myocardial IRI and identified the underlying mechanisms.
    Methods: In this study, we established IRI in an in vivo murine heterotopic heart transplantation model and an in vitro hypoxia-reoxygenation cell model. Inflammatory responses, oxidative stress level, mitochondrial function, and cardiomyocyte apoptosis were evaluated.
    Results: We found that hyperoside pretreatment alleviated through reducing MDA content, LDH activity, TUNEL positive cells, serum cTnI level, Bax protein expression and the level of inflammatory cytokines, and increasing SOD activity and Bcl-2 protein expression. Furthermore, hyperoside pretreatment improved Opa1-mediated mitochondrial fusion, upregulated mitochondrial ATP content and downregulated NADP+/NADPH and GSSG/GSH ratios. Opa1 inhibitor blunted the protective effects of hyperoside. Mechanistically, Co-immunoprecipitation experiments showed the binding property between Tom70 and Opa1, siRNA knockdown, AAV-mediated loss-of-function and gain-of-function approaches suggested that hyperoside-promoted Opa1-mediated mitochondrial fusion required the upregulation of Tom70.
    Conclusion: Collectively, we demonstrated for the first time that hyperoside administration alleviates myocardial IRI by promoting Opa1-mediated mitochondrial fusion in vivo and in vitro. The Tom70-Opa1 pathway was essential for cardioprotective effects of hyperoside treatment. The results in our study indicated that hyperoside or promotion of mitochondrial fusion might be a new potential option for the prevention and treatment of IRI in heart transplantation.
    Keywords:  heart transplantation; hyperoside; ischemia-reperfusion injury; mitochondrial fusion; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2025.1566674
  57. Biomolecules. 2025 Sep 08. pii: 1292. [Epub ahead of print]15(9):
    The Emerging Role of Mitochondrial Dysfunction in Thyroid Cancer: Mediating Tumor Progression, Drug Resistance, and Reshaping of the Immune Microenvironment.
    Yating Zhang, Hengtong Han, Tingting Zhang, Tianying Zhang, Libin Ma, Ze Yang, Yongxun Zhao.
      As the hub of energy metabolism and the cell's fate arbiter, mitochondria are essential for preserving cellular homeostasis and converting it from pathological states. Therefore, through mechanisms that drive metabolic reprogramming, oxidative stress, and apoptosis resistance, mitochondrial dysfunction (including mitochondrial DNA mutations, mitochondrial dynamics imbalance, mitochondrial autophagy abnormalities, mitochondrial permeability abnormalities, and metabolic disorder) can promote the progression of thyroid cancer (TC), resistance to treatment, and reshaping of the immune microenvironment. This article reviews the molecular mechanisms and characteristic manifestations of mitochondrial dysfunction in TC. It focuses on providing a summary of the main strategies currently used to target the mitochondria, such as dietary intervention and targeted medications like curcumin, as well as the clinical translational value of these medications when used in conjunction with current targeted therapies for TC and radioactive iodine (RAI) therapy in patients with advanced or RAI-refractory TC who rely on targeted therapies. The application prospects and existing challenges of emerging therapeutic methods, such as mitochondrial transplantation, are also discussed in depth, aiming to provide new perspectives for revealing the molecular mechanisms by which mitochondrial dysfunction drives the progression of TC, drug resistance, and the reshaping of its immune microenvironment, as well as providing new diagnostic and therapeutic strategies for patients with advanced or RAI-refractory TC who are reliant on targeted therapies.
    Keywords:  mitochondria; mitochondrial autophagy; mitochondrial dynamics; mitochondrial metabolism; thyroid cancer
    DOI:  https://doi.org/10.3390/biom15091292
  58. Toxicol Res (Camb). 2025 Oct;14(5): tfaf136
    Gibberellic acid induced oxidative stress, mitochondrial division/fusion imbalance, and autophagy in the ovary of Carassius auratus.
