bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–01–11
sixty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. [Research progress on regulation of mitochondrial homeostasis in vascular aging mechanism and intervention by traditional Chinese medicine].
  2. Targeting Fibrosis: ALA-PDT Triggers PINK1/Parkin-Dependent Mitophagy and Apoptosis in Fibroblasts.
  3. HMGA2 inhibits Pink1-mediated mitophagy and promotes vascular calcification.
  4. Mitophagy in the pathogenesis and management of disease.
  5. Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.
  6. Pharmaceutical Roots to Mitochondrial Routes: Targeting Neurodegeneration.
  7. Acteoside Ameliorates Hepatic Steatosis and Liver Injury in MASLD Mice Through Activation of PINK1/Parkin-Related Mitophagy Markers.
  8. Oxidative Stress, Mitochondrial Homeostasis, and Sirtuins in Atrial Fibrillation.
  9. Mitochondrial dynamics and signaling in stem cell differentiation.
  10. The many faces of p97/Cdc48 in mitochondrial homeostasis.
  11. Mitophagy-NLRP3 Inflammasome Crosstalk in Parkinson's Disease: Pathogenic Mechanisms and Emerging Therapeutic Strategies.
  12. Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.
  13. An upstream open reading frame regulates expression of the mitochondrial protein Slm35 and mitophagy flux.
  14. Genistein improves heart failure with preserved ejection fraction through BNIP3L-mediated mitophagy.
  15. Subcellular Stress Markers in Epithelial Ovarian Cancer.
  16. Characterizing the role of mitochondrial dynamics during Drosophila convergent extension using NADH fluorescence lifetime imaging.
  17. MiR-181c-5p-SIRT1 axis-driven Pink1/Parkin-mediated mitophagy prevents ferroptosis and vascular calcification in chronic kidney disease.
  18. [Effect of Jiawei Duhuo Jisheng Mixture in improving mitophagy to treat knee osteoarthritis based on PINK1/Parkin pathway].
  19. CTRP1 regulates skeletal muscle differentiation through quality control of mitochondrial dynamics and function.
  20. Inhibition of Annexin A2 Facilitates PHB2-Mediated Mitophagy in Cardiomyocytes to Alleviate Cardiac Injury and Remodeling After Infarction.
  21. Cancer cells surviving cisplatin chemotherapy increase stress-induced OMA1 activity and mitochondrial fragmentation.
  22. Mitochondria and the Actin Cytoskeleton in Neurodegeneration.
  23. [Cajanolactone A ameliorates hepatocyte steatosis by regulating mitochondrial quality control via PGC-1α].
  24. MDP25-VDAC3 Complex Orchestrates Actin Remodeling and Mitochondrial Dynamics to Modulate Innate Immunity in Arabidopsis.
  25. Biochanin A exerts neuroprotective effects in Parkinson's disease both in vivo and in vitro by improving mitochondrial dysfunction through the Sirt1 signaling pathway.
  26. USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy.
  27. Mitochondrial Health Through Nicotinamide Riboside and Berberine: Shared Pathways and Therapeutic Potential.
  28. NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord.
  29. Parkin-ACSL4 axis in ferroptosis regulation: a narrative review on therapeutic insights from exercise in aging cardiomyocytes.
  30. FGF9 drives mitochondrial biogenesis in glioblastoma by activating the CREB-PGC-1α axis.
  31. Features of Mitochondrial Dynamics in Different Brain Parts of Patients with Alzheimer's Disease.
  32. Neuroprotective effect of berberine-loaded niosomes against brain injury in dyslipidemic rats: The interplay between oxidative stress, mitochondrial dysfunction and apoptotic signals.
  33. Naringenin boosts Parkin-mediated mitophagy via estrogen receptor alpha to maintain mitochondrial quality control and heal diabetic foot ulcer.
