bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–09–14
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges.
  2. Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
  3. Unraveling the role of mitochondrial dynamics in cancer stem cells: Molecular basis and therapeutic implications.
  4. Mitochondrial Physiology and Beyond: Mechanistic Insights into Kaempferol Actions.
  5. Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
  6. SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
  7. Mitophagy: a novel avenue for herbal medicines alleviating myocardial ischemia/reperfusion injury.
  8. Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.
  9. Defective mitochondrial quality control in the aging of skeletal muscle.
  10. Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.
  11. A novel prognostic biomarker DUSP6 promote the malignant progression of bladder cancer through mTOR mediated mitophagy.
  12. Parkin Acetylation-Mediated Mitophagy Orchestrates Periodontal Ligament Stem Cell Osteogenesis and Bone Regeneration During Ageing.
  13. Exposure to an environmentally relevant mixture of polychlorinated biphenyls affects mitochondrial bioenergetics and plasticity.
  14. IL-1β restrains its own apoptosis-promoting activity via NF-κB (RelA) Ser276/p62-mediated elimination of damaged mitochondria in Chondrocytes.
  15. Interleukin-6 induces upregulation of BNIP3 in cardiomyocytes to protect against myocardial ischemia/reperfusion injury.
  16. SIRT3 Acetylation Regulates Mitophagy to Alleviate Deoxynivalenol-Induced Apoptosis in Porcine Alveolar Macrophages Cells.
  17. Ginsenoside Rh2 repressed the progression of prostate cancer through the mitochondrial damage induced by mitophagy and ferroptosis.
  18. Research Progress of Mitochondrial Dynamics and Autophagy in Diabetic Complications: New Treatment Strategies.
  19. Up-regulation of cell apoptosis, autophagy and mitochondrial dynamics in ovarian granulosa cells of Daurian ground squirrels during the pre-hibernation period.
  20. Artesunate Enhances DUSP1-Dependent Mitochondrial Integrity to Mitigate Renal Fibrosis in Diabetic Kidney Disease.
  21. Bacteria-Mitochondria Cross-talk: How Microbes Regulate Mitochondrial Dynamics and Bioenergetics of Host Cells.
  22. Effects of sini decoction-mediated cellular mitochondrial autophagy on M1 macrophage polarization and its impact on a mouse model of peripheral artery disease.
  23. Pyrimethamine Inhibits Human Ovarian Cancer by Triggering Lethal Mitophagy via Activating the p38/JNK/ERK Pathway.
  24. Mitochondrial dysfunction in diabetic ulcers: pathophysiological mechanisms and targeted therapeutic strategies.
  25. Spotlight on USP30: structure, function, disease and target inhibition.
  26. The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
  27. Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.
  28. EPA-enriched phospholipids and DHA-enriched phospholipids prevent dexamethasone-induced skeletal muscle atrophy via regulating protein turnover and mitochondrial quality.
  29. Fu's subcutaneous needling facilitates muscle repair by regulating mitochondrial homeostasis in rat with chronic peripheral nervous pain.
  30. Lycium barbarum alleviates oxidative stress-induced ferroptosis and enhances mitophagy in intervertebral disc degeneration.
  31. Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages.
  32. Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
  33. Salidroside Attenuates Cerebral Ischemia-Reperfusion Injury via ERβ/BNIP3-Mediated Mitochondrial Autophagy Activation in a Rat Model.
  34. Correction: The PGC-1α/SIRT3 pathway mediates the effect of DON on mitochondrial autophagy and liver injury in mice.
  35. NR3C1/GLMN-Mediated FKBP12.6 Ubiquitination Disrupts Calcium Homeostasis and Impairs Mitochondrial Quality Control in Stress-Induced Myocardial Damage.
  36. Neuroprotection in neonatal Hypoxia-ischaemia: melatonin targets NCX1 to inhibit mitochondrial autophagy via the PINK1-Parkin pathway.
  37. Investigation of the effects of resveratrol, lutein, and crocetin on ARPE-19 cells induced with oxidative damage by H2O2.
  38. KDM4A-induced tumor senescence enhances the efficacy of immunotherapy by inhibiting AGT-PHB1 axis-mediated mitophagy in colorectal cancer.
  39. Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
  40. Mitochondrial ClpX Inhibition Induces Ferroptosis and Blocks Pancreatic Cancer Cell Proliferation.
  41. Electrical Vagus Nerve Stimulation Ameliorates Cardiac Ischemia and Reperfusion Injury by Improving Mitochondrial Biogenesis Through the SIRT1/PGC-1α Pathway.
  42. Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway.
  43. Parkin Induces Ubiquitination and Large Extracellular Vesicle Release of HMGB1 to Activate Antitumor Immunity.
  44. Deletion of ABIN1-LIR motifs impairs hepatic lipid homeostasis and mitophagy via AMPK-TFEB axis in mice.
  45. The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
  46. Cucurbitacin B from Cucurbitaceae Plants: Treating Pancreatic Cancer via Inducing Mitophagy, Inhibiting Glycolysis, and Enhancing Immune Function.
  47. Wogonoside inhibits fibroblast activation and pulmonary fibrosis by dual regulation of Snail1 lactylation and PGC1α/PINK1-mediated mitophagy.
  48. Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke.
  49. Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
  50. SiO2 NP promotes allergic gastritis induced by degranulation of mouse MC9 cell through AQP4-mediated impairment of SIRT3-TFAM deacetylation and mitochondrial autophagy.
  51. Sorting nexin 3 promotes ischemic retinopathy through RIP1- and RIP3-mediated myeloid cell necroptosis and mitochondrial fission.
  52. Development of six novel dinuclear calcium(II) complexes based on 8-hydroxyquinoline as anticancer agents.
  53. Metabolic saboteurs: Tire wear particles hijack energy economy of zooplankton.
  54. Selective Autophagy in Type 2 Diabetes-Associated Cognitive Dysfunction: Insightful Mechanisms and Therapies.
  55. LONP1 Promotes Hepatocarcinogenesis by Degrading ACO2 to Alleviate Ferroptosis.
  56. Nanohybrid Hydrogels Spatiotemporally Restore Infectious Bone Defects via Mitochondrial Homeostasis-Driven Immunomodulation and Vascular-Bone Coupling Synergy.
  57. Adaptations in Mitochondrial Function Induced by Exercise: A Therapeutic Route for Treatment-Resistant Depression.
  58. LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
  1. Int J Mol Sci. 2025 Sep 06. pii: 8693. [Epub ahead of print]26(17):
    Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges.
    Agnieszka Dominiak, Elżbieta Gawinek, Agnieszka Anna Banaszek, Anna Wilkaniec.
      Mitochondrial quality control (MQC) mechanisms, including proteostasis, mitophagy, mitochondrial dynamics, and biogenesis, are essential for maintaining mitochondrial function and overall cellular health. Dysregulation of these systems is a common feature of both neurodegenerative diseases and cancer, but the outcomes differ. Neurons depend strongly on healthy mitochondria and are easily damaged when MQC fails, resulting in organellar dysfunction and oxidative stress. By contrast, cancer cells often adapt by using MQC pathways to sustain survival and resist cell death. The mitochondrial unfolded protein response (mtUPR) and mitophagy are central to these processes, yet their roles are context-dependent. In neurodegeneration, activation of these pathways may help neurons survive, yet persistent stimulation can shift towards harmful effects. In cancer, these same pathways enhance metabolic flexibility, promote resistance to treatment, and support tumor progression. Although therapeutic strategies targeting MQC are being explored, their translation to the clinic is difficult, partly due to opposite effects in different diseases. The observed inverse epidemiological link between cancer and neurodegeneration may also reflect the distinct regulation of MQC pathways. A clearer understanding of these mechanisms is needed to identify new treatment strategies for disorders that are clinically distinct but share common mitochondrial defects.
    Keywords:  cancer; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms26178693
  2. Autophagy. 2025 Sep 13.
    Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
    Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.
    Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2025.2561073
  3. Biochim Biophys Acta Rev Cancer. 2025 Sep 10. pii: S0304-419X(25)00192-1. [Epub ahead of print] 189450
    Unraveling the role of mitochondrial dynamics in cancer stem cells: Molecular basis and therapeutic implications.
    Gaia Giannitti, Sara Marchesi, Riccardo Garavaglia, Ivan Preosto, Fabrizio Fontana.
      Many tumors consist of heterogeneous cell populations derived from a minority of cancer stem cells (CSCs), which possess distinct metabolic profiles that contribute to resistance against conventional anticancer therapy and increase the risk of tumor relapse. These unique CSC phenotypes are largely supported by altered mitochondrial function and turnover, regulated through continuous cycles of mitochondrial biogenesis, fission, fusion, and mitophagy. Consequently, understanding mitochondrial regulatory mechanisms in CSCs could reveal novel targets for cancer therapy. This article explores how mitochondrial dynamics contribute to CSC metabolic adaptation and drug resistance, alongside recent advances in the development of mitochondria-targeted drugs and their therapeutic usage.
    Keywords:  Cancer stem cells; Cancer therapy; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial fission and fusion; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189450
  4. Chem Biol Interact. 2025 Sep 10. pii: S0009-2797(25)00373-4. [Epub ahead of print] 111743
    Mitochondrial Physiology and Beyond: Mechanistic Insights into Kaempferol Actions.
    Marcos Roberto de Oliveira.
      Kaempferol (KAE), a dietary flavonoid, has emerged as a potent modulator of mitochondrial physiology, exerting multifaceted actions on bioenergetics, redox balance, mitochondrial dynamics, biogenesis, and quality control. Thus, the aim of this review is to discuss the effects promoted by KAE on mitochondrial physiology from a mechanistic view. Data from diverse in vitro and in vivo models indicate that KAE enhances mitochondrial function by stimulating ATP production, preserving membrane potential, promoting calcium uptake, and increasing the activity or expression of oxidative phosphorylation (OXPHOS) complexes. KAE also activates key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, adenosine monophosphate-activated protein kinase/ peroxisome proliferator-activated receptor gamma coactivator 1-α (AMPK/PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to mitochondrial biogenesis, antioxidant defense, and cellular survival. In parallel, KAE modulates mitochondrial dynamics by inhibiting fission and promoting fusion, while also inducing mitophagy, particularly under neurotoxic or ischemic conditions. However, at elevated concentrations, KAE may disrupt mitochondrial homeostasis by inhibiting Complex V activity, inducing oxidative stress, and depolarizing mitochondria, suggesting a concentration- and context-dependent duality. Furthermore, nanotechnology-based delivery systems targeting KAE to mitochondria have demonstrated enhanced therapeutic potential in preclinical disease models, reinforcing its translational relevance. Collectively, these findings support KAE as a promising candidate for mitochondrial-targeted interventions in diseases characterized by mitochondrial dysfunction. Nonetheless, mechanistic gaps remain regarding its impact on mitochondrial protein acetylation, quality control signaling, and the long-term effects of chronic exposure. Future research should focus on dissecting these pathways and validating the therapeutic window of KAE in clinical settings.
    Keywords:  kaempferol; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial function; mitophagy; redox signaling
    DOI:  https://doi.org/10.1016/j.cbi.2025.111743
  5. EMBO J. 2025 Sep 08.
    Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
    Amanda L Gunawan, Irene Liparulo, Andreas Stahl.
      A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.
    Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-025-00549-3
  6. J Cell Biol. 2025 Oct 06. pii: e202406017. [Epub ahead of print]224(10):
    SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
    Rachel Shannon, Yadu Balachandran, Xindi Wang, Maxime Boutry, Hong Xie, Peter K Kim, William S Trimble.
      Mitochondria continually undergo fission to maintain their network and health. Nascent fission sites are marked by the ER, which facilitates actin polymerization to drive calcium flux into the mitochondrion and constrict the inner mitochondrial membrane. Septins are a major eukaryotic cytoskeleton component that forms filaments that can both directly and indirectly modulate other cytoskeleton components, including actin. Septins have been implicated in mitochondrial fission; however, a connection between septins and the regulation of cytoskeletal machinery driving fission is not known. We find that SEPTIN9 is present at mitochondrial fission sites from its early stages with the ER and prior to the fission factor dynamin-related protein 1 (DRP1). SEPTIN9 has an isoform-specific role in fission, dependent on its N-terminal interaction to activate a Rho guanine nucleotide exchange factor, ARHGEF18. Without SEPTIN9, mitochondrial calcium influx is impaired, indicating SEPTIN9-containing octamers play a critical role in the early stages of fission.
    DOI:  https://doi.org/10.1083/jcb.202406017
  7. Apoptosis. 2025 Sep 12.
    Mitophagy: a novel avenue for herbal medicines alleviating myocardial ischemia/reperfusion injury.
    Mengqi Liao, Ling Men, Ming Gong, Yuanyuan Li, Yan Wang, Desheng Xu, Jienan Luan, Hua Zhou, Mengnan Liu, Mingtai Chen.
      Myocardial ischemia-reperfusion injury (MIRI) has a high incidence and is difficult to cure. Studies have shown that mitophagy is the key mechanism. This review systematically summarizes all documented herbal preparations and bioactive monomers targeting mitophagy for MIRI treatment, which may serve as a valuable reference for future research on herbal medicine-mediated mitophagy regulation. We conducted comprehensive literature searches in PubMed, Embase, Web of Science, and CNKI databases using the keywords "cardiovascular diseases," "mitophagy," "myocardial ischemia-reperfusion injury," "herbal medicine," "mechanism," and "therapeutic" for studies published within the last five years up to July 2025. Studies on herbal medicine interventions unrelated to mitophagy were excluded. Our analysis reveals that mitophagy plays a crucial role in attenuating the detrimental effects of MIRI. Furthermore, herbal medicine demonstrates therapeutic efficacy in maintaining homeostatic balance of mitophagy during MIRI. Herbal medicines can precisely regulate mitophagy via the PTEN-induced putative kinase 1 (PINK1)-parkin pathway, and modulate the expression of BCL2 interacting protein 3 (BNIP3), FUN14 domain-containing protein 1 (FUNDC1), NIP3-like protein X (NIX). Herbal medicines exert protective effects against MIRI through diverse mechanisms and signaling pathways by targeting mitophagy. While mitophagy represents a promising frontier for future cardiovascular research, current herbal medicine applications remain predominantly confined to animal and cellular models, with only limited clinical translation. The findings presented herein are anticipated to provide clinicians and cardiovascular researchers with valuable therapeutic strategies and novel research directions.
    Keywords:  Autophagy; Herbal medicine; Mitophagy; Myocardial ischemia–reperfusion injury; Treatment
    DOI:  https://doi.org/10.1007/s10495-025-02178-x
  8. Cell Signal. 2025 Sep 08. pii: S0898-6568(25)00536-4. [Epub ahead of print]136 112121
    Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.