    Shan Chen, Lingling Guo, Runjie Ou, Tingting Zhao, Jingxuan Zhang, Jie-Qing Ma.
      Gibberellic acid (GA3), a widely used plant growth regulator, has the potential to enter the animal food chain. However, there is limited information regarding its reproductive toxicity in female fish. This study aimed to elucidate the potential mechanisms underlying GA3-induced reproductive toxicity in the ovaries of 120 female Carassius auratus (each weighing 10 ± 2 grams,) exposed to 0, 50, 100, and 150 mg/L of GA3 for 60 days. The results showed that GA3 exposure caused oxidative stress, hormonal imbalances, mitochondrial dysfunction, and autophagy in ovarian tissue. It also disrupted follicular development and lowered reproductive hormones LH and FSH. Additionally, GA3 down regulated steroidogenesis genes StAR and 3β-HSD, reduced antioxidant enzyme activity, and suppressed antioxidant gene expression (sod, gsh, gpx). It also inhibited Nrf2 signaling by reducing mRNA and protein levels of Nrf2, Nqo1, and Ho-1. GA3 disrupts mitochondrial division and fusion by altering genes like Drp1, Mff, Opa1, Mfn1, and Mfn2. It significantly upregulates autophagy-related genes (mTOR, p62, LC3-II, Atg5, Atg12) and activates the AMPK energy stress sensor, enhancing autophagy via the AMPK/ULK1/mTOR pathway. This study presents novel insights into GA3-induced oxidative stress, mitochondrial dysfunction, and autophagy, highlighting their critical roles in reproductive toxicity.
    Keywords:  Reprotoxicity; autophagy; gibberellic acid; mitochondrial dysfunction; ovary; oxidative stress
    DOI:  https://doi.org/10.1093/toxres/tfaf136
  59. Free Radic Biol Med. 2025 Sep 23. pii: S0891-5849(25)01001-9. [Epub ahead of print]
    Targeting FDX1 with Icaritin Attenuates Neuronal Cuproptosis by Reconciling Mitochondrial Fission-Fusion Dynamics and Bioenergetic Homeostasis.
    Yifan He, Tingting Yi, Ying Yao, Songyuan Duan, Lianhang Wang, Jianmei Gao, Qihai Gong.
      Copper overload triggers cuproptosis, a copper-dependent cell death pathway characterized by mitochondrial oxidative stress, dysfunction, and disrupted dynamics, posing significant threats to neuronal health. Icaritin (ICT), a bioactive flavonoid from Herbal Epimedii, exhibits antioxidant and neuroprotective properties, but its impact on cuproptosis remains unexplored. Thus, this study was aimed to investigate ICT's protective mechanisms against cuproptosis induced by the cupric sulfate and copper ionophore elesclomol (Cu-ES) in HT22 hippocampal neuronal cells. We found that Cu-ES effectively modeled cuproptosis, reducing viability by 50% and inducing severe mitochondrial damage, oxidative stress, dysfunction, tricarboxylic acid cycle disruption, and dynamics imbalance. While ICT's treatment concentration-dependently mitigated these injuries. Mechanistically, computational molecular interaction analysis and trajectory simulations, and surface plasmon resonance confirmed ICT directly binds ferredoxin 1 (FDX1) with high affinity and stability, downregulating its protein expression. ICT consequently inhibited the FDX1-mediated cuproptosis pathway, reducing dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, modulating cuproptosis sensitivity proteins, restoring copper homeostasis by increasing ATPase copper transporting beta (ATP7B) and decreasing solute carrier family 31 member 1 (SLC31A1), and suppressing the lipoylation pathway. Crucially, FDX1 knockdown abolished Cu-ES toxicity and potentiated ICT's protective effects against superoxide production, DLAT expression, and copper accumulation. Furthermore, ICT rescued mitochondrial dynamics by promoting fusion and inhibiting fission. Our findings demonstrate ICT is a potent inhibitor of neuronal cuproptosis, targeting FDX1 to alleviate mitochondrial oxidative stress, dysfunction, and dynamics disorder, presenting a promising therapeutic strategy.