  34. Cannabidiol Alleviates LPS-Induced Depressive-Like Behaviors Via Improving Mitochondria Function.
  35. AUF1 Restrains Hepatocyte Senescence by Maintaining Mitochondrial Homeostasis in AML12 Hepatocyte Model.
  36. Promoting Drp1-Mediated Mitochondrial Division in Nickel Nanoparticles-Induced Reproductive Toxicity in GC-2 Cells.
  37. Mitochondrial retrograde signaling initiates HIF-1α/BNIP3/NIX-mediated mitophagy in Tibetan high-altitude adaptation.
  38. METTL3 regulates α-KG-dependent mitophagy and apoptosis in nucleus pulposus cells through the MALAT1/miR-23c/IDH1 axis.
  39. ENTR1 stabilizes MAVS by inhibiting NIX-mediated mitophagy to restrict BPIV3 and VSV replication.
  40. Melatonin Alleviates High-Fructose-Induced Renal Injury in Male Mice, Which Might Be Associated with the Regulation of Mitophagy and Fatty Acid Oxidation.
  41. Corrigendum to "BL-918 alleviates oxidative stress in rats after subarachnoid hemorrhage by promoting mitophagy through the ULK1/PINK1/Parkin pathway" [Free Radic. Biol. Med. 224 (2024) 846-861].
  42. Anwulignan mitigates UVB-induced skin photodamage by dual activation of the Nrf2/PINK1/Parkin and Nrf2/SLC7A11/GPX4 signaling pathways.
  43. Cadmium exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission.
  44. Mitochondrial integrity modulates mTOR signaling and podocyte function.
  45. [Mechanisms of Danggui Buxue Decoction in alleviating myocardial injury caused by chronic intermittent hypoxia by activating AMPK/mTOR signaling pathway].
  46. Mitochondria-targeted co-assembled nanosystem with multimodal mitochondrial DNA level control to alleviate inflammation and promote chronic wound healing.
  47. Targeting VCP with V8 suppresses glioblastoma development via formation of aggregates and disruption of mitophagy flux.
  48. Author Correction: Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
  49. Islet regeneration protein Reg3g promotes macrophage clearance of β cell-derived dysfunctional mitochondria-rich vesicles to mitigate T2DM.
  50. Loss of Sugen Kinase 495 in macrophages alleviates chronic colitis by improving mitochondrial stress.
  51. HIF1α Attenuated the Lung Ischemia-Reperfusion Injury by Activating the miR-485/Notch1 Signalling.
  52. Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.
  53. Mitophagy-related gene TRIP13 predicts prognosis and immune response and promotes proliferation and migration in vitro and in vivo of clear cell renal cell carcinoma.
  54. Piezoelectric Nanofibers Synchronize Mitochondrial Dynamics and Immune Responses for Regeneration of Infected Wounds.
  55. Silencing GADD45B Ameliorates Epilepsy by Inhibiting Ferroptosis and Maintaining Mitochondrial Homeostasis Through the HIF-1 Signaling Pathway.
  56. RhoA accelerates atherosclerosis progression by interacting with Hspa5.
  57. Methionine synthase reductase regulates heterochromatin independently of methionine synthesis through mitochondrial homeostasis.
  58. Frequency-Selective Terahertz Irradiation Activates Mitochondrial Biogenesis.
  59. Mitochondrial presequences harbor variable strengths to maintain organellar function.
  60. No effect of pyrroloquinoline quinone on mouse body weight and energy metabolism with the concomitant increase in mitochondrial biogenesis and antioxidant ability.
  61. Nanoplatform for renal ischemia-reperfusion injury repair: Modulating macrophage polarization, oxidative stress, and mitophagy.
  62. Aberrant mitochondrial hsp60 expression affects mitochondria homeostasis and results in muscle dystrophy and premature death.
  63. Immunomodulatory microneedles restore mitochondrial homeostasis and balance TGF-β/TNF-α signaling to accelerate diabetic wound repair.
  64. Mitochondrial Retrograde Control of Transcription Evolves with Respiratory Stress, Metabolic Adaptation, and Virulence in Budding Yeasts.