    Chao Hu, Tianhong Su, Ying Zhang, Jing Yang, Xun Su, Zhikang Zhang, Xin Wang, Weiwei Zou, Dan Liang, Yajing Liu, Dongmei Ji, Yunxia Cao.
      Leber's hereditary optic neuropathy (LHON), a mitochondrial disorder marked by central vision loss, exhibits incomplete penetrance and male predominance. Since there are no adequate models for understanding the rapid vision loss associated with LHON, we generated induced pluripotent stem cells (iPSCs) from LHON patients carrying the pathogenic m.3635G > A mutation and differentiated them into retinal pigment epithelium (RPE) cells. The mutation disrupted mitochondrial dynamics, suppressing OPA1-mediated fusion and enhancing DRP1-dependent fission, resulting in decreased expression of ND1, ND5, NDUFB8, SDHB and COX2, impaired mitochondrial bioenergetic function, and cell proliferation. Additionally, the m.3635G > A mutation promoted intrinsic apoptosis, altered autophagic flux, evidenced by elevating levels in apoptotic proteins PARP1, caspase-3, and 9, reduced levels of autophagy protein LC3-II, and increased levels of substrate P62. Moreover, the m.3635G > A mutation inhibited PINK1-Parkin-dependent mitophagy. Based on sex-specific differences in hormone metabolism, we proposed that estrogen plays a protective role in women and showed that estrogen receptor α and β were downregulated in LHON. We demonstrated that estradiol improved cell viability by reducing apoptosis, inducing mitochondrial biogenesis through the PGC1α-NRF1/2-TFAM axis, and vigorously promoting PINK1-Parkin-dependent mitophagy in LHON iPSCs and iPSC-derived RPE cells. Our findings have highlighted the critical role of the m.3635G > A mutation in the pathogenetic process of LHON, and our observations support the hypothesis that estrogen is helpful in the preventive treatment of LHON.
    Keywords:  Autophagy; Induced pluripotent stem cell; Leber's hereditary optic neuropathy (LHON); Mitochondrial disease; Mitophagy; mtDNA mutation
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112121
  9. Mech Ageing Dev. 2025 Sep 08. pii: S0047-6374(25)00088-0. [Epub ahead of print]228 112112
    Defective mitochondrial quality control in the aging of skeletal muscle.
    Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Francesco Landi, Anna Picca.
      Age-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation-contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span.
    Keywords:  Autophagy; Damage associated molecular patterns; Mitochondrial DNA; Mitochondrial dynamics; Mitophagy; Myocyte; Proteasome
    DOI:  https://doi.org/10.1016/j.mad.2025.112112
  10. Prog Neuropsychopharmacol Biol Psychiatry. 2025 Sep 09. pii: S0278-5846(25)00245-3. [Epub ahead of print] 111491
    Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.
    Authors Jana Hroudová, Zdeněk Fišar.
      Alterations in mitochondrial energy metabolism, impaired processes of mitochondrial dynamics and mitophagy have recently been identified as important contributors to the pathophysiology of Alzheimer's disease (AD). Genetic predispositions and defects in mitochondrial metabolism, particularly within the electron transport chain of the oxidative phosphorylation system, have been linked to the pathology of intracellular and extracellular amyloid-beta (Aβ) and tau protein. This review summarizes the current molecular background of AD and explains the relationships between genetic factors, impaired energy metabolism, and the formation of pathological proteins. It highlights altered mitochondrial dynamics, impaired mitochondrial signaling, mitophagy, neuroinflammation, and apoptosis. Based on these findings, the review discusses mitochondrial biomarkers and novel molecules targeting mitochondrial dysfunction in the pathophysiology of AD.
    Keywords:  Alzheimer's disease; Amyloid beta; Energy metabolism; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1016/j.pnpbp.2025.111491
  11. Front Oncol. 2025 ;15 1603069
    A novel prognostic biomarker DUSP6 promote the malignant progression of bladder cancer through mTOR mediated mitophagy.
    Jianbiao Huang, Chongwei Zhou, Zhaojun Yu, Zhen Song, Huanhuan Deng, Haichao Chao, Tao Zeng.
      Bladder cancer (BC) is one of the most prevalent urinary malignant tumors that is intricately regulated by molecular pathways. Multiple studies have demonstrated a clear association between DUSP6 and malignant tumor progression; however, its role and underlying mechanisms in BC remain unclear. Here, we found that DUSP6 exhibits significantly elevated expression in BC tissues compared with normal tissues and is strongly associated with poor overall survival. Transcriptomic analysis revealed a robust correlation between DUSP6 expression and mitophagy, a selective form of autophagy crucial for maintaining mitochondrial integrity. In vitro and in vivo experiments demonstrated that knockdown of DUSP6 reduces tumor invasion, migration, and proliferation ability while enhancing mitophagy in BC cells. Notably, the anti-malignant effects of DUSP6 knockdown were partially reversed by the mitophagy inhibitor cyclosporin A. Mechanistically, DUSP6 modulates mitophagy by increasing the phosphorylation status of mTOR, a central autophagy regulator, and DUSP6 knockdown-induced mitophagy was partially restored after treatment with mTOR activator MHY1485. Our findings indicate that high DUSP6 expression promotes BC progression by inhibiting mTOR-mediated mitophagy, leading to a poor prognosis for BC patients. These insights suggest DUSP6 as a potential therapeutic target in the treatment of BC.
    Keywords:  DUSP6; bladder cancer; mTOR; mitophagy; prognostic
    DOI:  https://doi.org/10.3389/fonc.2025.1603069
  12. J Clin Periodontol. 2025 Sep 07.
    Parkin Acetylation-Mediated Mitophagy Orchestrates Periodontal Ligament Stem Cell Osteogenesis and Bone Regeneration During Ageing.
    Kehan Zhang, Xiangyao Wang, Yuxiao Zhang, Yuanyuan Li, Yaxin Wu, Gaoshaer Nuerlan, Qilin Li, Jing Mao, Shiqiang Gong, Yan Liu.
       AIM: To investigate the functional significance of mitophagy in age-related osteogenic decline and the underlying mechanisms using in vivo and in vitro models.
    MATERIALS AND METHODS: An alveolar bone defect model in aged mice and a serial passaging-induced ageing model of human periodontal ligament stem cells (PDLSCs) were established. Osteogenic potential in mice was assessed by micro-CT, immunofluorescence, immunohistochemical analyses and histological staining. Osteogenic differentiation, mitochondrial function and mitophagy in PDLSCs were assessed using molecular techniques, cytochemical assays and imaging approaches. HDAC2-Parkin interactions and Parkin acetylation status were examined by mass spectrometry and immunoprecipitation to uncover key mechanisms.
    RESULTS: Senescent PDLSCs exhibited impaired mitophagy and osteogenic capacity. Enhancing mitophagy restored osteogenesis of senescent PDLSCs and bone regeneration in aged mice. Mechanistically, HDAC2-mediated deacetylation of Parkin suppressed mitophagy and osteogenesis during ageing.
    CONCLUSION: Activation of mitophagy reverses age-associated declines in osteogenic function, highlighting mitophagy as a therapeutic target for enhancing bone repair in the ageing population.
    Keywords:  acetylation; ageing; bone regeneration; mitophagy; osteogenesis
    DOI:  https://doi.org/10.1111/jcpe.70031
  13. Redox Biol. 2025 Sep 05. pii: S2213-2317(25)00375-1. [Epub ahead of print]87 103862
    Exposure to an environmentally relevant mixture of polychlorinated biphenyls affects mitochondrial bioenergetics and plasticity.
    Maria Carolina Peixoto-Rodrigues, Vladimir Pedro Peralva Borges-Martins, José Raphael Monteiro-Neto, Bruno Vicente, Lucas José Guimarães, Clara Fernandes-Carvalho, Antonio Galina, Victor Midlej, Michal Toborek, Rachel Ann Hauser-Davis, Daniel Adesse.
      Adaptations of cells to environmental insults typically require tightly regulated processes to preserve the organismal steady state, particularly in metabolically active cells such as neural cells. Polychlorinated biphenyls (PCBs) are persistent organic pollutants widely recognized for their neurotoxic potential. Due to their lipophilic nature, these compounds readily accumulate in the brain, where they can disrupt neuronal homeostasis. Herein, we examined the effects of exposure to an environmentally relevant PCB mixture on mitochondrial dynamics, ultrastructure, and function in the mouse neuroblastoma Neuro2a cell line. Ultrastructural examinations indicated evident signs of mitochondrial damage, including swelling, cristae disruption, and increased frequency of autophagic structures. Quantification of mitochondrial networks confirmed a shift from tubular to fragmented morphologies, accompanied with the modulation of the gene expression of genes involved in mitochondrial fusion and fission. Specifically, mitofusin 2 protein levels were increased at 24 and 48 h of treatment, and OPA1 at 48 h, whereas Drp1, phosphorylated at Ser616 was increased at 24 h. Markers of mitophagy PINK1 and Parkin were elevated at 72 and 48 h of exposure, respectively, whereas Atg5 and Atg7, markers of autophagy were increased at 24 h. We observed a decrease in mitochondrial membrane potential and increase in mtDNA levels in PCB-treated cultures at 24 h. Oxidative stress was also implicated by overexpression and increased enzymatic activity of superoxide dismutase 1 (SOD1). Functional tests revealed a transient impairment of mitochondrial respiration and ATP synthesis, which was later restored, pointing to the recruitment of compensatory mechanisms. Together, these results indicate that PCB exposure activates an integrated stress response with oxidative imbalance, mitochondrial bioenergetics, remodeling, and autophagy features, revealing the neural cell vulnerability and plasticity to environmental insult.
    Keywords:  Central nervous system; Mitochondrial plasticity; Pollutants; Polychlorinated biphenyls
    DOI:  https://doi.org/10.1016/j.redox.2025.103862
  14. Biosci Biotechnol Biochem. 2025 Sep 09. pii: zbaf119. [Epub ahead of print]
    IL-1β restrains its own apoptosis-promoting activity via NF-κB (RelA) Ser276/p62-mediated elimination of damaged mitochondria in Chondrocytes.
    Junzheng Hu, Weituo Zhang, Zhe Zhao.
      Interleukin-1β (IL-1β) is a central proinflammatory cytokine implicated in osteoarthritis (OA), but its precise role in chondrocyte apoptosis remains to be fully elucidated. In this study, we demonstrate that IL-1β triggers mitophagy in chondrocytes by promoting Parkin translocation and p62 recruitment to damaged mitochondria, thereby reducing mitochondrial dysfunction and apoptosis. Loss of p62 resulted in impaired mitophagy, excessive mitochondrial superoxide accumulation, and increased cell death. Mechanistically, IL-1β enhanced NF-κB (RelA) phosphorylation at Ser276 and Ser536, accompanied by elevated MSK1 expression. Inhibition of MSK1 selectively suppressed Ser276 phosphorylation without affecting Ser536, leading to reduced p62 expression and disrupted mitophagy. These findings reveal a previously unrecognized intrinsic regulatory mechanism by which IL-1β limits its own apoptosis-promoting effect through activation of the NF-κB (RelA) Ser276-p62-mitophagy axis. This pathway facilitates the clearance of damaged mitochondria and preserves chondrocyte viability, offering potential therapeutic insight into inflammation-associated cartilage degeneration in OA.
    Keywords:  Chondrocytes; IL-1β; Mitophagy; NF-κB; p62
    DOI:  https://doi.org/10.1093/bbb/zbaf119
  15. Int Immunopharmacol. 2025 Sep 11. pii: S1567-5769(25)01464-X. [Epub ahead of print]165 115473
    Interleukin-6 induces upregulation of BNIP3 in cardiomyocytes to protect against myocardial ischemia/reperfusion injury.
    Jiawei Wu, Zihan Li, Yuwei Wang, Hao Hu, Likun Ma.
      Myocardial ischemia/reperfusion (I/R) injury primarily results from mitochondrial dysfunction and cardiomyocyte death. Mitophagy helps maintain mitochondrial function and offers protective effects to reperfused cardiac tissue. Interleukin-6 (IL-6), a cytokine released in response to acute injury, is expressed by multiple cell types, including cardiomyocytes. Recombinant IL-6 has been shown to limit myocardial infarctions in mice, suggesting its cardioprotective potential. This study aimed to explore the role of mitophagy in IL-6-induced cardioprotection and the underlying cellular mechanisms. Our findings revealed that silencing IL-6 with cardiotropic recombinant adeno-associated virus serotype 9 (rAAV9) in mouse hearts led to a significant increase in infarct sizes during myocardial I/R. We assessed mitophagy by analyzing mitophagy flux and related proteins. The results indicated that IL-6 knockdown notably reduced mitophagy induced by myocardial I/R both in vivo and in vitro. Additionally, myocardial I/R caused a significant rise in Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), which was reversed by IL-6 silencing. Importantly, BNIP3 deficiency countered the mitophagy induced by recombinant IL-6 and nullified its cardioprotective effects. Mechanistically, IL-6 was shown to enhance the translocation of forkhead transcription factor Foxo3a to the nucleus, which increased the transcriptional activity of Foxo3a, leading to elevated BNIP3 levels in cardiomyocytes. BNIP3 was identified as a transcriptional target of Foxo3a, with Foxo3a binding to the BNIP3 promoter to activate its transcription. Notably, deletion of Foxo3a reduced the cardioprotective effects of recombinant IL-6. Based on these results, we propose that direct stimulation of mitophagy represents a novel mechanism through which IL-6 protects cardiomyocytes from myocardial I/R injury.
    Keywords:  BNIP3; Foxo3a; Mitophagy; Myocardial ischemia/reperfusion
    DOI:  https://doi.org/10.1016/j.intimp.2025.115473
  16. Int J Mol Sci. 2025 Aug 25. pii: 8222. [Epub ahead of print]26(17):
    SIRT3 Acetylation Regulates Mitophagy to Alleviate Deoxynivalenol-Induced Apoptosis in Porcine Alveolar Macrophages Cells.
    Peng Fan, Huidan Deng, Ya Wang, Zhihua Ren, Junliang Deng.