    Keywords:  cuproptosis; ferredoxin 1; icaritin; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.044
  60. Lung. 2025 Sep 22. 203(1): 95
    FUNDC1 Promoted Ferroptosis via JNK Pathway in Cigarette Smoking-Induced Chronic Obstructive Pulmonary Disease.
    Yi Feng, Jiali Weng, Chenfei Li, Qi Liu, Qing Chang, Hai Zhang, Mengnan Li, Kai Wang, Xiaohui Wang, Kian Fan Chung, Ian M Adcock, Feng Li.
       BACKGROUND: Cigarette smoking (CS), the major risk factor for chronic obstructive pulmonary disease (COPD), induces oxidative stress, mitophagy, and ferroptosis. Because FUN14 domain-containing protein 1 (FUNDC1), a mitophagy receptor, may drive the onset and progression of COPD, we investigated its role in CS-induced ferroptosis in COPD and to explore the underlying cellular signaling mechanisms.
    METHODS: Wild-type (C57BL/6J background) and FUNDC1-knockdown (KD) mice were exposed to CS for 12 weeks. FUNDC1-KD and FUNDC1-overexpressing (OE) alveolar epithelial A549 cells were exposed to CS extracts (CSE) in the presence and absence of the JNK inhibitor, SP6001 (10 mM). Oxidative stress, inflammation, mitochondrial function, and ferroptosis were measured.
    RESULTS: FUNDC1 expression was increased in lung tissues from COPD patients and CS-exposed mice. CS exposure induced airway inflammation, reduced lung function, and enhanced ferroptosis in mice. FUNDC1-KD prevented CS-induced lung injury in mice. Similarly, CSE exposure up-regulated FUNDC1 expression, promoted ferroptosis, inflammation, oxidative stress, lipid peroxidation, and mitochondrial damage in A549 cells. FUNDC1-KD prevented CSE-induced cellular damage. Transcriptomic data indicated that FUNDC1 mediated ferroptosis through the JNK pathway. These in vitro results were further confirmed by pretreatment with the JNK inhibitor SP6001.
    CONCLUSION: FUNDC1 plays an important role in CS-exposed alveolar epithelial cells and in a mouse model of COPD through the JNK-ferroptosis pathway.
    Keywords:  Chronic obstructive pulmonary disease; FUNDC1; Ferroptosis; JNK; Mitochondria
    DOI:  https://doi.org/10.1007/s00408-025-00850-2
  61. Mol Cell. 2025 Sep 23. pii: S1097-2765(25)00737-3. [Epub ahead of print]
    Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
    Selver Altin, Tânia Simões, Christina Behrendt, Vincent Anton, Dennis Domke, Kai Mayor Völtzke, Rajesh Kumar, Hendrik Nolte, Thomas Hermanns, Nahal Brocke-Ahmadinejad, Katja Bendrin, Marcel Zimmermann, Reinhard Büttner, Natascia Ventura, Marcus Krüger, R Jürgen Dohmen, Kay Hofmann, Thorsten Hoppe, Andreas S Reichert, Mafalda Escobar-Henriques.
      Ubiquitin is a conserved modifier regulating the stability and function of numerous target proteins. In all eukaryotes, polyubiquitin precursors are generated and processed into ubiquitin monomers. The final ubiquitin unit always contains a C-terminal extension, but its physiological significance is unknown. Here, we show that C-terminally extended ubiquitin, termed CxUb, is essential for stress resistance, mitophagy, and longevity in Saccharomyces cerevisiae and Caenorhabditis elegans. CxUb forms ubiquitin chains and binds to a previously undescribed region within the ubiquitin chain-elongating E4 enzyme Ufd2, which also functions during stress and aging. Ufd2 recognizes CxUb and conjugates it to substrate proteins, triggering their degradation. By contrast, CxUb is not required for basal housekeeping functions of the ubiquitin-proteasome system. These data suggest that the CxUb encodes a functionally unique ubiquitin form, specialized for proteostasis defects, expanding the code of post-translational modification processes.