  1. Zhongguo Zhong Yao Za Zhi. 2025 Nov;50(22): 6234-6241
    [Research progress on regulation of mitochondrial homeostasis in vascular aging mechanism and intervention by traditional Chinese medicine].
    Bo-Yu Zhong, Zhuo-Er Chen, Qiong-Wen Hu, Xin Huang, Jia-Mei Yao, Guang-Wei Zhong, Shao-Wu Cheng.
      The pathogenesis of vascular aging is complex, and its pathological mechanisms mainly include mitochondrial dysfunction, oxidative stress, epigenetic changes, telomere dysfunction, endothelial dysfunction, and chronic inflammation. However, the pathological mechanism of vascular aging has not yet been fully elucidated. Mitochondria are key organelles regulating metabolism in eukaryotic cells. The imbalance of mitochondrial homeostasis leads to abnormal vascular function. Therefore, regulating mitochondrial homeostasis is considered an important target for the prevention and treatment of vascular aging in the future. Many studies have elucidated that traditional Chinese medicine(TCM) formulas, single herbs, and active components can specifically regulate mitochondrial homeostasis in vascular cells by affecting apoptosis or autophagy, thereby delaying vascular aging. This paper reviewed the role of mitochondrial homeostasis regulation in the pathogenesis of vascular aging from several aspects, including mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and mitochondrial oxidative stress. It also summarized research progress on TCM and its extracts that protect mitochondrial function, maintain mitochondrial homeostasis, and delay vascular aging. These findings provide new ideas and methods for preventing and treating vascular aging with TCM from the perspective of mitochondrial homeostasis.
    Keywords:  mechanism of action; mitochondrial homeostasis; traditional Chinese medicine; vascular aging
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250807.202
  2. FASEB J. 2026 Jan 15. 40(1): e71367
    Targeting Fibrosis: ALA-PDT Triggers PINK1/Parkin-Dependent Mitophagy and Apoptosis in Fibroblasts.
    Jie Ren, Jingtao Zhang, Min Jiang, Qinyi Chen, Xiaoyao Fan, Ye Liu, Ying Ma.
      Fibroblasts are key contributors to fibrosis due to their hyperproliferative and apoptosis-resistant phenotype. This study explores how 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) induces apoptosis in fibroblasts by modulating mitochondrial quality control. ALA-PDT significantly reduces cell viability and proliferation, increases LDH release, and triggers apoptotic signaling. Mechanistically, ALA-PDT promotes excessive accumulation of mitochondrial and cytosolic reactive oxygen species (ROS), leading to mitochondrial dysfunction and energy stress. These alterations activate the AMPK/mTOR signaling cascade, which in turn upregulates PINK1/Parkin-mediated mitophagy. Suppression of mitophagy through siRNA targeting PINK1 or Parkin, or with pharmacological autophagy inhibitors, markedly attenuates ALA-PDT-induced apoptosis, confirming the pivotal role of mitophagy in this process. Transmission electron microscopy shows abundant autophagosome formation, while Western blotting validates the amount of mitophagy-related and apoptotic proteins. These findings establish a mechanistic link between ALA-PDT-induced oxidative stress and mitophagy-dependent apoptosis, identifying a novel anti-fibrotic pathway involving ROS-AMPK/mTOR-PINK1/Parkin signaling. The results offer a compelling molecular basis for using ALA-PDT as a targeted therapeutic strategy against fibrotic diseases by promoting the selective elimination of activated fibroblasts.
    Keywords:  ALA‐PDT; AMPK/mTOR signaling; PINK1/Parkin pathway; fibroblast apoptosis; fibrosis therapy; mitophagy
    DOI:  https://doi.org/10.1096/fj.202502230RR
  3. Biochim Biophys Acta Mol Basis Dis. 2026 Jan 06. pii: S0925-4439(25)00499-5. [Epub ahead of print] 168149
    HMGA2 inhibits Pink1-mediated mitophagy and promotes vascular calcification.