      Deoxynivalenol (DON), a global mycotoxin contaminant, induces immunotoxicity in swine and humans by disrupting mitochondrial membrane integrity and activating mitophagy. SIRT3 plays an important role in regulating cell metabolism and various diseases. It also regulates apoptosis (caused by DON) by regulating the mitophagy pathway, but this pathway has not been studied yet. Gene knockout and overexpression of SIRT3 were performed for proteomics and acetylation modification. Therefore, in this study, PAM cells were selected as an in vitro model of DON (1.1 μg/mL) exposure for 24 h. The results showed that the knockout impaired mitochondrial antioxidant function, whereas overexpression improves damage stimulation. DON can also affect the metabolism of immune pathways, but SIRT3 can enrich these substances' metabolism. The results of the acetylation modification analysis showed that knockout affected the mRNA metabolism and others, while overexpression affected apoptosis and others. DON exposure caused fatty acid degradation, and altered MAPK signaling pathway. Knockout and overexpression of SIRT3 under DON exposure were enriched in PPAR, Ferroptosis pathway. Overexpression attenuated DON-induced mitophagy by reducing cellular ROS, as well as the expression of LC3, P62 and PINK1/Parkin. Finally, SIRT3 reduced cell apoptosis by reducing the expression of BAX and CASP3 and increasing the expression of BCL-2. These results indicated that SIRT3 could alleviate DON-induced cell damage by reducing apoptosis through the mitophagy pathway.
    Keywords:  DON; PAM; SIRT3; acetylation; apoptosis; mitophagy
    DOI:  https://doi.org/10.3390/ijms26178222
  17. Front Oncol. 2025 ;15 1633891
    Ginsenoside Rh2 repressed the progression of prostate cancer through the mitochondrial damage induced by mitophagy and ferroptosis.
    Zhen He, Jianxi Shi, Bing Zhu, Zhentao Tian, Zhihong Zhang, Changwen Zhang.
       Introduction: Prostate cancer (PC), the most common male genitourinary malignancy and second leading cause of global cancer deaths in men, frequently progresses to lethal castration-resistant PC (CRPC). Ginsenoside Rh2 (GRh2), a ginseng-derived bioactive compound, exhibits antitumor potential, but its efficacy and mechanisms in PC remain unclear.
    Methods: PC3 cells were treated with GRh2 to assess proliferation (IC50 calculation), migration, and invasion. Mitochondrial function (membrane potential, ROS, ATP/ADP), mitophagy markers (PINK1/Parkin, VDAC1/TOM20, autophagosomes), and ferroptosis indicators (lipid ROS, MDA, Fe2+, GSH, SLC7A11/GPX4) were evaluated. Specific inhibitors (Mdivi-1 for mitophagy, Fer-1 for ferroptosis) validated mechanistic causality. Subcutaneous xenograft models in nude mice assessed in vivo efficacy.
    Results: GRh2 potently inhibited PC3 cell proliferation (IC50 = 19.3 μg/mL), migration, and invasion. It induced mitochondrial dysfunction (depolarized membrane, elevated ROS, disrupted ATP/ADP) and activated mitophagy, evidenced by upregulated PINK1/Parkin, reduced VDAC1/TOM20, and autophagosome accumulation. Concurrently, GRh2 triggered ferroptosis via lipid ROS accumulation, increased MDA/Fe2+, GSH depletion, and SLC7A11/GPX4 downregulation. All effects were reversed by Mdivi-1 or Fer-1, confirming pathway-specific causality. In vivo, GRh2 significantly suppressed tumor growth.
    Discussion: This study provides the first evidence that GRh2 exerts synergistic antitumor effects in PC through dual induction of mitophagy-associated mitochondrial damage and ferroptosis. The reversibility of both pathways by specific inhibitors establishes a causal mechanistic framework. GRh2 thus represents a multifaceted therapeutic agent against PC by targeting mitochondrial integrity.
    Keywords:  Chinese medicine; PC; ferroptosis; ginsenoside Rh2; mitochondrial damage; mitophagy
    DOI:  https://doi.org/10.3389/fonc.2025.1633891
  18. Diabetes Metab Syndr Obes. 2025 ;18 3167-3180
    Research Progress of Mitochondrial Dynamics and Autophagy in Diabetic Complications: New Treatment Strategies.
    XiaoPei Wu, Ji Yang, JunDong He.
      Diabetes has emerged as a critical global health issue, with its associated complications posing a severe threat to patients' quality of life. Current research demonstrates that imbalance in mitochondrial dynamics and autophagic dysregulation play pivotal roles in the pathogenesis of diabetic complications, particularly in diabetic cardiomyopathy, nephropathy, peripheral neuropathy and retinopathy. Strategic modulation of mitochondrial function and autophagic activity represents a promising therapeutic approach for managing diabetic complications. Furthermore, integrating mitochondrial dynamics and autophagy, we have outlined the application prospects of strategies related to diabetic complications, including mitochondrial fission inhibitors, autophagy inducers, and certain compounds extracted from traditional Chinese medicines, and incorporated new breakthroughs in mitochondrial imaging, omics, and artificial intelligence-based therapeutic prediction. This review systematically examines the intricate relationship between diabetic complications and dysregulations in mitochondrial dynamics and autophagic dysfunction, while elucidating the underlying molecular mechanisms, and highlights the significance of mitochondrial dynamics and autophagy in diabetic complications. Imbalances in mitochondrial dynamics-whether abnormal fission or fusion-and autophagic dysregulation do not exist in isolation. A comprehensive understanding of the interplay between diabetic pathophysiology and the mitochondrial-autophagy axis may provide novel research perspectives for therapeutic development. This paper provides a comprehensive review of the literature to clarify the above content, using a narrative review approach. Future investigations should prioritize translational exploration to harness the clinical potential of these mechanistic insights, thereby advancing precision medicine strategies for the management of diabetic complications.
    Keywords:  diabetic cardiomyopathy; diabetic nephropathy; diabetic peripheral neuropathy; diabetic retinopathy
    DOI:  https://doi.org/10.2147/DMSO.S541768
  19. Comp Biochem Physiol A Mol Integr Physiol. 2025 Sep 09. pii: S1095-6433(25)00126-6. [Epub ahead of print] 111927
    Up-regulation of cell apoptosis, autophagy and mitochondrial dynamics in ovarian granulosa cells of Daurian ground squirrels during the pre-hibernation period.
    Xi Wang, Hao Li, Zhaomei Dong, Wenjing Lu, Jirui Chen, Haolin Zhang, Zhengrong Yuan, Yuning Liu, Qiang Weng, Yingying Han.
      Daurian ground squirrel (Spermophilus dauricus) exhibits both seasonal breeding and hibernation characteristics, but the adaptive changes in ovaries during the transition from seasonal reproduction to hibernation remain poorly understood. The aim of this study is to investigate the regulatory characteristics of granulosa cell apoptosis, autophagy and mitochondrial dynamics in the ovaries of wild Daurian ground squirrels across the April (breeding period), June (non-breeding period), and September (non-breeding and pre-hibernation period). The results proved that ovarian weight, as well as serum reproductive hormones, significantly decreased in June and September compared with April. Interestingly, unlike in June, many growing antral follicles emerged in the ovaries of wild Daurian ground squirrels during September. Furthermore, the molecular studies revealed a significant increase in ovarian gene expression related to cell apoptosis (Casp3, Bax/Bcl-2), autophagy (Becn1, Pink1, Parkin, Sqstm1) and mitochondrial dynamics (Mfn1, Mfn2, Drp1) during September compared to June. Additionally, immunohistochemical results indicated that the protein levels of the aforementioned genes and LC3A/B were concurrently upregulated, predominantly located in ovarian granulosa cells. Consistently, comparative analysis of ovarian transcriptomic data across different periods further confirmed that genes differentially expressed during the three periods were enriched in pathways related to apoptosis, autophagy, and mitochondrial dynamics. In summary, these results revealed a significant up-regulation of cell apoptosis, autophagy, and mitochondrial dynamism in ovarian granulosa cells of wild ground squirrels during the pre-hibernation period, may play a critical role in ovarian development for hibernation and subsequent stage.
    Keywords:  Apoptosis; Autophagy; Mitochondrial dynamics; Ovary; Wild Daurian ground squirrel
    DOI:  https://doi.org/10.1016/j.cbpa.2025.111927
  20. Phytother Res. 2025 Sep 11.
    Artesunate Enhances DUSP1-Dependent Mitochondrial Integrity to Mitigate Renal Fibrosis in Diabetic Kidney Disease.
    Zikang Liu, Hongtu Hu, Yuxuan Jin, Jiwen Bao, Hanxue Zhao, Yurong Lin, Binbin Dai, Yangbin Pan.
      Renal fibrosis is a hallmark of diabetic kidney disease (DKD), and currently available therapies offer limited efficacy. Artesunate (ART), a repurposed antimalarial agent, has recently demonstrated potential in mitigating renal fibrosis. This study aimed to investigate whether ART protects mitochondrial integrity and attenuates fibrosis in tubular epithelial cells (TECs) via the dual-specificity phosphatase 1 (DUSP1) pathway. Mitochondrial morphology and DUSP1 expression were examined in kidney tissues from DKD patients and db/db mice. ART (25 mg/kg) was administered to db/db mice to evaluate its in vivo effects on fibrosis, mitochondrial dynamics, and inflammation. In vitro, TECs stimulated with high glucose were used to assess mitochondrial function and fibrotic response after ART treatment. Mechanistic studies included RNA sequencing, molecular docking, and genetic modulation (DUSP1 knockdown and overexpression). Mitochondrial swelling, cristae disruption, and TFAM downregulation were observed in both human DKD samples and db/db mice, correlating with tubulointerstitial fibrosis. ART treatment restored mitochondrial structure, reduced fibrotic markers, and suppressed inflammatory cytokines in vivo. In vitro, ART reversed high-glucose-induced mitochondrial dysfunction and fibrotic signaling. Mechanistically, ART directly bound to and stabilized DUSP1, thereby inhibiting MAPK signaling. Knockdown of DUSP1 abolished the protective effects of ART, while DUSP1 overexpression mimicked ART's therapeutic actions. Notably, DUSP1 expression was significantly reduced in DKD patients, associated with greater fibrosis and worse renal function. ART attenuates renal fibrosis and restores mitochondrial homeostasis in DKD through DUSP1 stabilization and MAPK pathway inhibition. These findings support ART as a potential therapeutic agent targeting mitochondrial integrity and inflammation in diabetic kidney disease.
    Keywords:  Artesunate; diabetic kidney disease; dual‐specificity phosphatase 1; mitochondrial dynamics; renal fibrosis
    DOI:  https://doi.org/10.1002/ptr.70091
  21. Infect Disord Drug Targets. 2025 Aug 19.
    Bacteria-Mitochondria Cross-talk: How Microbes Regulate Mitochondrial Dynamics and Bioenergetics of Host Cells.
    Tasbir Amin, Md Asaduzzaman Shishir, Mohammad Mamun Alam, Mohammad Badrul Anam, Nayeema Bulbul, Jinath Sultana Jime, Md Fakruddin.
      Mitochondria are the cellular powerhouses and are considered to be central to energy metabolism, dynamics, and homeostasis. There is growing evidence that the gut microbiome regulates mitochondrial biogenesis, dynamics (fission, fusion, mitoph-agy), and bioenergetics, and that it does so by connecting bacterial metabolites and signaling molecules. This review discusses the molecular mechanisms that underlie the interplay between bacteria and mitochondria, with a particular focus on the modulation of mitochondrial activities by microbial products, including bile acids, immunological mediators, and short-chain fatty acids (SCFAs). The evolutionary relationship between bacteria and mitochondria is explored, along with the implications of microbial dysbio-sis on mitochondrial dysfunction, which is linked to a variety of inflammatory, meta-bolic, and neurodegenerative disorders. Additionally, we emphasised the therapeutic potential of focusing on the microbiota to treat illnesses associated with the mitochon-dria and to restore mitochondrial health. A better understanding of the complex rela-tionship between bacteria and mitochondria can open up new avenues for disease man-agement and novel treatment possibilities.
    Keywords:  Mitochondria; bacteria-mitochondria cross-talk; bioenergetics; dysbiosis.; gut microbi-ota; microbial metabolites; microbiome; mitochondrial biogenesis; mitochondrial dynamics; short-chain fatty acids (SCFAs)
    DOI:  https://doi.org/10.2174/0118715265362556250717063603
  22. J Bioenerg Biomembr. 2025 Sep 10.
    Effects of sini decoction-mediated cellular mitochondrial autophagy on M1 macrophage polarization and its impact on a mouse model of peripheral artery disease.
    Zhe Liu, Luoqin Guo, Li Jin, Yudong Fang.
      This study aimed to investigate the therapeutic effects of Sini Decoction on a murine model of peripheral arterial disease (PAD) and to explore its potential mechanisms of action related to mitochondrial autophagy and M1 macrophage polarization. A total of 36 specific-pathogen-free Kunming mice were used to establish a PAD model and were randomly assigned into four groups: the experimental group (EG, administered Sini Decoction via gavage), the control group (CG, administered rapamycin via gavage), the model group (MG, administered 0.9% sodium chloride solution via gavage), and the normal group (NG, administered 0.9% sodium chloride solution via gavage). Serum inflammatory cytokines, mitochondrial autophagy-related proteins (LC3bII and p62), M1 macrophage markers (iNOS and COX2), key proteins in the mitochondrial autophagy pathway (PINK1 and Parkin), relative mitochondrial DNA (mtDNA) content, and mitochondrial function indicators [oxygen consumption rate (OCR) and extracellular acidification rate (ECAR)] were measured and analyzed. The serum levels of IL-6, IL-1β, TNF-α, IL-10, and MCP-1 were significantly decreased in both the EG and CG compared to the MG (P < 0.05), with the EG showing considerably greater reductions than the CG (P < 0.05). Compared with the CG, the EG exhibited significantly increased protein and mRNA expression levels of LC3bII, p62, iNOS, and COX2 (P < 0.05), considerably elevated mitochondrial OCR, and considerably reduced ECAR (P < 0.05). Additionally, the relative mtDNA content and the percentage of atherosclerotic lesion area were markedly lower in the EG than in the CG (P < 0.05). Moreover, the expression level of PINK1 and Parkin proteins were significantly increased in both the EG and CG compared to the MG (P < 0.05). Sini Decoction demonstrated superior efficacy in ameliorating PAD compared to the autophagy inducer rapamycin. Its therapeutic effects may be associated with the promotion of mitochondrial autophagy and the induction of M1 macrophage polarization.
    Keywords:  M1 macrophage polarization; Mitophagy; Peripheral artery disease; Serum inflammatory markers; Traditional chinese medicine sini decoction
    DOI:  https://doi.org/10.1007/s10863-025-10072-z
  23. Oncol Res. 2025 ;33(9): 2421-2434
    Pyrimethamine Inhibits Human Ovarian Cancer by Triggering Lethal Mitophagy via Activating the p38/JNK/ERK Pathway.
    Lingjuan Linghu, Hongying Zhou, Gang Zheng, Tao Yi.
       Objectives: Ovarian cancer, a leading cause of gynecological malignancy-related mortality, is characterized by limited therapeutic options and a poor prognosis. Although pyrimethamine has emerged as a promising candidate demonstrating efficacy in treating various tumors, the precise mechanisms of its antitumor effects remain obscure. This study was specifically designed to investigate the mode of action underlying the antitumor effects of pyrimethamine in preclinical settings.