    Keywords:  CxUb; E4; Ufd2; aging; mitochondria; mitofusin; mitophagy; proteostasis; stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.032
  62. Biomedicines. 2025 Sep 18. pii: 2290. [Epub ahead of print]13(9):
    Rebuilding Mitochondrial Homeostasis and Inhibiting Ferroptosis: Therapeutic Mechanisms and Prospects for Spinal Cord Injury.
    Qin Wang, Qingqing Qin, Wenqiang Liang, Haoran Guo, Yang Diao, Shengsheng Tian, Xin Wang.
      During the pathological process of spinal cord injury (SCI), ferroptosis is closely related to mitochondrial homeostasis. Following the occurrence of SCI, the interruption of local blood supply leads to mitochondrial damage within cells and a reduction in Adenosine triphosphate (ATP) production. This results in the loss of transmembrane ion gradients, causing an influx of Ca2+ into the cells, which in turn generates a significant amount of Reactive oxygen species (ROS) and reactive nitrogen species. This leads to severe mitochondrial dysfunction and an imbalance in mitochondrial homeostasis. Ferroptosis is a form of programmed cell death that differs from other types of apoptosis, as it is dependent on the accumulation of iron and lipid peroxides, along with their byproducts. The double bond structures in intracellular polyunsaturated fatty acids (PUFA) are particularly susceptible to attack by ROS, leading to the formation of lipid alkyl free radicals. This accumulation of lipid peroxides within the cells triggers ferroptosis. After SCI, the triggering of ferroptosis is closely associated with the "death triangle"-a core network that catalyzes cell death through the interaction of three factors: local iron overload, collapse of antioxidant defenses, and dysregulation of PUFA metabolism (where PUFA are susceptible to attack by reactive ROS leading to lipid peroxidation). These three elements interact to form a central network driving cell death. In the pathological cascade of SCI, mitochondria serve as both a major source of ROS and a primary target of their attack, playing a crucial role in the initiation and execution of cellular ferroptosis. Mitochondrial homeostasis imbalance is not only a key inducer of the "death triangle" (such as the intensification of lipid peroxidation by mitochondrial ROS), but is also reverse-regulated by the "death triangle" (such as the destruction of mitochondrial structure by lipid peroxidation products). Through the cascade reaction of this triangular network, mitochondrial homeostasis imbalance and the "death triangle" jointly drive the progression of secondary damage. This study aims to synthesize the mechanisms by which various therapeutic approaches mitigate SCI through targeted regulation of mitochondrial homeostasis and inhibition of ferroptosis. Unlike previous research, we integrate the bidirectional regulatory relationship between "mitochondrial homeostasis disruption" and "ferroptosis" in SCI, and emphasize their importance as a synergistic therapeutic target. We not only elaborate in detail how mitochondrial homeostasis-including biogenesis, dynamics, and mitophagy-modulates the initiation and execution of ferroptosis, but also summarize recent strategies that simultaneously target both processes to achieve neuroprotection and functional recovery. Furthermore, this review highlights the translational potential of various treatments in blocking the pathological cascade driven by oxidative stress and lipid peroxidation. These insights provide a novel theoretical framework and propose combinatory therapeutic approaches, thereby laying the groundwork for designing precise and effective comprehensive treatment strategies for SCI in clinical settings.
    Keywords:  ferroptosis; mechanism; mitochondrial homeostasis; progress; spinal cord injury
    DOI:  https://doi.org/10.3390/biomedicines13092290
  63. Adv Sci (Weinh). 2025 Sep 24. e07759
    Mitochondria-Localized Nestin Protects Mesenchymal Stem Cells from Senescence by Maintaining Cristae Structure and Function.