    Shengjue Xiao, Zhengdong Chen, Yiqing Yang, Liqun Ren, Yuyu Yao, Naifeng Liu.
      Mitochondrial dysfunction is implicated in the development of vascular calcification, whereas protective mitophagy helps to hinder its progression. HMGA2 plays a pivotal role in regulating mitochondrial integrity and mitophagy. However, the precise impact of HMGA2-controlled mitophagy on vascular calcification remains unclear. In our study, we observed elevated HMGA2 expression during both Vitamin D3-induced aortic calcification in mice and β-GP-induced calcification of mouse aortic vascular smooth muscle (MOVAS). Additionally, we identified dynamic changes in mitophagy in MOVAS and demonstrated that HMGA2 knockdown promoted mitophagy, exerting a protective effect against vascular calcification in both in vivo and in vitro settings. Preconditioning with the autophagy inhibitor chloroquine diminished the protective effect of HMGA2 knockdown on aortic calcification in mice by inhibiting mitophagy. Furthermore, we observed an increase in cytoplasmic HMGA2 levels in MOVAS following vascular calcification, along with its binding to PTEN induced kinase 1 (Pink1) in the cytoplasm. This affects the distribution of Pink1, which cannot be transferred to the mitochondrial outer membrane to initiate mitophagy. Subsequently, silencing Pink1 exacerbated mitochondrial damage and apoptosis by inhibiting mitophagy, thereby promoting vascular calcification in β-GP-treated MOVAS. Our results indicated that cytosolic HMGA2 bound to Pink1, inhibiting mitophagy by impeding Pink1's relocation from the cytosol to the mitochondria, thereby reducing mitophagy activation, inducing apoptosis, ultimately accelerating the transition of MOVAS to an osteoblastic phenotype and calcium deposition. In conclusion, inducing mitophagy pharmacologically by targeting HMGA2 may represent a promising therapeutic approach for managing vascular calcification.
    Keywords:  Cytoplasm; HMGA2; Mitophagy; Pink1; Vascular calcification
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168149
  4. Cell Res. 2026 Jan;36(1): 11-37
    Mitophagy in the pathogenesis and management of disease.
    Qi Wang, Yu Sun, Terytty Yang Li, Johan Auwerx.
      Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy - from receptors and stress-responsive triggers to lysosomal degradation - illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.
    DOI:  https://doi.org/10.1038/s41422-025-01203-7
  5. Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00492-6. [Epub ahead of print]89 103979
    Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.
    William M Curtis, Patrick C Bradshaw.
      The mechanism of selecting dysfunctional mitochondria for mitophagy is only partially understood. Evidence suggests the mechanism involves reactions of superoxide (O2-•), hydrogen peroxide (H2O2), nitric oxide (NO•), peroxynitrite (ONOO-), carbonate radicals (•CO3-), nitrogen dioxide radicals (•NO2), hydroxyl radicals (•OH), oxygen (•O2• or O2), and carbon dioxide (CO2). However, the larger picture of how these reactions are organized to induce mitophagy is unclear. Extensive evidence suggests that increased mitochondrial matrix O2-• is associated with the mitophagy of dysfunctional organelles. In most cells, mitochondrial O2-• is mainly produced by the reaction of O2 with free radical intermediate forms of coenzyme Q (CoQ) and flavins, which are generated in substantial amounts in the inner membrane and matrix space of dysfunctional mitochondria. Mitochondrial O2-• plays two key roles in orchestrating mitophagy. First, it is dismutated by mitochondrial matrix superoxide dismutase 2 (SOD2) to H2O2. This diffusible messenger directs the nuclear and cytoplasmic compartments to prepare for mitophagy, including the generation of cytoplasmic NADPH and glutathione and the increased synthesis of membrane-diffusible NO•. Second, mitochondrial matrix space O2-• readily reacts with NO• to form ONOO-, which initiates a cascade of free radical reactions culminating in mitochondrial membrane depolarization and PINK1 and Parkin-driven mitophagy. Compelling observations that support the proposed mechanism are given. This mechanism could be targeted for the treatment of diseases characterized by dysfunctional mitophagy, such as Parkinson's disease. Because of the central role of mitochondrial O2-• as a sentinel for selective mitophagy, we have named this hypothesis the superoxide sentinel hypothesis of mitochondrial quality control.