    Methods: The effects of pyrimethamine on cellular proliferation were meticulously assessed using both the cell counting kit 8 (CCK-8) assay and the colony formation assay, with the effects further confirmed in a murine model. A confocal microscope was utilized to monitor the dynamic alterations in mitochondria within ovarian cancer cells. Additionally, adenosine triphosphate (ATP) and reactive oxygen species (ROS) assays were conducted to measure mitochondrial damage induced by pyrimethamine in ovarian cancer cell lines. The mitochondrial membrane potential was assessed using fluorescent dyes as an indicator of mitochondrial functional status. Furthermore, transcriptome analysis and immunohistochemical techniques were employed to detect the impact of pyrimethamine on ovarian cancer cells.
    Results: Our results demonstrated that pyrimethamine induced ovarian cancer cell death through mitochondrial dysfunction and lethal mitophagy. Transcriptome profiling analysis and Western blot demonstrated that activation of the p38/JNK/ERK signaling pathway was implicated in the process of pyrimethamine-induced mitophagy in ovarian cancer cells. Importantly, combination treatment with pyrimethamine and paclitaxel in vitro and in vivo showed a synergistic antitumor effect.
    Conclusions: Altogether, these findings indicate that the antitumor effects of pyrimethamine result from the induction of lethal mitophagy via regulation of the p38/JNK/ERK pathway in ovarian cancer. Considering the low toxicity and high tolerance associated with pyrimethamine, it is suggested that pyrimethamine be evaluated in the treatment of ovarian cancer, either as a monotherapy or in combination with paclitaxel.
    Keywords:  P38/JNK/ERK pathway; Pyrimethamine; drug repurposing; mitophagy; ovarian cancer
    DOI:  https://doi.org/10.32604/or.2025.063724
  24. Front Cell Dev Biol. 2025 ;13 1625474
    Mitochondrial dysfunction in diabetic ulcers: pathophysiological mechanisms and targeted therapeutic strategies.
    Yu Pan, Lin Chen, Yan Chen, Elizabeth Rosalind Thomas, Shiying Zhou, You Yang, Kezhi Liu, Jianming Wu, Xiang Li.
      Diabetic foot ulcers (DFUs) are a serious complication of diabetes, characterized by delayed wound healing, recurrent infection, and risk of amputation. Mitochondrial dysfunction has emerged as a central pathological mechanism underlying impaired wound healing. Persistent hyperglycemia triggers a cascade of mitochondrial abnormalities like disrupted calcium homeostasis, excessive ROS production, impaired autophagy, increased apoptosis, and imbalanced mitochondrial dynamics. These alterations hinder ATP production, damage repair cells and delays tissue regeneration. This review comprehensively explores the mechanism of action of oxidative stress, mitochondrial apoptosis, autophagy dysfunction, calcium imbalance and ferroptosis on DFU pathogenesis. It also highlights promising mitochondrial targeted therapies. As mitochondria regulates key cellular processes, targeting mitochondrial dysfunction represents a novel and promising strategy. Future research should focus on integrated approaches to restore mitochondrial homeostasis in diabetic wound healing.
    Keywords:  ROS; apoptosis; diabetes; mitochondria; trauma
    DOI:  https://doi.org/10.3389/fcell.2025.1625474
  25. Front Pharmacol. 2025 ;16 1629709
    Spotlight on USP30: structure, function, disease and target inhibition.
    Jiapeng Du, Yiyang Gao, Guoqing Xue, Zhuoyue Zhao, Ying Yang, Peng Chu, Xingping Duan.
      This review comprehensively summarizes the current understanding of ubiquitin-specific protease 30 (USP30), covering its structural characteristics, functions in cellular processes, associations with diseases, diagnostic and therapeutic strategies, as well as controversies and future perspectives. USP30, a deubiquitinating enzyme, plays crucial roles in mitochondrial quality control, autophagy regulation, and cellular homeostasis. It is implicated in the progression of several malignancies, including hepatocellular carcinoma, breast carcinoma, and glioblastoma, as well as neurodegenerative disorders such as Parkinson's disease. This involvement is mediated through its regulation of mitochondrial autophagy, stabilization of oncoproteins like Snail and c-Myc, and facilitation of metabolic reprogramming. Inhibition of USP30 has demonstrated potential in reversing the malignant phenotype of tumors and enhancing neuroprotection, highlighting its promise as a versatile therapeutic target. Pharmacological inhibition of USP30, using agents such as S3, MF-094, and FT3967385, enhances ubiquitination and reactivates mitophagy, indicating potential therapeutic benefits in preclinical models. The development of USP30-targeted therapies holds promise but also faces challenges. Further research on USP30 is expected to provide new insights into disease mechanisms and therapeutic interventions.
    Keywords:  USP30; disease; signaling pathway; structure; target inhibition
    DOI:  https://doi.org/10.3389/fphar.2025.1629709
  26. Front Biosci (Landmark Ed). 2025 Aug 27. 30(8): 27634
    The Role of Phospholipids in Mitochondrial Dynamics and Associated Diseases.
    Solenn Plouzennec, Juan Manuel Chao de la Barca, Arnaud Chevrollier.
      The bioenergetic machinery of the cell is protected and structured within two layers of mitochondrial membranes. The mitochondrial inner membrane is extremely rich in proteins, including respiratory chain complexes, substrate transport proteins, ion exchangers, and structural fusion proteins. These proteins participate directly or indirectly in shaping the membrane's curvature and facilitating its folding, as well as promoting the formation of nanotubes, and proton-rich pockets known as cristae. Recent fluorescent super-resolution images have demonstrated the strong dynamics of these events, with constant remodeling processes. The mitochondrial outer membrane itself is also highly dynamic, interacting with the endoplasmic reticulum and its environment to ensure a rapid diffusion of surface components throughout the mitochondrial networks. All these movements occur besides migration, fusion, and fission of the mitochondria themselves. These dynamic events at the level of mitochondrial membranes are primarily dependent on their unique lipid composition. In this review, we discuss the latest advances in phospholipid research, focusing on their metabolism and role in mitochondrial dynamics. This process emphasizes the importance of interactions with the endoplasmic reticulum and mitochondrial matrix enzymes, extending its relevance to lipid sources, in particular, cardiolipins and phosphatidylethanolamines at the cellular, tissue and even whole-organism level. Given the expanding array of characterized mitochondrial functions, ranging from calcium homeostasis to inflammation and cellular senescence, research in the field of mitochondrial lipids is particularly significant. As mitochondria play a central role in various pathological processes, including cancer and neurodegenerative disorders, lipid metabolism may offer promising therapeutic approaches.
    Keywords:  dynamic; lipids; membrane; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.31083/FBL27634
  27. Exp Eye Res. 2025 Sep 08. pii: S0014-4835(25)00403-8. [Epub ahead of print] 110632
    Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.
    Hetong Sun, Bin Li, Yu Gu, Fei Li, Guohu Di, Peng Chen.
      Mitochondria play a crucial role in energy production and are intimately associated with ocular function. Mitochondrial dysfunction can trigger oxidative stress and inflammation, adversely affecting key ocular structures such as the lacrimal gland, lens, retina, and trabecular meshwork. This dysfunction may compromise the barrier properties of the trabecular meshwork, impeding aqueous humour outflow, elevating intraocular pressure, and resulting in optic nerve damage and primary open-angle glaucoma. Additionally, impaired mitochondrial homeostasis can contribute to dry eye, cataracts, and age-related macular degeneration (AMD) by disrupting the function of the lacrimal gland, lens, and macula. Imbalanced mitochondrial homeostasis primarily involves four pathological features: disruption of mitochondrial quality control, mitochondrial damage (inducing inflammation), excessive production of mitochondrial reactive oxygen species (ROS) (initiating oxidative stress), and disturbances in mitochondrial calcium (Ca2+) homeostasis. Oxidative stress and inflammation are central mechanisms of cellular injury. Pharmacological strategies aimed at reducing excessive ROS, restoring redox balance, and mitigating oxidative and inflammatory damage show therapeutic promise. Moreover, enhancing mitochondrial function through pharmacological agents, replacing damaged mitochondria, and promoting mitochondrial rejuvenation represent emerging treatment avenues. This review explores the relationship between mitochondrial dysfunction and ocular diseases such as dry eye, glaucoma, cataracts, and AMD, with a focus on associated mechanisms and potential therapeutic interventions.
    Keywords:  AMD; Cataracts; Dry eye; Glaucoma; Mitochondrial Dysfunction; Oxidative Stress; Targeted Therapy
    DOI:  https://doi.org/10.1016/j.exer.2025.110632
  28. Food Res Int. 2025 Nov;pii: S0963-9969(25)01424-3. [Epub ahead of print]219 117086
    EPA-enriched phospholipids and DHA-enriched phospholipids prevent dexamethasone-induced skeletal muscle atrophy via regulating protein turnover and mitochondrial quality.
    Ying-Chao Li, Shi-Xiang Wu, Qing-Yan Zou, Yan Zheng, Zi-Jian Wu, Xin-Yue Zhao, Xiang Gao, Yu-Hong Yang, Lei Du.
      The present study aimed to investigate the protective effects and underlying mechanisms of EPA-enriched phospholipids (EPA-PL) and DHA-enriched phospholipids (DHA-PL) against dexamethasone (DEX)-induced skeletal muscle atrophy both in vitro and in vivo. Results revealed that EPA-PL and DHA-PL significantly attenuated DEX-induced reduction in C2C12 myotube diameter. Additionally, supplementation with 1 % EPA-PL or 1 % DHA-PL for 6 weeks effectively alleviated DEX-induced declines in grip strength, skeletal muscle mass, and myofiber cross-sectional areas in mice. Data also manifested that EPA-PL and DHA-PL exerted strong roles on improving skeletal muscle protein turnover in DEX-treated mice, as evidenced by suppressing forkhead box O3a (FoxO3a)-mediated proteolysis, and enhancing protein synthesis via activation of the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Moreover, EPA-PL and DHA-PL notably reduced DEX-induced excessive reactive oxygen species accumulation and apoptosis in skeletal muscle, likely due to their ability to mitigate mitochondrial damage. The mechanisms underlying the attenuation of DEX-induced mitochondrial damage by EPA-PL and DHA-PL may be attributed to their role in improving mitochondrial quality through the regulation of molecular signals involved in mitochondrial biogenesis, dynamics, and mitophagy. Overall, EPA-PL and DHA-PL could serve as promising functional ingredients for preventing skeletal muscle atrophy.
    Keywords:  DHA-enriched phospholipids; Dexamethasone; EPA-enriched phospholipids; Mitochondrial quality; Protein turnover; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.foodres.2025.117086
  29. Front Physiol. 2025 ;16 1640735
    Fu's subcutaneous needling facilitates muscle repair by regulating mitochondrial homeostasis in rat with chronic peripheral nervous pain.
    Po-En Chiu, Zhonghua Fu, Hung-Chuan Pan, Yi-Ching Tsai, Chia-Yun Tsai, Wei-Jen Hsu, Li-Wei Chou, De-Wei Lai.
      Sciatica, often resulting from lumbar disc herniation or nerve compression, disrupts electrical signal transmission, leading to muscle atrophy, mitochondrial dysfunction, and impaired energy metabolism. This study explored the therapeutic effects of Fu's subcutaneous needling (FSN) in a chronic constriction injury (CCI) rat model, assessing its impact on neuropathic pain, muscle mass, and structural integrity. Histological and ultrastructural analyses demonstrated that FSN alleviated hypersensitivity, reduced muscle atrophy, preserved mitochondrial density, and maintained glycogen storage. Gene expression and pathway enrichment analyses revealed FSN's involvement in PI3K-Akt, MAPK signaling, oxidative phosphorylation, and mitophagy, suggesting its role in modulating energy metabolism and cellular repair. FSN also normalized energy-related proteins FGFR1, FGFR3 and phosphorylated FOXO3, highlighting their significance in muscle repair and regeneration. These findings provide novel insights into FSN's potential for counteracting neuropathy-induced muscle damage and improving mitochondrial function, supporting its clinical application. Additionally, FSN's role in muscle repair suggests a connection between growth factor signaling and nerve regeneration, offering a foundation for future research on muscle-neural recovery mechanisms.
    Keywords:  Fu’s subcutaneous needling; chronic constriction injury; gastrocnemius muscles; mitophagy; vastus lateralis
    DOI:  https://doi.org/10.3389/fphys.2025.1640735
  30. Cell Signal. 2025 Sep 06. pii: S0898-6568(25)00529-7. [Epub ahead of print] 112114
    Lycium barbarum alleviates oxidative stress-induced ferroptosis and enhances mitophagy in intervertebral disc degeneration.
    Haicheng Dou, Yutao Chen, Jiaoxiang Chen, Yuxuan Zhu, Shu Yang, Yingzhao Yan, Yan Lin, Sunli Hu.
      Lycium barbarum is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions, such as antioxidation, neuroprotection, and immune modulation. The therapeutic effect of Lycium barbarum on intervertebral disc degeneration (IVDD) has not been conclusively established. In our study, we investigated the mechanisms of Lycium barbarum extract (LBE) using Network pharmacology and bioinformatic analyses. In vitro experiments, the levels of ferroptosis were assessed using Western blot analysis and detection kits for MDA, Ferric iron and GSH. Transmission electron microscopy and Mitotracker were used to detect mitochondrial morphology. Immunofluorescence and Western blot were employed to detect the levels of mitophagy and lysosomal permeability. In vivo experiments, X-ray imaging, morphological staining, and immunohistochemical staining were used to assess the degree of intervertebral disc degeneration. As a result of the intersection between target genes of complex compounds and disease-related genes, 61 overlapping genes were identified, with PTGS2 ranking as the top overlapping gene. Molecular docking revealed that six compounds were highly stable in the Cys41 active site pocket of PTGS2. Moreover, LBE exhibited potential therapeutic effects through inhibiting mitochondrial dysfunction and ferroptosis. Besides, LBE can reduce lysosomal membrane permeability and enhance mitophagy caused by oxidative stress via regulating phosphatidylinositol metabolism. The administration of LBE in vivo can effectively slow the progression of intervertebral disc degeneration. The findings of this study suggest that LBE exhibits maybe a potential therapeutic candidate for intervertebral disc degeneration.
    Keywords:  Ferroptosis; Intervertebral disc degeneration; Lycium barbarum extract; Mitophagy; PTGS2
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112114
  31. Int Immunopharmacol. 2025 Sep 10. pii: S1567-5769(25)01517-6. [Epub ahead of print]165 115526
    Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages.