    Hainan Chen, Jinsi Chen, Li Huang, Xingqiang Lai, Kai Xia, Qiying Lu, Bingbing Xie, Yinong Huang, Yuan Qiu, Tao Wang, Jianqi Feng, Yuanjun Guan, Siyao Che, Jiancheng Wang, Andy Peng Xiang.
      Nestin, a well-characterized intermediate filament protein expressed in stem cells, is increasingly recognized for its non-canonical roles in diverse subcellular compartments. Here, a novel mitochondrial localization of Nestin in human mesenchymal stem cells (hMSCs) is identified, where it functions as a critical protector against mitochondrial dysfunction and cellular senescence. It is demonstrated that Nestin is imported into the mitochondrial intermembrane space via its N-terminal mitochondrial targeting sequence through Translocase of the Outer Mitochondrial Membrane 20 (TOM20)-dependent machinery. Within mitochondria, Nestin directly interacts with Mic60 to maintain cristae architecture and sustain oxidative phosphorylation. Genetic ablation of mitochondrial Nestin triggers cristae disorganization, respiratory deficiency, and premature senescence in hMSCs. Strikingly, targeted restoration of the Mic60-binding Tail3 domain of Nestin is sufficient to rescue cristae morphology, mitochondrial function, and senescence phenotypes. These findings establish a non-filamentous role for Nestin in mitochondrial quality control and propose a new therapeutic strategy for age-related disorders through modulation of mitochondrial Nestin-Mic60 interactions.
    Keywords:  Cellular senescence; Mic60; Mitochondria; Nestin; human mesenchymal stem cells (hMSCs)
    DOI:  https://doi.org/10.1002/advs.202507759
  64. Biomolecules. 2025 Sep 18. pii: 1339. [Epub ahead of print]15(9):
    Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review.
    Eunseuk Lee, Adaobi Amelia Ozigbo, Joseph Varon, Mathew Halma, Madison Laezzo, Song Peng Ang, Jose Iglesias.
      Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance. This review synthesizes an understanding of how mitochondrial redox signaling and impaired clearance of damaged mitochondria contribute to chronic inflammation and multisystem organ symptoms in both long COVID and post-vaccine injury. We discuss translational biomarkers and non-invasive techniques, exploring therapeutic strategies that include pharmacological, non-pharmacological, and nutritional approaches, as well as imaging modalities aimed at assessing and restoring mitochondrial health. Recognizing long COVID as a mitochondrial disorder that stems from redox imbalance will open new options for personalized treatment and management guided by biomarkers. Future clinical trials are essential to validate these approaches and translate mitochondrial resuscitation into effective care for patients suffering from long COVID and related post-viral syndromes.
    Keywords:  SARS-CoV-2; autophagy; biomarkers; long COVID; mitochondrial dysfunction; mitochondrial reactive oxygen species; mitophagy
    DOI:  https://doi.org/10.3390/biom15091339
  65. J Anim Sci. 2025 Sep 25. pii: skaf321. [Epub ahead of print]
    Mitochondrial adaptations and regulation of OPA1 and PERK in Tibetan sheep myocardium under high altitude conditions.
    Guan Wang, Yanyan Cui, Hongjian Hou, Junfang Hao, Jincheng Han, Guangli Yang.