    Keywords:  DJ-1; Mitophagy; NADPH; Nitric oxide synthase; Parkinson's disease; Superoxide sentinel hypothesis
    DOI:  https://doi.org/10.1016/j.redox.2025.103979
  6. Pharm Res. 2026 Jan 08.
    Pharmaceutical Roots to Mitochondrial Routes: Targeting Neurodegeneration.
    Abhilasha Sood, Arpit Mehrotra.
       BACKGROUND: Mitochondria besides being the powerhouse of the cell are also involved in performing a multitude of critical cellular functions. Any failure in maintenance of these organelles is implicated in multiple human pathologies, including neurodegenerative disorders. Over the past two decades, significant efforts have been made to investigate the pharmacodynamic propensity of various potential compounds, which could be engaged as efficient therapeutic approach in modulating mitochondrial dynamics during neuronal dysfunctions.
    METHOD: This review comprehensively overviews the contribution of potential compounds that could be employed as mitochondrial medicine in reversing neurological pathologies, with special focus on their significant roles as: metabolic antioxidants, conjugated molecules for mitochondrial function modulation, mitochondrial targeted peptides, optogenetic based induction of the mitochondria, potential mitochondrial biomarkers and other advanced transportation systems for mitochondrial delivery to brain.
    RESULTS AND DISCUSSION: The manuscript discusses the mechanism of action of potential compounds (natural and pharmacologically synthesized), and other advance approaches that could efficiently modulate mitochondrial machinery in terms of regulating mitochondrial biogenesis, mitophagy, bioenergetics pathways, oxidative stress, calcium homeostasis and mitochondrial DNA stability.
    CONCLUSION: The optimal maintenance of mitochondrial dynamics offered by variety of mitochondria targeting compounds highlights their prospective value for considering them as futuristic neurotherapeutic agents, which could be considered in managing neurodegenerative conditions.
    Keywords:  antioxidants; mitochondria; mitochondrial dynamics; neuroprotection; pharmaceutics
    DOI:  https://doi.org/10.1007/s11095-025-04004-0
  7. Nutrients. 2025 Dec 29. pii: 118. [Epub ahead of print]18(1):
    Acteoside Ameliorates Hepatic Steatosis and Liver Injury in MASLD Mice Through Activation of PINK1/Parkin-Related Mitophagy Markers.
    Meili Cong, Xinxin Qi, Hongguang Sun, Xinxuan Zhang, Yunxin Yan, Tao Liu, Jun Zhao.
      Objective: Acteoside (ACT) has different pharmacological properties such as antioxidant, hepatoprotective and anti-inflammatory effects. Impaired mitophagy has been recognized as an important pathogenic factor in metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, the possible therapeutic role of ACT in MASLD and the exact effect of ACT on mitophagy regulation are not explored. This study aims to elucidate the therapeutic efficacy of ACT in a high-fat and high-sugar (HFHS) diet-induced mouse model of MASLD and to determine whether its effects are related to the activation of PINK1/Parkin-related mitophagy markers. Methods: C57BL/6J mice were randomly allocated to control, model, rosuvastatin (RSF, 3 mg/kg), and ACT (30, 60, and 120 mg/kg) groups. Following a 14-week continuous intervention, biochemical parameters, liver histology, and mitophagy-related markers were assessed. Results: ACT administration significantly improved serum lipid profiles, liver function and insulin resistance, marked by reduced levels of MDA, IL-6, TNF-α, IL-1β, LDL-C, TC, TG, AST, ALT, HOMA-IR (p < 0.05), while increasing HDL-C and enhancing hepatic GSH-Px and SOD activities (p < 0.05). Histological examination revealed a notable attenuation of hepatic steatosis and lipid accumulation. At the molecular level, ACT promoted mitophagy activation, as indicated by upregulated PINK1, LC3II/I, and Parkin expression and downregulated P62 and p-P62. Electron microscopy further validated the restoration of mitochondrial morphology and reduction in lipid droplets. Conclusions: These results demonstrate that ACT ameliorates MASLD progression by improving metabolic homeostasis, reducing inflammation and oxidative stress, and alleviating PINK1/Parkin-related mitophagy impairment to restore mitophagy homeostasis. Our study highlights the potential of ACT as a new therapeutic agent for MASLD.