    Ting Liu, Weidong Zhang, Wenzheng Bao, Xiaorui Wang, Fan Zhang, Jie Guo, Minqi Li.
      Alzheimer's disease (AD) is associated with progressive bone loss, but the underlying mechanisms remain unclear. This study focused on how amyloid-β (Aβ) disrupted bone vascular homeostasis by impairing macrophage efferocytosis in APP/PS1 mice. We found that Aβ accumulation in bone tissue impaired MerTK-mediated macrophage efferocytosis and promoted excessive accumulation of apoptotic endothelial cells (ECs). Mechanistically, Aβ triggered excessive mitochondrial fission via GSK-3β-mediated DRP1 phosphorylation, resulting in elevated reactive oxygen species (ROS) and subsequent ADAM17 activation. ADAM17 cleaved MerTK, a critical efferocytosis receptor, impairing apoptotic cells (ACs) clearance. Pharmacological inhibition of GSK-3β (LiCl and TDZD-8) or mitochondrial fission (Mdivi-1) restored MerTK expression, improved efferocytosis, and reduced inflammatory cytokine release (such as TNF-α, IL-6), while enhancing vascular endothelial growth factors (VEGFs). In vivo, LiCl treatment ameliorated bone loss and vascular dysfunction in APP/PS1 mice. These findings revealed that Aβ disrupted the mitochondrial fission-efferocytosis axis in macrophages, contributing to AD-related bone pathology, and highlighted GSK-3β as a potential therapeutic target for preserving bone vascular homeostasis in AD.
    Keywords:  ADAM17; Alzheimer's disease; Bone loss; Efferocytosis; GSK-3β; MerTK; Mitochondrial fission
    DOI:  https://doi.org/10.1016/j.intimp.2025.115526
  32. Redox Biol. 2025 Sep 04. pii: S2213-2317(25)00372-6. [Epub ahead of print]86 103859
    Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
    Nada Ahmed Selim, Andrew P Wojtovich.
      Mitochondria are central to cellular function, acting as metabolic hubs that regulate energy transduction to communicate cellular status. A key component of this energetic regulation is the mitochondrial membrane potential (MMP), a charge separation across the inner mitochondrial membrane generated by the electron transport chain. Beyond MMP's canonical role in driving ATP synthesis, MMP acts as a dynamic signaling hub. MMP rapidly adjusts to acute changes in cellular energy demand and undergoes sustained modifications during developmental processes, such as neuronal remodeling. Changes in MMP influence reactive oxygen species (ROS) production, calcium handling, and mitochondrial quality control, enabling localized and time-sensitive regulation of cellular function. In neurons, changes in MMP coordinate synaptic plasticity by linking metabolic state to structural changes at synapses. This review highlights the non-canonical roles of MMP in signal integration, spatial organization, and stress adaptation, providing a broader framework for understanding mitochondrial contributions to health and disease.
    Keywords:  Bioenergetics; Metabolic specialization; Mitochondria; Mitophagy; Neuron plasticity
    DOI:  https://doi.org/10.1016/j.redox.2025.103859
  33. Neurochem Res. 2025 Sep 11. 50(5): 297
    Salidroside Attenuates Cerebral Ischemia-Reperfusion Injury via ERβ/BNIP3-Mediated Mitochondrial Autophagy Activation in a Rat Model.
    Xing Rong, Peipei Lu, Yu Li, Hongxiang Wang, Yuanjia Yue, Huimin Wang, Zhao Ji, Lin Jiang.
      This study aimed to assess the neuroprotective effects of salidroside (SAL) on cerebral ischemia-reperfusion injury (CIRI) in a rat model and to elucidate the underlying mechanisms, with a focus on the role of estrogen receptor beta (ERβ) and BCL2 interacting protein 3 (BNIP3)-mediated mitochondrial autophagy as potential therapeutic targets in ischemic stroke. A total of 165 female Sprague-Dawley rats were randomly assigned into 11 groups (n = 15 per group). One group served as the control. The remaining animals underwent bilateral ovariectomy and were subsequently allocated into the following groups: ovariectomy-only, middle cerebral artery occlusion/reperfusion (MCAO/R), estradiol control, ERβ inhibitor, two inhibitor arms (inhibitor-only and inhibitor-plus-SAL), three SAL treatment groups (low, mediummitochondrial division, high dose), and a positive control (edaravone). All groups, except the control and ovariectomy-only groups, were subjected to MCAO for one hour followed by 24 h of reperfusion. Neurological function, cerebral infarct volume, blood-brain barrier (BBB) permeability, and brain water content were evaluated. Histopathological alterations were assessed, and transmission electron microscopy was employed to detect autophagosomes. Western blot analysis was performed to quantify protein expression levels of ERβ, BNIP3, NIP3-like protein X, and microtubule-associated protein 1 A/1B-light chain 3. Administration of SAL and edaravone significantly reduced neurological impairment, infarct volume, BBB disruption, and cerebral edema in the MCAO/R model. SAL treatment upregulated ERβ and BNIP3 expression and enhanced mitochondrial autophagy-associated protein levels. These effects were attenuated by the use of ERβ and mitochondrial division inhibitors, indicating a mechanistic link between SAL-mediated neuroprotection and activation of the ERβ/BNIP3 signaling axis. SAL exerts a neuroprotective effect against CIRI in rats, primarily through activation of ERβ and enhancement of BNIP3-mediated mitochondrial autophagy. These findings suggest that modulation of the ERβ/BNIP3 pathway may represent a promising therapeutic approach for ischemic stroke.
    Keywords:  BNIP3; Cerebral ischemia; ERβ; Mitochondrial autophagy; Salidroside
    DOI:  https://doi.org/10.1007/s11064-025-04535-3
  34. Mycotoxin Res. 2025 Sep 08.
    Correction: The PGC-1α/SIRT3 pathway mediates the effect of DON on mitochondrial autophagy and liver injury in mice.
    Yihan Wang, Jiali Fu, Danni Zhou, Zhihua Ren, Junliang Deng.
      
    DOI:  https://doi.org/10.1007/s12550-025-00606-0
  35. Int J Mol Sci. 2025 Aug 25. pii: 8245. [Epub ahead of print]26(17):
    NR3C1/GLMN-Mediated FKBP12.6 Ubiquitination Disrupts Calcium Homeostasis and Impairs Mitochondrial Quality Control in Stress-Induced Myocardial Damage.
    Jingze Cong, Lihui Liu, Rui Shi, Mengting He, Yuchuan An, Xiaowei Feng, Xiaoyu Yin, Yingmin Li, Bin Cong, Weibo Shi.
      Excessive stress disrupts cardiac homeostasis via complex and multifactorial mechanisms, resulting in cardiac dysfunction, cardiovascular disease, or even sudden cardiac death, yet the underlying molecular mechanisms remain poorly understood. Accordingly, we aimed to elucidate how stress induces calcium dysregulation and contributes to cardiac dysfunction and injury through the nuclear receptor subfamily 3 group c member 1 (NR3C1)/Glomulin (GLMN)/FK506-binding protein 12.6 (FKBP12.6) signaling pathway. Using mouse models of acute and chronic restraint stress, we observed that stress-exposed mice exhibited reduced left ventricular ejection fraction, ventricular wall thickening, elevated serum and myocardial cTnI levels, along with pathological features of myocardial ischemia and hypoxia, through morphological, functional, and hormonal assessments. Using transmission electron microscopy and Western blotting, we found that stress disrupted mitochondrial quality control in cardiomyocytes, evidenced by progressive mitochondrial swelling, cristae rupture, decreased expression of fusion proteins (MFN1/OPA1) and biogenesis regulator PGC-1α, along with aberrant accumulation of fission protein (FIS1) and autophagy marker LC3. At the cellular level, ChIP-qPCR and siRNA knockdown confirmed that stress activates the glucocorticoid receptor NR3C1 to repress its downstream target GLMN, thereby preventing FKBP12.6 ubiquitination and degradation, resulting in calcium leakage and overload, which ultimately impairs mitochondrial quality control and damages cardiomyocytes. In conclusion, our findings reveal that stress induces myocardial damage through NR3C1/GLMN-mediated FKBP12.6 ubiquitination, disrupting calcium homeostasis and mitochondrial quality control, and lay a theoretical foundation for dissecting the intricate molecular network of stress-induced cardiomyopathy.
    Keywords:  calcium ions; mitochondrion; myocardial injury; stress
    DOI:  https://doi.org/10.3390/ijms26178245
  36. J Mol Histol. 2025 Sep 13. 56(5): 313
    Neuroprotection in neonatal Hypoxia-ischaemia: melatonin targets NCX1 to inhibit mitochondrial autophagy via the PINK1-Parkin pathway.
    Tongfei Cheng, Shanlong Du, Yi Cao, Ziyan Lu, Yingjun Xu.
       OBJECTIVE: Hypoxic ischaemic (HI) damage is a major cause of white matter damage (WMD) in the brains of newborns, especially preterm infants; early neuroprotection is essential to improve cognitive outcomes. This study aimed to investigate the effect of melatonin on nerve injury by inhibiting mitochondrial autophagy.
    METHODS: We established a neonatal WMD model through HI induction in postnatal day 3 (P3) Sprague-Dawley (SD) rats. Following four days of intraperitoneal melatonin administration (10 mg/kg/d), temporal changes in expression of sodium-calcium exchanger 1 (NCX1), myelin integrity markers (myelin-associated glycoprotein [MAG]/proteolipid protein [PLP]), and mitophagy-related proteins (microtubule-associated protein 1 light chain 3β [LC3β], PTEN-induced kinase 1 [PINK1], and Parkin RBR E3 ubiquitin-protein ligase [Parkin]) were systematically quantified. Neuronal hyperexcitability was evaluated by whole-cell patch-clamp recordings, whereas myelin pathology was assessed by luxol fast blue (LFB) staining, and mitochondrial ultrastructures were evaluated by transmission electron microscopy. Cognitive recovery was determined using Morris water maze testing at postnatal day 28.
    RESULTS: Our results demonstrated that rats subjected to HI presented biphasic alterations in NCX1 expression, characterised by transient upregulation on day 7 followed by a progressive decline (P < 0.001). Concurrently, expression of mitochondrial autophagy markers (LC3β, PINK1, and Parkin) was significantly increased (P < 0.001). Histological analysis revealed distinct mitochondrial structural damage and autophagosome formation. Electrophysiological measurements revealed increased neuronal excitability (P < 0.05), which was correlated with spatial learning and memory deficits. Although melatonin treatment effectively attenuated these pathological alterations, subsequent pharmacological inhibition of NCX1 via SN6 administration in melatonin-treated rats resulted in the recurrence of mitochondrial ultrastructural abnormalities and the reactivation of autophagic pathways.
    CONCLUSION: Melatonin attenuated activation of the PINK1-Parkin-dependent mitochondrial autophagy pathway in neonatal rats with HI-induced WMD through mediating the dynamic expression of NCX1. This intervention effectively reduced neuronal hyperexcitability, ameliorated demyelinating lesions, and improved long-term learning and cognitive functions.
    CLINICAL TRIAL REGISTRATION: Not applicable.
    Keywords:  Hypoxia–ischaemia; Melatonin; Mitochondria; Neuronal excitability; Newborn
    DOI:  https://doi.org/10.1007/s10735-025-10601-5
  37. Tissue Cell. 2025 Sep 09. pii: S0040-8166(25)00415-X. [Epub ahead of print]98 103133
    Investigation of the effects of resveratrol, lutein, and crocetin on ARPE-19 cells induced with oxidative damage by H2O2.
    Ayşegül Yabaş, Veysel Levent Karabaş, Selenay Furat, Ecem Önder Tokuç, Ahmet Öztürk, Candan Altuntaş, Özgür Doğa Özsoy, Gökhan Duruksu, Yusufhan Yazır.
       OBJECTIVE: This study aimed to evaluate and compare the antioxidant effects, influence on autophagy and mitophagy, and impact on cell viability of resveratrol, lutein, and crocetin in hydrogen peroxide (H₂O₂)-induced oxidative damage in ARPE-19 cells as an in vitro model of age-related macular degeneration (AMD).
    METHODS: Oxidative damage was induced in ARPE-19 cells by exposure to 800 μM H₂O₂ for 1 h. Cell viability was assessed using the WST-1 assay. Subsequently, ARPE-19 cells were treated with lutein (5 and 10 μM), crocetin (10 and 20 μM), or resveratrol (100 μM), and the levels of oxidative damage biomarkers including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were quantified via spectrophotometry. The autophagy- and mitophagy-related markers, LC3B, PINK1, and PARKIN, were visualized using confocal microscopy, and LC3B and PARKIN were further evaluated by western blotting (WB).
    RESULTS: Cell viability results were 100 % in the control group, decreased to 73.5 % and 69.1 % with 10 and 20 μM crocetin, 62.7 % and 59.3 % with 5 and 10 μM lutein, and 52.7 % with 100 μM resveratrol, respectively, while H₂O₂ exposure reduced viability to 0.04 %. Exposure to H₂O₂ (800 µM, 1 h) induced significant oxidative damage in ARPE-19 cells, as indicated by a reduction in GSH levels (p < 0.01) and an increase in MDA (p < 0.001) and NO (p < 0.001) compared to the control group, along with a notable decrease in WST-1 viability. Among the interventions, 10 µM crocetin significantly decreased MDA (p = 0.019) and NO (p = 0.05) levels compared to those in the damage group, although the 20 µM concentration also reduced these markers without achieving statistical significance. 5 µM Lutein significantly reduced NO levels compared to the damage group, whereas reductions in MDA at concentrations of 5-10 µM were not statistically significant. GSH levels exhibited a numerical, albeit non-significant, increase with 10 µM lutein (p = 0.09), and showed modest, non-significant increases with crocetin and resveratrol. The highest LC3B expression was observed in the 5 μM lutein group compared to control and other treatment groups, while PARKIN expression was significantly elevated in the 10 μM lutein, 20 μM crocetin, and 100 μM resveratrol groups, with 20 μM crocetin and resveratrol levels also exceeding lutein 5 μM.
    CONCLUSIONS: 10 μM Crocetin demonstrated the strongest antioxidant protection, while 5 μM lutein primarily improved cell survival, likely through autophagy activation and 100 μM resveratrol also activated both autophagy and mitophagy. These results highlighted the complementary concentration-dependent mechanisms of natural antioxidants in protecting RPE cells from oxidative stress related to AMD.
    Keywords:  ARPE-19 cells; Autophagy; Crocetin; Lutein; Mitophagy; Resveratrol
    DOI:  https://doi.org/10.1016/j.tice.2025.103133
  38. Autophagy. 2025 Sep 09. 1-22
    KDM4A-induced tumor senescence enhances the efficacy of immunotherapy by inhibiting AGT-PHB1 axis-mediated mitophagy in colorectal cancer.