      To elucidate the physiological mechanisms by which Tibetan sheep myocardium adapts to chronic hypoxia in high-altitude environments, this study investigated the effects of altitude on Optic Atrophy 1 (OPA1) and Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) expression, mitochondrial morphology, and functional integrity. Utilizing transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and reverse transcription quantitative PCR (RT-qPCR), we analyzed the protein localization and gene/protein expression levels of PERK and OPA1, the activities of malate dehydrogenase (MDH), citrate synthase (CS), and oxidative phosphorylation (OXPHOS) complexes I, II, and IV, as well as mitochondrial ultrastructure in the myocardium of Tibetan sheep inhabiting high-altitude and very-high-altitude environments. Results demonstrated significantly elevated expression levels of OPA1 and PERK proteins and their corresponding genes in very-high-altitude myocardium compared to high-altitude counterparts (P < 0.05), with a strong positive correlation between their protein expressions. Mitochondrial density in very-high-altitude cardiac muscle was markedly reduced (P < 0.05), yet these mitochondria exhibited enhanced fusion-fission dynamics, increased number and density of cristae, and a more compact arrangement (P < 0.05). Concurrently, the activity of MDH and OXPHOS complex IV was significantly higher in very-high-altitude myocardium (P < 0.05), indicative of augmented tricarboxylic acid cycle flux. Furthermore, mitochondria-associated endoplasmic reticulum (ER) membranes were more abundant in very-high-altitude samples. Collectively, these findings suggest that chronic hypoxia drives coordinated upregulation of OPA1 and PERK, remodeling mitochondrial architecture and enhancing metabolic activity. This adaptive response likely underpins the superior energy production capacity of high-altitude Tibetan sheep myocardium, ensuring functional integrity under sustained hypoxic stress.
    Keywords:  Altitude; Myocardial mitochondria; OPA1; PERK; Tibetan Sheep
    DOI:  https://doi.org/10.1093/jas/skaf321
  66. Int J Physiol Pathophysiol Pharmacol. 2025 ;17(4): 131-147
    Formoterol promotes mitochondrial biogenesis, improves liver regeneration, and suppresses liver injury and inflammation after liver resection in mice with endotoxemia.
    Amir K Richardson, Devadoss J Samuvel, Yasodha Krishnasamy, John J Lemasters, Zhi Zhong.
       OBJECTIVES: Clinically, liver regeneration is often impaired by infections causing endotoxemia, although mechanisms are unclear. Since energy supply is essential for liver regeneration, we assessed whether formoterol (FMT), a β2-adrenergic agonist that increases peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis (MB), restores liver regeneration after partial hepatectomy (PHX) in endotoxin (LPS)-treated mice.
    METHODS: Mice underwent sham-operation, two-thirds PHX, PHX with LPS injection (PHX+LPS, 5 mg/kg, i.p.), or PHX+LPS followed by FMT (0.1 mg/kg, i.p.) after 2 h.
    RESULTS: At 48 h after PHX, 5'-bromo-2'-deoxyuridine incorporation, mitotic cells, proliferating cell nuclear antigen, and cyclin-D1 markedly increased, signifying liver regeneration. By contrast, after PHX+LPS, liver regeneration was almost completely suppressed. FMT restored liver regeneration after PHX+LPS. PGC1α, mitochondrial transcription factor-A (controlling mitochondrial DNA replication/transcription), and mitochondrial oxidative phosphorylation proteins ATP synthase-β and NADH dehydrogenase-3 decreased after PHX+LPS, signifying suppressed MB. FMT largely reversed these effects. Mitochondrial oxidative stress stimulates inflammation by activating inflammasomes. In addition to promoting MB, PGC1α reportedly inhibits oxidative stress and inflammation. 8-Hydroxy-deoxyguanosine, NLRP3, and inflammatory cytokines increased after PHX+LPS, demonstrating increased oxidative stress and inflammasome activation. Many necro-inflammatory foci occurred in liver sections after PHX+LPS. FMT increased expression of antioxidant protein thioredoxin-2, decreased oxidative stress, and blunted inflammatory responses. Additionally, FMT decreased alanine aminotransferase release and necrosis caused by PHX+LPS.
    CONCLUSIONS: FMT restores liver regeneration during endotoxemia and decreases liver injury and inflammation, most likely by increasing PGC1α. Therefore, FMT is a promising therapy for liver failure caused by loss of liver mass complicated with sepsis.