    Keywords:  PINK1/Parkin pathway; acteoside; lipid accumulation; liver steatosis
    DOI:  https://doi.org/10.3390/nu18010118
  8. Int J Mol Sci. 2025 Dec 23. pii: 175. [Epub ahead of print]27(1):
    Oxidative Stress, Mitochondrial Homeostasis, and Sirtuins in Atrial Fibrillation.
    Jan Krekora, Elzbieta Pawlowska, Marcin Derwich, Jarosław Drożdż, Janusz Blasiak.
      Atrial fibrillation (AF) is the most common cardiac arrhythmia. Yet, its treatment has serious challenges and is unsuccessful in a considerable fraction of patients. One reason may be a limited understanding of the molecular mechanisms underlying AF. Recent studies suggest that oxidative stress is involved in AF pathogenesis. Enhanced oxidative stress is largely determined by disrupted mitochondrial homeostasis, as cardiomyocytes heavily rely on mitochondrial energy production and calcium transfer between mitochondria and the sarcoplasmic reticulum. Atrial fibrillation involves metabolic, structural, and electrical remodeling, all of which are influenced by mitochondrial mechanisms. Mitochondrial homeostasis is controlled by mitochondrial quality control (mtQC), which is a multi-pathway mechanism to maintain integrity and functionality of mitochondria. Impaired mtQC may result in disturbed mitochondria-related calcium handling, decreased energy production, mitochondria-related inflammation and fibrosis, and impaired mitophagy. Sirtuins (SIRTs) are a family of seven members of histone deacetylases which have antioxidant properties, and three of them are localized to mitochondria. Therefore, at least some SIRTs may ameliorate enhanced oxidative stress related to damaged mitochondria. SIRTs have shown potential to improve AF outcomes in studies on AF patients and animal models. Therefore, SIRTs may have potential to ameliorate AF by decreasing oxidative stress and restoring mitochondrial homeostasis disrupted in AF. In this narrative review, we provide information on how mitochondrial dysfunctions, expressed as a disturbance in mtQC, contribute to AF through oxidative stress, calcium handling abnormalities, energy deficiency, inflammation and fibrosis, and genetic changes. In addition, we present the protective potential of sirtuins in AF.
    Keywords:  AF; atrial fibrillation; calcium handling; fibrosis; inflammation; metabolic remodeling; mitochondrial quality control; mitophagy; oxidative stress; sirtuins
    DOI:  https://doi.org/10.3390/ijms27010175
  9. J Cell Sci. 2026 Jan 01. pii: jcs263847. [Epub ahead of print]139(1):
    Mitochondrial dynamics and signaling in stem cell differentiation.
    Rahul Kumar Verma, Somya Madan, Richa Rikhy.