    Tanxing Cai, Zhenxing Liang, Zhiping Chen, Yang Li, Wei Xiao, Wenfeng Liang, Hao Xie, Huashan Liu, Ziwei Zeng, Xin Yang, Shuanglin Luo, Xiaobin Zheng, Keli Zhong, Liang Huang, Li Xiong, Liang Kang.
      Immune checkpoint inhibitors (ICIs) can re-active the immune response and induce a complete response in mismatch repair-deficient and microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, most CRCs exhibit proficient mismatch repair and microsatellite stable (pMMR/MSS) phenotypes with limited immunotherapy response because of sparse intratumoral CD8+ T-lymphocyte infiltration. Cellular senescence has been reported to involve immune cell infiltration through a senescence-associated secretory phenotype (SASP). However, the relationship between CRC cellular senescence and CD8+ T-lymphocyte infiltration remains unclear. Through integrated analysis of clinical cohorts and transcriptomic data across mismatch repair (MMR) subtypes, we identified cellular senescence as a hallmark of dMMR tumors, accompanied by elevated expression of KDM4A (lysine demethylase 4A). Clinically, KDM4Ahigh CDKN2A/p16high expression correlated with improved CRC patient prognosis. Mechanistically, KDM4A upregulated AGT (angiotensinogen) expression through H3K9me3 demethylation and promoted CRC cellular senescence. Meanwhile, KDM4A-driven senescence suppressed tumor growth and enhanced intratumoral CD8+ T-lymphocyte infiltration via enhancing SASP-associated secretion. Furthermore, AGT disrupted PHB1 (prohibitin 1)-mediated basal mitophagy, triggering cytoplasmic mitochondrial DNA (mtDNA) accumulation that activated CGAS-STING1 signaling and enhanced SASP secretion. Crucially, KDM4A overexpression potentiated anti-PDCD1/PD1 efficacy in MSI-H CRC and reversed therapy resistance in MSS CRC. Conclusively, we established a KDM4A-AGT-PHB1 (KAP) grade system that robustly predicts immunotherapy responsiveness in pMMR CRC patients.Abbreviation: AGT: angiotensinogen; BafA: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRC: colorectal cancer; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CHX: cycloheximide; Co-IP: co-immunoprecipitation; dMMR: deficient mismatch repair; EdU: 5-ethynyl-2'-deoxyuridine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IL6: interleukin 6; IL8: interleukin 8; IHC: immunohistochemical; KDM4A: lysine demethylase 4A; mtDNA: mitochondrial DNA; MS: mass spectrometry; NFKB/NF-κB: nuclear factor kappa B; PHB1: prohibitin 1; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; pMMR: proficient mismatch repair; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; SASP: senescence-associated secretory phenotype; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TRIM21: tripartite motif containing 21; TUBB/beta-tubulin: tubulin beta class I.
    Keywords:  Cellular senescence; KDM4A; colorectal cancer; immunotherapy; mismatch repair; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2551680
  39. RSC Med Chem. 2025 Aug 01.
    Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
    Pradeep Kodam, Vaishali Kumar, Paramita Pattanayak, Praharsh Vitta, Tanmay Chatterjee, Shuvadeep Maity.
      Mitochondrial dysfunction is one of the primary cellular conditions involved in developing Huntington's disease (HD) pathophysiology. The accumulation of mutant huntingtin protein with abnormal PolyQ repeats resulted in the death of striatal neurons with enhanced mitochondrial fragmentation. In search of neuroprotective molecules against HD conditions, we synthesized a set of isoxazole-based small molecules to screen their suitability as beneficial chemicals improving mitochondrial health. Systematic characterization of one of these isoxazole derivatives, C-5, demonstrated improved mitochondrial health with reduced apoptosis via rebalancing fission-fusion dynamics in HD condition. Gene and protein expression analysis confirmed that C-5 treatment enhanced the expression of mitochondrial fusion regulators (MFN1/2) via transcriptional upregulation of PGC-1α, a transcriptional co-activator controlling mitochondrial biogenesis. Collectively, this novel fusion agonist can potentially become a new therapeutic alternative for treating PolyQ-mediated mitochondrial dysfunction, a hallmark of HD pathology.
    DOI:  https://doi.org/10.1039/d5md00345h
  40. Chembiochem. 2025 Sep 11. e202500551
    Mitochondrial ClpX Inhibition Induces Ferroptosis and Blocks Pancreatic Cancer Cell Proliferation.
    Pengyu Wang, Ranran Zhang, Yihui Pan, Wei Wu, Tao Zhang, Cai-Guang Yang.
      The ATPase caseinolytic protease X (ClpX), forming the ClpXP complex with caseinolytic protease P (ClpP), is essential for mitochondrial protein homeostasis. While ClpP targeting is a recognized anticancer strategy, the role of ClpX in cancer remains underexplored. In pancreatic ductal adenocarcinoma (PDAC), elevated CLPX expression correlates with poor prognosis, suggesting its oncogenic function. CLPX knockdown disrupts mitochondrial homeostasis, and reduces oxidative phosphorylation, thus leading to mitochondrial dysfunction and impaired PDAC cell proliferation. The ClpX-mediated mitochondrial dysfunction induces oxidative stress, unfolded protein response (UPR), and ferroptosis, which is evidenced by increased reactive oxygen species, ferrous iron, lipid peroxidation, and malondialdehyde levels. Screening ATPase inhibitors identifies MSC1094308 as a hit compound for ClpX inhibition, which suppresses ClpXP activity and induces UPR and ferroptosis in PDAC cells. These findings highlight ClpX inhibition as a promising therapeutic strategy for PDAC.
    Keywords:  ClpX; ferroptosis; inhibitor; mitochondria; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1002/cbic.202500551
  41. Appl Biochem Biotechnol. 2025 Sep 11.
    Electrical Vagus Nerve Stimulation Ameliorates Cardiac Ischemia and Reperfusion Injury by Improving Mitochondrial Biogenesis Through the SIRT1/PGC-1α Pathway.
    Yingqiang Guo, Yu Zhang, Jinzhou Zhang, Xingwan Bai, Wei Kang, Yujie Guo, Xianming Zeng.
      Vagus nerve stimulation (VNS) has demonstrated cardioprotective effects in a variety of cardiovascular diseases, including cardiac ischemia and reperfusion (IR) injury. However, the mechanisms responsible for these effects have not been completely understood. The present work aimed to uncover the potential mechanisms through which VNS confers protection against cardiac IR injury. Rats subjected to cardiac IR injury received electrical VNS through the right cervical vagus nerve. This intervention led to a notable reduction in cardiac dysfunction and injury, as well as decreased cardiac apoptosis, oxidative stress, and inflammation. Moreover, VNS treatment improved mitochondrial biogenesis by upregulating estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and transcriptional factor A mitochondrial (TFAM). In addition, VNS treatment not only increased the copy number of mitochondrial DNA (mtDNA) and the content of adenosine triphosphate (ATP), but also effectively reduced mitochondrial damage. VNS also upregulated the expression of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in IR-injured hearts. Inhibition of either SIRT1 or PGC-1α significantly reversed the effects of VNS on mitochondrial biogenesis and abolished its cardioprotective benefits. Notably, VNS increased the level of acetylcholine (ACh) in IR-injured hearts. Administration of atropine, a muscarinic ACh receptor (mAChR) antagonist, counteracted the effects of VNS on the SIRT1/PGC-1α pathway, mitochondrial biogenesis, and the associated cardioprotective outcomes. These findings suggest that VNS protects against cardiac I/R injury by enhancing mitochondrial biogenesis. This beneficial effect of VNS on mitochondrial biogenesis is attributed to activation of the SIRT1/PGC-1α pathway through the ACh/mAChR axis. Therefore, this research offers fresh perspectives on the mechanisms underlying the cardioprotective effects of VNS.
    Keywords:  Acetylcholine; Cardiac ischemia and reperfusion injury; Mitochondrial biogenesis; Mitochondrial damage; Vagus nerve stimulation
    DOI:  https://doi.org/10.1007/s12010-025-05359-1
  42. Behav Brain Res. 2025 Sep 05. pii: S0166-4328(25)00392-4. [Epub ahead of print]495 115805
    Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway.
    Weigang Luo, Wei Bu, Guisong Zhang, Yujuan Dong, Yuling Wang, Jinyang Wang, Cuicui Liu, Xiaokai Hu, Yanan Jia, Huiling Ren.
       BACKGROUND: Mitochondrial dysfunction is considered to be an important pathogenesis of cognitive impairment in Alzheimer's disease(AD). Activation of Nrf2 can improve cognitive impairment in AD mice, but the underlying mechanism remains to be elucidated. This research aims to investigate the intrinsic molecular mechanism of Nrf2 in mitochondrial biogenesis related to cognitive impairment of AD mice.
    METHODS: APP/PS1 mice were used as AD model mice, and Nrf2 down-regulated mouse model was established by injecting lentivirus into hippocampus. Morris water maze test was used to evaluate the learning and memory ability of mice. The biochemical assays were used to detect the expression of Nrf2, mitochondrial biogenesis-related genes, and Aβ protein.Transmission electron microscopy was used to observe the number of mitochondria and synaptic structure in neurons. Chromatin immunoprecipitation was used to observe the binding of Nrf2 protein to the PGC1α promoter; Co-Immunoprecipitation was used to observe the interaction between PPARγ protein and PGC1α protein.
    RESULTS: Downregulation of Nrf2 reduced mitochondrial biogenesis, aggravated Aβ protein deposition and synaptic damage, and in turn aggravated cognitive impairment in mice. Compared with control mice, AD model mice had reduced levels of Nrf2, PPARγ, PGC1α, NRF1, TFAM protein, mitochondrial number and MAP2, increased Aβ protein deposition, and worsened synaptic damage and cognitive impairment. Lentivirus-induced Nrf2 downregulation downregulates PPARγ, PGC1α, NRF1, and TFAM protein expression, reduces mitochondrial number and MAP2 levels, and aggravates Aβ protein deposition, synaptic damage, and cognitive impairment. Nrf2 protein bound to the PGC1α gene promoter, and PPARγ protein interacted with PGC1α protein.
    CONCLUSION: Nrf2 can directly regulate PGC1α transcription, and can also regulate PPARγ followed by binding to the PGC1α protein, thereby modulating mitochondrial biogenesis.Nrf2 downregulation reduces the expression of PPARγ and PGC1α proteins, thereby reducing their interaction. This suppression impairs mitochondrial biogenesis, exacerbates mitochondrial dysfunction, intensifies Aβ deposition and synaptic damage, and ultimately worsens cognitive impairment in AD mice.
    Keywords:  Alzheimer's disease; Cognitive impairment; Mitochondrial biogenesis; Nrf2; PGC1α; PPARγ
    DOI:  https://doi.org/10.1016/j.bbr.2025.115805
  43. Cancer Res. 2025 Sep 10.
    Parkin Induces Ubiquitination and Large Extracellular Vesicle Release of HMGB1 to Activate Antitumor Immunity.
    Minjeong Yeon, Michela Perego, Khaled M Elokely, Magid Abou-Gharbia, Wayne E Childers, Andrew T Milcarek, Irene Bertolini, Hsin-Yao Tang, Lucia R Languino, Gary S Stein, Prachi N Ghule, Brad P Vietje, Douglas T Taatjes, Dario C Altieri.
      Parkin is a mitochondria-associated E3 ubiquitin (Ub) ligase that mediates mitophagy and organelle quality control. More recently, Parkin has been implicated in stimulating antitumor immunity and reprogramming the tumor immune microenvironment. Here, we showed that Parkin ubiquitinates the alarmin molecule, high mobility group box-1 (HMGB1) on Lys146 (K146) using predominantly K48 linkages. By molecular modeling, the in-between-ring (IBR) domain of Parkin (Gln326-Leu358) made extensive contacts with the amino-terminus A box of HMGB1 (Met1-Ser42), forming a mitochondria-associated Parkin-HMGB1 complex that juxtaposes K146 to Ub active site residues Gly76 and Arg74. Instead of proteasomal degradation, Parkin ubiquitination of K146 enabled the loading of HMGB1, but not HMGB1 K146A mutant, onto autophagy- and mitochondria-derived large extracellular vesicles (LEV). In turn, released Parkin-HMGB1 LEV stimulated a potent interferon (IFN) and cytokine response in recipient cells, expanding CD8+ T cell subsets with effector (CD69+/KLRG1+), self-renewal (TCF-1+/PD-1+), and cytotoxic (KLRG1+/GrzB+) properties. Conditional expression of Parkin induced HMGB1 release, activated intratumoral CD8+ T cells, and suppressed syngeneic tumor growth in vivo in a response that was abolished by HMGB1 silencing. These data identify that Parkin-LEV regulated release of HMGB1 reprograms antitumor immunity via stimulation of IFN signaling and expansion of specialized CD8+ T cell subsets.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0904
  44. Am J Physiol Cell Physiol. 2025 Sep 08.
    Deletion of ABIN1-LIR motifs impairs hepatic lipid homeostasis and mitophagy via AMPK-TFEB axis in mice.
    Lisa Sophie Huber, Rosetta Merline, Jinyang Zeng-Brouwers, Rajkumar Vutukuri, Nico Kraus, Cristina Ortiz, Stefan Guenther, Eva Miriam Buhl, Lisa Hahnefeld, Robert Gurke, Julia Bein, Madina Karimova, Patrick Wurzel, Peter Boor, Christoph Welsch, Peter Wild, Josef Pfeilschifter, Donat Kögel, Malgorzata Wygrecka, Jonel Trebicka, Rafal Bartoszewski, Ivan Dikic, Liliana Schaefer.
      The A20 binding inhibitor of nuclear factor-kappa B (NF-κB)-1 (ABIN-1) serves as a ubiquitin sensor and autophagy receptor, crucial for modulating inflammation and cell death. Our previous in vitro investigation identified the LC3-interacting region (LIR) motifs 1 and 2 of ABIN-1 as key mitophagy regulators. This study aimed to explore the in vivo biological significance of ABIN1-LIR domains using a novel CRISPR-engineered ABIN1-ΔLIR1/2 mouse model, which lacks both LIR motifs. Comprehensive morphological, serum, and tissue histochemical analyses revealed increased body, fat, and liver weights, altered serum and hepatic lipid profiles, and substantial hepatic lipid droplet accumulation, indicative of altered hepatic lipid metabolism, dyslipidemia, and hepatic steatosis in ABIN1-ΔLIR1/2 mice. Transcriptomic, metabolomic, and lipidomic analyses indicated dysregulated hepatic mitochondrial metabolism, favoring lipogenesis. Mechanistically, LIR1/2 deletion inhibited the expression and activity of transcription factor EB (TFEB) and AMP-activated protein kinase β1 (AMPKβ1), resulting in compromised autophagy and lipophagy. ABIN1 interacted with TFEB and colocalization was observed in both the cytoplasmic and nuclear compartments of hepatocytes. Impaired mitophagy was evidenced by the decreased expression of parkin and optineurin, along with increased levels of mitochondrial cytochrome c oxidase subunit II. These findings were corroborated by liver biopsies of patients with metabolic dysfunction-associated steatotic liver disease. Thus, this study underscores the functional role of ABIN1-LIR motifs in modulating the ABIN1-AMPK-TFEB axis, which is critical for mitochondria-associated lipid metabolism and mitophagy, offering insights into the mechanistic pathways contributing to the pathogenesis of steatosis-associated liver diseases with potential therapeutic implications.