    Keywords:  Endotoxin; formoterol; liver regeneration; liver resection; mitochondrial biogenesis; oxidative stress
    DOI:  https://doi.org/10.62347/JMWH4994
  67. Antioxidants (Basel). 2025 Sep 15. pii: 1119. [Epub ahead of print]14(9):
    Inhibitory Infrared Light Attenuates Mitochondrial Hyperactivity and Accelerates Restoration of Mitochondrial Homeostasis in an Oxygen-Glucose Deprivation/Reoxygenation Model.
    Lucynda Pham, Tasnim Arroum, Paul T Morse, Jamie Bell, Moh H Malek, Thomas H Sanderson, Maik Hüttemann.
      Ischemia/reperfusion (I/R) injury following stroke results in increased neuronal cell death due to mitochondrial hyperactivity. Ischemia results in loss of regulatory phosphorylations on cytochrome c oxidase (COX) and cytochrome c of the electron transport chain (ETC), priming COX for hyperactivity. During reperfusion, the ETC operates at maximal speed, resulting in hyperpolarization of the mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) production. We have shown that COX-inhibitory near-infrared light (IRL) provides neuroprotection in small and large animal models of brain I/R injury. IRL therapy is non-invasive and non-pharmacological and does not rely on blood flow. We identified specific wavelengths of IRL, 750 and 950 nm, that inhibit COX activity. To model the mitochondrial effects following neuronal I/R, SH-SY5Y cells underwent oxygen-glucose deprivation/reoxygenation (OGD/R) ± IRL applied at the time of reoxygenation. Untreated cells exhibited ΔΨm hyperpolarization, whereas IRL treated cells showed no significant difference compared to control. IRL treatment suppressed ROS production, decreased the level of cell death, and reduced the time to normalize mitochondrial activity to baseline levels from 4-5 to 2.5 h of reperfusion time. We show that IRL treatment is protective by limiting ΔΨm hyperpolarization and ROS production, and by speeding up cellular recovery.
    Keywords:  cytochrome c oxidase; ischemia/reperfusion injury; mitochondria; mitochondrial membrane potential; near-infrared light; phosphorylations; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox14091119
  68. J Transl Med. 2025 Sep 24. 23(1): 1012
    Hypoxia reverses the early anti-inflammatory microglial response to the β-amyloid peptide: mitochondrial involvement and beneficial roles of melatonin and naringenin.
    Cristiana Lucia Rita Lipari, Aurora Patti, Stefano Conti-Nibali, Angela Anna Messina, Andrea Magrì, Maria Angela Sortino, Sara Merlo.
       BACKGROUND: Early Alzheimer's disease (AD) is characterized by anti-inflammatory microglial responses to the beta amyloid peptide (Aβ), which later switch to pro-inflammatory. Such transition is relevant to disease progression and can be affected by concurrent insults, such as hypoxia (HY). This study explored whether a mild hypoxic stimulus could anticipate the microglial phenotypic switch, focusing in particular on involvement of SIRT1 and mitochondrial function.
    METHODS: HMC3 human microglia were polarized to an anti-inflammatory phenotype by 3 h of exposure to 0.2 μM of Aβ42 to mimic early AD and transferred to a hypoxic chamber with 3% of O2 for 1 h. Effects on microglial activation were investigated by analysis of the SIRT1-BDNF axis activation and enzymatic and ELISA assays of inflammatory markers. Mitochondrial function and morphology were analyzed by high resolution respirometry and laser scanning confocal microscopy.
    RESULTS: Hypoxia (HY) prevented the Aβ42-induced early induction of SIRT1 translocation and BDNF release and significantly increased caspase 1 and NF-kB activity. Moreover, mitochondrial oxygen flows evaluated by high resolution respirometry were significantly reduced, while mitochondrial area, perimeter and branching were increased by Aβ42 + HY, compared to Aβ alone. These changes were contrasted by both melatonin (1 μM) and naringenin (10 μM), natural substances able to induce SIRT1. However, use of the selective SIRT1 inhibitor EX-527 (5 μM) suggested only a partial involvement for SIRT1 in the observed effects, prevalent for naringenin.