      Mitochondrial dynamics are defined by the continuous processes of fusion and fission that regulate mitochondrial shape, distribution and activity. They are also involved in cellular functions of mitochondria, such as energy production, metabolic adaptation, apoptosis and cellular stress responses. Consequently, these organelle dynamics play a crucial role in development, growth, differentiation and disease. Mitochondrial morphology is controlled by Drp1 (also known as DNM1L) and Fis1, which drive fission, whereas Opa1, Mfn1 and Mfn2 mediate fusion. The transcription, activation and degradation of these proteins are often regulated by signaling cascades that are crucial for stem cell maintenance and differentiation. In turn, mitochondrial dynamics regulate key outcomes of these pathways. We explore the interplay between mitochondrial fusion and fission proteins and such signaling pathways, including Notch, receptor tyrosine kinase, JNK, Hippo and mTOR signaling, finding that stem cell renewal and differentiation states are dependent on the regulation of signaling pathways by mitochondrial morphology and activity. Overall, this Review highlights how mitochondrial morphology and activity crucially regulate stem cell division for renewal and differentiation, examining their impact across diverse systems.
    Keywords:  Drp1; Marf; Mfn; Mitochondria; Opa1; Signaling; Stem cells
    DOI:  https://doi.org/10.1242/jcs.263847
  10. Essays Biochem. 2025 Dec 22. pii: EBC20253045. [Epub ahead of print]69(5):
    The many faces of p97/Cdc48 in mitochondrial homeostasis.
    Jonathan Ram, Michael H Glickman.
      Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.
    Keywords:  Cdc48; ERAD; MAD; P97; VCP; mitochondria; mitostasis; proteasome; ubiquitin
    DOI:  https://doi.org/10.1042/EBC20253045
  11. Int J Mol Sci. 2026 Jan 03. pii: 486. [Epub ahead of print]27(1):
    Mitophagy-NLRP3 Inflammasome Crosstalk in Parkinson's Disease: Pathogenic Mechanisms and Emerging Therapeutic Strategies.
    Sahabuddin Ahmed, Tulasi Pasam, Farzana Afreen.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and pathological α-synuclein aggregation. Growing evidence identifies chronic neuroinflammation-particularly NLRP3 inflammasome activation in microglia-as a central driver for PD onset and progression. Misfolded α-synuclein, mitochondrial dysfunction, and environmental toxins act as endogenous danger signals that prime and activate NLRP3 inflammasome, leading to caspase-1-mediated maturation of IL-1β and IL-18 and subsequent pyroptotic cell death. Impaired mitophagy, due to defects in PINK1/Parkin pathways or receptor-mediated mechanisms, permits accumulation of dysfunctional mitochondria and release DAMPs, thereby amplifying NLRP3 activity. Studies demonstrate that promoting mitophagy or directly inhibiting NLRP3 attenuates neuroinflammation and protects dopaminergic neurons in PD models. Autophagy-inducing compounds, along with NLRP3 inhibitors, demonstrate neuroprotective potential, though their clinical translation remains limited due to poor blood-brain barrier penetration, off-target effects, and insufficient clinical data. Additionally, the context-dependent nature of mitophagy underscores the need for precise therapeutic modulation. This review summarizes current understanding of inflammasome-mitophagy crosstalk in PD, highlights major pharmacological strategies under investigation, and outlines its limitations. Future progress requires development of specific modulators, targeted delivery systems, and robust biomarkers of mitochondrial dynamics and inflammasome activity for slowing PD progression.
    Keywords:  NLRP3 inflammasomes; PINK1/Parkin pathway; Parkinson’s disease; mitophagy; neuroinflammation; neuroprotection
    DOI:  https://doi.org/10.3390/ijms27010486
  12. Life Sci. 2026 Jan 06. pii: S0024-3205(26)00005-6. [Epub ahead of print]387 124197
    Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.
    Yan-Zi Liang, Meng-Zhen Jiang, Xue-Ting Xu, Ting Zhu, Hui Guo, Li Ding, Hao Zhong, Jian Bao, Li-Qiang Qin, Yun-Hong Li.
       AIMS: Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.
    MATERIALS AND METHODS: APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.
    RESULTS: Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of DRP1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.
    CONCLUSIONS: CA-Lip effectively ameliorates hypoxic cognitive impairment by reducing Aβ generation and improving mitochondrial function.