    Keywords:  ABIN1; AMPK; Hepatic steatosis; Mitophagy; TFEB
    DOI:  https://doi.org/10.1152/ajpcell.00544.2025
  45. Neurobiol Dis. 2025 Sep 04. pii: S0969-9961(25)00301-8. [Epub ahead of print]215 107084
    The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.
    L Daniel Estrella, Xiaoke Xu, Collin White, Jane E Manganaro, Lexi Sheldon, Trey Farmer, Kelly L Stauch.
      Amongst the major histopathological hallmarks in Alzheimer's disease are intracellular neurofibrillary tangles consisting of hyperphosphorylated and aggregated Tau, synaptic dysfunction, and synapse loss. We have previously shown evidence of synaptic mitochondrial dysfunction in a mouse model of Tauopathy that overexpresses human Tau (hTau). Here, we questioned whether the levels or activity of Parkin, an E3 ubiquitin ligase involved in mitophagy, can influence Tau-induced synaptic mitochondrial dysfunction. Here, we generated novel mouse strains by crossing hTau mice with either Parkin knockout mice or mice expressing mutant Parkin (ParkinW402A, shown to lead to constitutively active Parkin in vitro). We found that Parkin levels are increased in synaptic mitochondria isolates from hTau compared to WT mice, suggesting increased mitophagy; while ParkinW402A surprisingly led to decreased levels of Parkin in hTau mice. Furthermore, we showed that absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction; however, ParkinW402A did not show functional rescuing effects. When compared to WT, proteomic analyses of synaptosomes demonstrated that hTau mice display protein changes that predict alterations to pathways related to mitochondrial metabolism, synaptic long-term potentiation, and synaptic calcium homeostasis. Both the absence of Parkin and expression of ParkinW402A led to distinct changes in the hTau mouse synaptic proteome. Finally, we showed that Parkin-null hTau mice have higher levels of phosphorylated Tau in the hippocampal Dentate Gyrus, with no observable changes in hTau mice expressing ParkinW402A. The data presented here illustrate the protective role that Parkin plays under Tau-induced mitochondrial and proteomic alterations, particularly at the synaptic level.
    Keywords:  Alzheimer's disease; Mitophagy; Parkin; ParkinW402A; Phosphorylated Tau; Synapse; Synaptic mitochondria; Tauopathy
    DOI:  https://doi.org/10.1016/j.nbd.2025.107084
  46. Nutrients. 2025 Aug 29. pii: 2809. [Epub ahead of print]17(17):
    Cucurbitacin B from Cucurbitaceae Plants: Treating Pancreatic Cancer via Inducing Mitophagy, Inhibiting Glycolysis, and Enhancing Immune Function.
    Dongge Yin, Hongyue Chen, Xiaohong Jing, Shuting Lin, Yufei Sun, Rongrong Chang, Yang Feng, Xiaoxv Dong, Changhai Qu, Jian Ni, Xingbin Yin.
       BACKGROUND: Cucurbitacin B (CuB) is a relatively unique and valuable component in plants of the Cucurbitaceae family due to its diverse and remarkable physiological activities, but its specific mechanisms in regulating tumor metabolism and immune response remain unclear. The hypoxic tumor microenvironment (TME) of pancreatic cancer induces metabolic reprogramming in cancer cells, causing them to rely on glycolysis for energy. LDHA, a key enzyme in glycolysis, can suppress glycolysis and tumor growth when inhibited.
    OBJECTIVE: The objective of this study was to investigate the mechanism of CuB against pancreatic cancer and its effect on the immune system.
    METHODS: In this study, cell migration/invasion assays, immunofluorescence, ELISA, Western blot, CETSA, flow cytometry, mouse models, and metabolomic and transcriptomic analyses were utilized to systematically elucidate the mechanism by which CuB inhibits pancreatic cancer and activates the immune system.
    RESULTS: This study confirms that CuB inhibits pancreatic cancer by suppressing the PI3K/Akt/mTOR pathway and activating PINK1/Parkin to induce mitophagy, thereby inhibiting cell migration, invasion, and proliferation. It downregulates the expression of LDHA to block glycolysis, reduce lactate production and efflux, and improve the acidic TME. CuB also induces ICD to activate dendritic cells, promote CD8+ T-cell and M1 macrophage infiltration, and reduce the levels of regulatory T cells. Metabolomic and transcriptomic analyses validate CuB's dual effects on metabolic reprogramming and immune activation.
    CONCLUSIONS: This study, for the first time, reveals that CuB induces mitophagy via the PI3K/Akt/mTOR and PINK1/Parkin pathways to selectively eliminate damaged mitochondria and suppress tumor energy metabolism. CuB inhibits pancreatic cancer through a triple mechanism-inducing mitophagy, inhibiting glycolysis, and activating immunity-which provides innovative insights for pancreatic cancer therapy.
    Keywords:  Cucurbitacin B; glycolysis; immunity; mitophagy; pancreatic cancer
    DOI:  https://doi.org/10.3390/nu17172809
  47. Phytomedicine. 2025 Sep 06. pii: S0944-7113(25)00879-7. [Epub ahead of print]147 157240
    Wogonoside inhibits fibroblast activation and pulmonary fibrosis by dual regulation of Snail1 lactylation and PGC1α/PINK1-mediated mitophagy.
    Jianzhi Wu, Yijie Li, Yun Yang, Ranyun Chen, Hong Wang, Kaihong Xie, Jianhang Lan, Mengyu Guo, Yinhao Zhang, Xiaojiaoyang Li.
       BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal disease characterized by the activation of lung fibroblasts (LFs). Wogonoside (WG), a natural compound with multiple pharmacological properties including anti-fibrotic activities, shows promise in treating IPF.
    PURPOSE: This study aims to investigate the pharmacological effects and underlying mechanisms of WG on LF activation and the progression of IPF.
    METHODS: Initially, we validated the anti-fibrotic properties of WG using a bleomycin (Bleomycin)-induced IPF model in mice, followed by RNA sequencing to identify its pharmacological targets. Subsequent in vitro experiments assessed the activities of key enzymes involved in the whole processes of glycolysis and lactic acid production, the changes of cellular energy metabolism and mitophagy-related pathways in LFs treated with transforming growth factor beta (TGF-β) or WG. Finally, reverse validation experiments were performed by further administration of lactic acid or cyclosporin A (CsA) into mice.
    RESULTS: We demonstrated that WG reduced the production of lactic acid and the lactylation of lactate of snail homolog 1 (Snail1) at K9 site by promoting pyruvate kinase isozymes R/l (PKLR) and inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH), while triggered mitophagy and reduced reactive oxygen species production and mtDNA release by promoting peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and PTEN-induced kinase 1 (PINK1)/PARKIN pathways. These two processes compatibly inhibited the TGF-β transcription and ultimately LF activation, which were reversed by lactic acid supplementation or mitophagy depletion in mice.
    CONCLUSION: Overall, our findings first underscore the potential pharmacological benefits of WG in the treatment of IPF by impeding lactate accumulation and mitophagy damage, thereby providing a novel theoretical framework for therapies targeting pulmonary diseases.
    Keywords:  Lactylation; Mitophagy; Pulmonary fibrosis; Transforming growth factor-β; Wogonoside
    DOI:  https://doi.org/10.1016/j.phymed.2025.157240
  48. Front Pharmacol. 2025 ;16 1600435
    Gypenoside XLIX inhibiting PI3K/AKT/FOXO1 signaling pathway mediated neuronal mitochondrial autophagy to improve patients with ischemic stroke.
    Yonglei Liu, Hongdie Mao, Zhengguang Sha, Jishuai Zhao, Hui Cai, Rong Xi, Zhenzhu Zhao, Xiaoling Yin, Lin Yang, Changyun Liu.
       Introduction: Ischemic stroke is a leading cause of mortality and disability worldwide, with limited therapeutic options and high rates of recurrence. Mitochondrial dysfunction plays a critical role in neuronal injury during ischemia-reperfusion, making mitochondrial autophagy a potential therapeutic target. Gypenoside XLIX, a major active metabolite of Gynostemma pentaphyllum, exhibits antioxidant and organ-protective properties, but its effects on neuronal mitochondrial damage in stroke remain unclear. This study aimed to explore the neuroprotective mechanisms of Gypenoside XLIX in ischemic stroke, focusing on the PI3K/AKT/FOXO1 signaling pathway.
    Methods: Neuroprotective effects were evaluated in oxygen-glucose deprivation (OGD) neuronal cells and middle cerebral artery occlusion (MCAO) rat models. Cell viability, apoptosis, ROS production, mitochondrial membrane potential, and autophagic flux were assessed by CCK-8, flow cytometry, ELISA, TMRE staining, immunofluorescence, and Western blotting. Signaling pathway involvement was examined using PI3K inhibitor LY294002, AKT activator SC79, and FOXO1 knockdown.
    Results: Gypenoside XLIX significantly improved neuronal viability (p < 0.01), reduced apoptosis (p < 0.01), and decreased ROS levels (p < 0.001) in OGD cells. It enhanced p-PI3K and p-AKT expression while suppressing FOXO1 (p < 0.05), promoted Beclin-1, LC3, PINK1, and Parkin expression (p < 0.001), and reduced p62 (p < 0 .01). In MCAO rats, Gypenoside XLIX decreased infarct volume (p < 0.001), brain edema (p < 0.01), and TUNEL-positive cells (p < 0.001), while elevating mitochondrial membrane potential and antioxidant enzyme levels (SOD, GSH-Px, CAT; all p < 0.001).
    Conclusion: Gypenoside XLIX alleviates ischemic stroke injury by activating the PI3K/AKT/FOXO1 pathway, enhancing mitochondrial autophagy, and reducing oxidative stress, supporting its potential as a novel neuroprotective agent in stroke management.
    Keywords:  FoxO1; PI3K/AKT; gypenoside XLIX; ischemic stroke; mitochondrial autophagy
    DOI:  https://doi.org/10.3389/fphar.2025.1600435
  49. Nat Aging. 2025 Sep 10.
    Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
    Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.
      Membraneless organelles assembled by liquid-liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. In Caenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid-liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress.
    DOI:  https://doi.org/10.1038/s43587-025-00942-x
  50. J Hazard Mater. 2025 Sep 01. pii: S0304-3894(25)02640-8. [Epub ahead of print]497 139721
    SiO2 NP promotes allergic gastritis induced by degranulation of mouse MC9 cell through AQP4-mediated impairment of SIRT3-TFAM deacetylation and mitochondrial autophagy.
    Yutian Lei, Xiaodan Wang, Hao Wu, Meichen Gao, Tong Xu, Hongjin Lin.
      Silicon dioxide nanoparticles (SiO2 NPs) are a novel material with a wide range of applications whose cumulative effects in the body pose certain health risks. The types of gastric injuries caused by different-sized SiO2 NPs and their mechanisms, however, remain unclear. Based on this, we established a mouse subchronic exposure model (10 mg/kg/d, 21 consecutive days of tube-feeding) with different SiO2 NP sizes (50, 300, and 1000 nm) in conjunction with in vitro MC9 and BMMCs models (160 μg/mL exposure for 24 h) to explore the gastric injury mechanisms. The results showed that SiO2 NP exposure mediated oxidative stress after activating AQP4 water channels, and interfered with the deacetylation of TFAM by SIRT3 while enhancing the ability of TMEM175 to efflux protons. This resulted in mitochondrial dysfunction and lysosomal damage, a decrease in autophagic flux, a massive release of mtDNA into the cytoplasm, and the downstream activation of NLRP3 inflammasomes that induced pyroptosis. This leads to degranulation of the mast cells and release of inflammatory factors. Moreover, SiO2 NP with a particle size of 300 nm were the most toxic. CONCLUSION: SiO2 NP promote allergic gastritis induced by the degranulation of mouse mast cells through the AQP4-mediated impairment of SIRT3-TFAM deacetylation and mitochondrial autophagy. This study reveals a new mechanism of nanoparticle immunotoxicity through AQP4-mediated epigenetic modification (SIRT3-TFAM deacetylation), and establishes a particle size-effect model with 300 nm as the critical value of nanoparticle gastric toxicity. These findings provide specific biomarkers (e.g., TFAM acetylation levels) for the early detection of gastrointestinal side effects of nanomedicines, where modulation of SIRT3 activity or targeting of the TMEM175 channel may be potential strategies for combating nanomaterial-induced allergic reactions.
    Keywords:  Allergic gastritis; Lysosomal dysfunction; Mast cells degranulation; Mitochondrial autophagy; SIRT3-TFAM deacetylation; SiO(2) NP
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.139721
  51. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2426578122
    Sorting nexin 3 promotes ischemic retinopathy through RIP1- and RIP3-mediated myeloid cell necroptosis and mitochondrial fission.
    Jiaojiao Wang, Chunhong Zhou, Kai Zhuang, Jiami Zou, Wanlu Qiu, Mei Jin, Weile Ye, Pinglian Yang, Zhihua Zheng, Qing Zhou, Zunnan Huang, Yuanxiang Wang, Peiqing Liu, Jing Lu, Yuqing Huo, Zhiping Liu.