    CONCLUSIONS: Our results suggest that mild hypoxic insults during early asymptomatic stages of AD can pose as a risk factor for an accelerated progression of the disease and show the benefits of SIRT1 induction strategies, including use of natural substances like melatonin and naringenin.
    Keywords:  Alzheimer’s disease; High resolution respirometry; Hypoxia; Microglial HMC3 cells; Mitochondrial dynamics; Natural substances; Neuroinflammation; SIRT1
    DOI:  https://doi.org/10.1186/s12967-025-07044-7
  69. Front Med (Lausanne). 2025 ;12 1594702
    Erastin-induced multi-pathway cell death in endometriosis: a mechanistic and translational narrative review.
    Zhe Gao, Juan Du.
      This narrative review examines the therapeutic potential of Erastin and its derivatives for endometriosis (EMS) by integrating mechanistic, preclinical, and translational perspectives. We conducted a focused review of literature from PubMed and Web of Science Core Collection (WoSCC) through August 2025; following a systematic screening and de-duplication process, 91 studies were included for synthesis. The evidence indicates that within the iron-rich, ROS-prone microenvironment of EMS, Erastin inhibits the system Xc- transporter, depletes intracellular glutathione (GSH), and inactivates GPX4, thereby driving ferroptosis in ectopic endometrial stromal cells. This process engages a coordinated network of regulated cell death that extends beyond ferroptosis to include crosstalk with necroptosis and pyroptosis, while being critically modulated by ferritinophagy and the paradoxical role of defective mitophagy. Despite the development of next-generation analogs with improved pharmacological properties, clinical translation is constrained by a narrow therapeutic window due to on-target and off-target toxicities. To overcome these limitations, we propose that future strategies must prioritize lesion-focused drug delivery, such as nanocarriers and triggerable prodrugs, alongside biomarker-guided treatment regimens to decouple efficacy from systemic risk, paving a credible path for the clinical application of Erastin-class agents in EMS.
    Keywords:  Erastin; endometriosis; ferroptosis; mitophagy; necroptosis
    DOI:  https://doi.org/10.3389/fmed.2025.1594702
  70. Subcell Biochem. 2025 ;109 241-256
    Macromolecular Crowding in Mitochondria.
    Semen V Nesterov, Vladimir N Uversky.
      The chapter reviews the various effects of crowding on mitochondrial structure and function. Data illustrate that, as a rule, the concentration of macromolecules in the mitochondrial matrix and inner membrane is at least as high as in other parts of the cytoplasm, while the intermembrane space is sparse. The effect of crowding on mitochondrial shape, the role of disordered protein domains, and the role of changes in crowding during mitochondrial swelling are discussed. Because of the excluded volume in the matrix, real changes in ion and metabolite concentrations under swelling are substantially higher than believed, and the inner membrane is highly curved at least partly due to crowding of the matrix. The high concentration of integral proteins in the mitochondrial inner membrane leads to enrichment with non-bilayer lipid cardiolipin to compensate for their induced membrane deformations. Also crowding may be one of the stimuli for the formation of enzyme supercomplexes. All reviewed data suggest that the structure of mitochondria is adapted exactly to the conditions of high crowding, and crowding itself is one of the key factors in the regulation of mitochondrial structure and function, the role of which is significantly underestimated in the scientific literature.
    Keywords:  Enzyme supercomplexes; Intermembrane space; Intrinsically disordered proteins; Matrix; Mitochondrial function; Mitochondrial shape; Mitochondrial structure; Mitochondrial swelling
    DOI:  https://doi.org/10.1007/978-3-032-03370-3_11
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