      Proliferative retinopathy is a leading cause of irreversible blindness in humans; however, the molecular mechanisms behind the immune cell-mediated retinal angiogenesis remain poorly elucidated. Here, using single-cell RNA sequencing in an oxygen-induced retinopathy (OIR) model, we identified an enrichment of sorting nexin (SNX)-related pathways, with SNX3, a member of the SNX family that is involved in endosomal sorting and trafficking, being significantly upregulated in the myeloid cell subpopulations of OIR retinas. Immunostaining showed that SNX3 expression is markedly increased in the retinal microglia/macrophages of mice with OIR, which is mainly located within and around the neovascular tufts. Myeloid cell-specific deficiency of Snx3 inhibited retinal neovascularization, hyperpermeability, and dysfunction in OIR mice. Using glutathione S-transferase pull-down, coimmunoprecipitation, and immunofluorescent staining, we found that SNX3 interacted with receptor-interacting protein 1/3 (RIP1 and RIP3). We further demonstrated that RIP1/3 degradation was accelerated in SNX3-deleted microglia/macrophages, causing an inhibition of hypoxia-induced necroptosis and mitochondrial fission, thereby decreasing the production of proinflammatory and proangiogenic factors (FGF2 and MMP12). Moreover, OIR retinas from myeloid cell-specific SNX3 overexpression transgenic mice presented more angiogenic tufts, while RIP1/3 inhibition largely ablated SNX3 overexpression-induced pathological angiogenesis. Based on the structure of SNX3, we identified a small-molecule inhibitor, W1122. Intriguingly, we found that W1122 effectively inhibited retinal angiogenesis in the OIR model, and combination treatment with anti-Vascular Endothelial Growth Factor (VEGF) yielded enhanced antiangiogenic effects. Collectively, our findings disclose a link between SNX3 and RIP1/3 signaling and implicate SNX3 in the development of ischemic retinopathy.
    Keywords:  macrophage; microglia; necroptosis; retinal angiogenesis; retinopathy
    DOI:  https://doi.org/10.1073/pnas.2426578122
  52. J Inorg Biochem. 2025 Sep 04. pii: S0162-0134(25)00235-1. [Epub ahead of print]274 113055
    Development of six novel dinuclear calcium(II) complexes based on 8-hydroxyquinoline as anticancer agents.
    Xiao-Mei Huang, Yue Xu, Si-Mei Qin, Ming-Xiong Tan, Qi-Pin Qin, Tai-Ming Shao, Hong Liang.
      This study reports the synthesis and antitumor evaluation of six novel dinuclear calcium(II) complexes with the general formula [Ca2(μ2-O)2(QMx)4(QHy)2], designated as CaQ1 through CaQ6. These complexes incorporate various deprotonated 8-hydroxyquinoline ligands (H-QM1-H-QM4) and 1,10-phenanthroline derivatives (QH2), synthesized using Ca(NO3)2·4H2O. The specific compositions are as follows: CaQ1: H-QM1 = 5,7-dibromo-8-hydroxyquinoline (x = 1), QH1 = bathophenanthroline; CaQ2: H-QM2 = 5,7-dichloro-8-quinolinol (x = 2), QH1 = bathophenanthroline; CaQ3: H-QM3 = 5,7-diiodo-8-hydroxyquinoline (x = 3), QH2 = 1,10-phenanthroline; CaQ4: H-QM2 = 5,7-dichloro-8-quinolinol (x = 2), QH2 = 1,10-phenanthroline; CaQ5: H-QM4 = clioquinol (x = 4), QH2 = 1,10-phenanthroline; CaQ6: H-QM1 = 5,7-dibromo-8-hydroxyquinoline (x = 1), QH2 = 1,10-phenanthroline. Cytotoxicity was assessed using the cell counting kit-8 assay, and the results showed that CaQ1-CaQ6 exhibited greater selectivity toward cisplatin-resistant SK-OV-3/DDP ovarian (cis-SK3) cancer cells compared to both nontumorigenic HL-7702 liver cells and parental SK-OV-3 ovarian cancer cells. Notably, CaQ1 and CaQ2, which contain the active H-QM1, H-QM2, and QH1 ligands, showed the most potent cytotoxicity, with IC50 values of 3.59 ± 0.67 μM and 2.73 ± 0.25 μM, respectively, against cis-SK3 cells. Apoptosis induced by CaQ1 and CaQ2 was mediated by mitophagy activation and adenosine triphosphate depletion, with CaQ2 being more effective than CaQ1-likely due to the presence of QM2 and QH1 ligands in the CaQ2 complex. In conclusion, these findings suggest that the synthesized 8-hydroxyquinoline-based binuclear calcium(II)-1,10-phenanthroline complexes (CaQ1-CaQ6) represent promising Ca(II)-based anticancer drug candidates.
    Keywords:  8-hydroxyquinoline; Anticancer activity; Calcium (II) complexes; Mitophagy pathway
    DOI:  https://doi.org/10.1016/j.jinorgbio.2025.113055
  53. J Hazard Mater. 2025 Sep 06. pii: S0304-3894(25)02712-8. [Epub ahead of print]497 139793
    Metabolic saboteurs: Tire wear particles hijack energy economy of zooplankton.
    Hairong Lian, Chuhan Xu, Pengrui Xu, Da Tong, Zhizhong Li, Xinfeng Cheng, Kai Zhang, Xianling Xiang.
      Tire wear particles (TWP) represent a significant source of marine microplastic pollution and have been shown to pose a considerable threat to marine organisms. In this study, the marine rotifer Brachionus plicatilis was employed as a model organism to systematically assess the effects of micron-sized and nano-sized TWP, as well as their leachates, on rotifer behavior, and underlying molecular mechanisms. The results revealed that TWP exposure significantly reduced rotifer motility, evidenced by decreased swimming speed and acceleration. Further investigation revealed that TWP-induced suppression of rotifer motility was mechanistically linked to metabolic disturbances (reduced amylase activity, triglyceride, and neutral lipid levels) and mitochondrial dysfunction (oxidative stress, ATP depletion, and autophagy activation). Concurrently, rotifers counteracted TWP-induced stress by activating oxidative stress responses and mitophagy pathways, while concurrently initiating compensatory feeding to alleviate energy depletion. Notably, N-acetylcysteine supplementation significantly mitigated TWP-induced mitochondrial dysfunction and metabolic disturbances. Furthermore, a significant dose-dependent decline in Biomarker Response Index (BRI) values was observed with increasing TWP concentrations. This study elucidates TWP's toxic mechanisms in aquatic organisms and underscores low-concentration exposure risks, providing key evidence for assessing long-term ecological impacts of microplastic pollution.
    Keywords:  Brachionus plicatilis; Lipid metabolism; Microplastics; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.139793
  54. Pharmacol Res. 2025 Sep 10. pii: S1043-6618(25)00372-X. [Epub ahead of print] 107947
    Selective Autophagy in Type 2 Diabetes-Associated Cognitive Dysfunction: Insightful Mechanisms and Therapies.
    Li Luo, Mengxin Que, Lian Zeng, Xuan Wang, Tianning Sun, Zhiqiang Zhou, Yilin Zhao, Shiyong Li, Ailin Luo.
      Type 2 diabetes-associated cognitive dysfunction (TDACD) is an escalating yet underestimated global health challenge, reflecting a complex convergence of metabolic dysregulation and neurodegenerative pathogenesis. Despite increasing concern, its underlying neuropathogenesis remains partially elucidated. It should be noted that T2DM and neurodegenerative diseases exhibit a high degree of overlap in pathological mechanisms, including impaired insulin signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and autophagy dysregulation, and these shared mechanisms constitute the neuropathogenesis of TDACD. Accumulating findings have identified selective autophagy as a pivotal mechanism in preserving neuronal integrity and mitigating cellular stress under diabetic conditions. Distinct from non-selective autophagy, selective autophagy enables the precise degradation of specific subcellular substrates, mitochondria, endoplasmic reticulum, lysosomes, ferritin, lipid droplets, and glycogen, each of which contributes uniquely to neuroprotection or pathology. This review comprehensively synthesizes current mechanistic insights into how these selective autophagic subtypes modulate neural function in the context of TDACD, underscoring their respective roles in mitochondrial quality control, ER stress resolution, iron homeostasis, lipid metabolism, and energy regulation. Furthermore, we summarize potential therapeutic strategies targeting specific autophagic pathways, offering a novel perspective for the prevention or treatment of TDACD. By positioning selective autophagy as a critical interface between neurodegeneration and metabolic stress responses, this review proposes a pathway-specific and precision-based framework for mitigating cognitive decline in type 2 diabetes.
    Keywords:  Cognitive dysfunction; ER-phagy; Ferritinophagy; Lipophagy; Mitophagy; Neurodegeneration; Selective autophagy; Type2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.phrs.2025.107947
  55. Front Biosci (Landmark Ed). 2025 Aug 29. 30(8): 41226
    LONP1 Promotes Hepatocarcinogenesis by Degrading ACO2 to Alleviate Ferroptosis.
    Yanfeng Zhong, Liusheng Wu, Zhen Peng, Wei Mao, Ting Wang, Bo Wu, Zhendong Yu, Xiaoqiang Li, Erbao Chen.
       BACKGROUND: Lon protease 1 (LONP1), an adenosine triphosphate (ATP)-dependent protease encoded by nuclear DNA that is highly conserved, maintains the mitochondrial protein balance and regulates adaptive responses to cellular stress. LONP1 dysfunction ultimately results in various forms of cellular and tissue damage. The function of LONP1 in hepatocellular carcinoma (HCC) and how it affects HCC growth were investigated in this work.
    METHODS: The RNA and protein expression levels of LONP1 were determined in paired HCC and adjacent tissue samples through real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) staining. The correlation between LONP1 expression and clinical features was evaluated via statistical analysis. Overexpression (OE) and knockdown (KD) experiments, small RNA interference, Cell Counting Kit-8 (CCK8) and wound-healing assays, and animal experiments were employed to assess the potential mechanism by which LONP1 promotes the proliferation and migration of HCC cells both in vitro and in vivo.
    RESULTS: In HCC samples, LONP1 expression was higher than in the equivalent surrounding tissues. Compared to patients with low LONP1 expression, individuals with high LONP1 expression had shorter disease-free survival and overall survival periods. Functionally, LONP1 facilitated the proliferation and migration of HCC cells, whereas LONP1 knockdown mitigated the growth of HCC subcutaneous tumors. Mechanistically, LONP1 affects the processes of ferroptosis and cuproptosis processes by regulating the stability of aconitase 2 (ACO2). Histological analysis showed that the expression of LONP1 in liver cancer tissues was significantly upregulated, accompanied by a decrease in the level of ACO2 protein (Hematoxylin-Eosin (HE) staining and IHC verification). Mitochondrial function experiments indicated that overexpression of LONP1 led to a significant decrease in mitochondrial membrane potential suggesting mitochondrial dysfunction and reduced susceptibility to ferroptosis.
    CONCLUSIONS: Our results suggest that LONP1 promotes HCC proliferation and migration by inhibiting ferroptosis and cuproptosis through the degradation of ACO2. Therefore, targeting LONP1 might be an effective therapeutic strategy to inhibit HCC growth.
    Keywords:  Lon protease 1 (LONP1); aconitase 2 (ACO2); ferroptosis regulation; hepatocellular carcinoma; survival prognosis
    DOI:  https://doi.org/10.31083/FBL41226
  56. ACS Appl Mater Interfaces. 2025 Sep 07.
    Nanohybrid Hydrogels Spatiotemporally Restore Infectious Bone Defects via Mitochondrial Homeostasis-Driven Immunomodulation and Vascular-Bone Coupling Synergy.
    Jiangshan Liu, Jiawei Wei, Shiqi Xiao, Yi Zuo, Yubao Li, Jidong Li.
      Regeneration of infected bone defects (IBDs) requires biomaterials capable of dynamically coordinating antimicrobial, anti-inflammatory, and osteogenic functions. Overcoming the spatiotemporal mismatches in treating IBDs remains a critical challenge. Here, we designed a temporally controlled therapy based on gelatin methacrylate (GelMA)-based nanocomposite hydrogels (GCS) coembedded with sulfur quantum dots (SQDs) nanoenzymes and calcium-phosphorus oligomers (CPOs.) The GCS platform enables a three-phase therapy targeting the healing of IBDs: (1) effective inactivation of bacteria is achieved by SQDs weakly interacting with the hydrogel after early and rapid release; (2) the mitochondrial homeostatic balance is maintained through SQDs-mediated reactive oxygen species scavenging that restores ATP synthesis, which in turn inhibits inflammatory cascade-associated protein expression and drives macrophage M2 polarization; and (3) sustained CPO delivery initiates vascular coupling and osteogenic differentiation during tissue regeneration. In a rat model of IBDs, GCS reached a complete bone bridge at week 8 with a 46.6 ± 2.3% new bone volume. This work pioneers nanozyme-driven mitochondrial-immune axis regulation through programmable material dynamics, offering a paradigm for functional hydrogel design in infected tissue regeneration.
    Keywords:  antimicrobial and anti-inflammatory; infected bone defects; mitochondrial homeostasis; nanocomposite hydrogels; vascularized bone regeneration
    DOI:  https://doi.org/10.1021/acsami.5c14131
  57. Int J Mol Sci. 2025 Sep 06. pii: 8697. [Epub ahead of print]26(17):
    Adaptations in Mitochondrial Function Induced by Exercise: A Therapeutic Route for Treatment-Resistant Depression.
    Arnulfo Ramos-Jiménez, Mariazel Rubio-Valles, Javier A Ramos-Hernández, Everardo González-Rodríguez, Verónica Moreno-Brito.
      Mitochondrial dysfunction is a key factor in the pathophysiology of major depressive disorder (MDD) and treatment-resistant depression (TRD), connecting oxidative stress, neuroinflammation, and reduced neuroplasticity. Physical exercise induces specific mitochondrial changes linked to improvements in mental health. The aim of this paper was to examine emerging evidence regarding the effects of physical exercise on mitochondrial function and treatment-resistant depression, highlighting the clinical importance of the use of mitochondrial biomarkers to personalize exercise prescriptions for patients with depression, particularly those who cannot tolerate standard treatments. Physical exercise improves mitochondrial function, enhances biogenesis and neuroplasticity, and decreases oxidative stress and neuroinflammation. Essential signaling pathways, including brain-derived neurotrophic factor, AMP-activated protein kinase, active peroxisome proliferator-activated receptor-γ coactivator-1α, and Ca2+/calmodulin-dependent protein kinase, support these effects. Most studies have concentrated on the impact of low- and moderate-intensity aerobic exercise on general health. However, new evidence suggests that resistance exercise and high-intensity interval training also promote healthy mitochondrial adaptations, although the specific exercise intensity required to achieve this goal remains to be determined. There is strong evidence that exercise is an effective treatment for MDD, particularly for TRD, by promoting specific mitochondrial adaptations. However, key gaps remain in our understanding of the optimal exercise dose and which patient subgroups are most likely to benefit from it (Graphical Abstract).
    Keywords:  behavioral stress; mitochondrial dynamics; mood disorders; neurophysiological disturbances; neuroplasticity; physical exercise; sedentarism; treatment-resistant depression
    DOI:  https://doi.org/10.3390/ijms26178697
  58. Clin Genet. 2025 Sep 10.
    LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
    Undiagnosed Diseases Network
      LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.
    Keywords:  CODAS; LONP1; congenital diaphragmatic hernia; mitochondrial encephalopathy; neurodevelopmental disorder
    DOI:  https://doi.org/10.1111/cge.70057
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