    Keywords:  Alzheimer's disease; Cognitive dysfunction; Intermittent hypoxia; Mitochondrial damage; p-Coumaric acid liposome
    DOI:  https://doi.org/10.1016/j.lfs.2026.124197
  13. FEBS Lett. 2026 Jan 09.
    An upstream open reading frame regulates expression of the mitochondrial protein Slm35 and mitophagy flux.
    Hernán Romo-Casanueva, Ariann E Mendoza-Martínez, P Abril Medina-Flores, Carlos Campero-Basaldua, Alexander DeLuna, Soledad Funes.
      Mitochondrial protein Slm35 is linked to TOR1 signaling, mitophagy, and stress response in Saccharomyces cerevisiae. Nonetheless, little is known about its regulation or how it affects stress adaptation. In this work, we identified stress-related transcription factor binding sites and two upstream open reading frames (uORFs) in the 5'-UTR of SLM35. Using transcriptional reporters, we showed that the transcription factor Gis1 represses SLM35 transcription; however, Slm35 protein levels increased under oxidative stress and in early stationary phase, suggesting post-transcriptional regulation. Site-directed mutagenesis revealed that one uORF negatively regulates translation, with its disruption leading to altered Slm35 levels and a reproducible increase in mitophagy flux. These findings reveal multilayered control of SLM35 expression and underscore the role of uORF-mediated translation in mitochondrial stress responses. Impact statement This study shows that SLM35, encoding a mitochondrial protein, is controlled through multiple regulatory layers, combining transcriptional repression by stress-responsive factors with uORF-mediated translational regulation. By linking these mechanisms to mitophagy, the work provides new insight into mitochondrial quality control under stress.
    Keywords:  SLM35; Saccharomyces cerevisiae; gene expression; mitochondria; mitophagy; stress‐response; upstream open reading frame
    DOI:  https://doi.org/10.1002/1873-3468.70269
  14. Biochem Pharmacol. 2026 Jan 05. pii: S0006-2952(26)00011-0. [Epub ahead of print] 117680
    Genistein improves heart failure with preserved ejection fraction through BNIP3L-mediated mitophagy.
    Zijia Dou, Dianya Sun, Qiang Huang, Huimin Li, Yuan Lin, Tong Zhao, Run Xu, Yang Hong, Jin Gao, Yiyang Li, Ning Wang, Song Wang, Xin Liu.
      Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular disorder, for which effective therapeutic strategies remain lacking. Mitochondrial dysfunction and impaired mitophagy are key mechanisms contributing to HFpEF. BNIP3L, a crucial receptor in mitochondrial autophagy, plays a significant role in maintaining cardiomyocyte energy balance. Here, we first report the therapeutic potential of genistein, a natural flavonoid, in treating HFpEF and its impact on BNIP3L-mediated mitophagy. HFpEF was induced in C57BL/6 mice through a high-fat diet (HFD) combined with Nω-nitro-L-arginine methyl ester (L-NAME). Mice and cardiomyocytes were treated with genistein, and heart function and pharmacological mechanisms was assessed. Genistein treatment significantly improved myocardial remodeling and heart function in HFpEF mice, as evidenced by improved echocardiographic parameters, blood pressure, and exercise performance. Histological analysis showed a reduction in myocardial damage, indicating genistein's protective effect. Mechanistically, Genistein directly interacts with BNIP3L protein, stabilizing its dimeric conformation and promoting its expression in cardiomyocytes. This interaction is critical for enhancing BNIP3L-mediated mitophagy. These findings suggest that genistein exerts a cardioprotective effect in HFpEF through BNIP3L-mediated mitophagy, positioning it as a promising therapeutic candidate for HFpEF.
    Keywords:  BNIP3L; Dimer; Genistein; HFpEF; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.bcp.2026.117680
  15. Int J Mol Sci. 2025 Dec 28. pii: 342. [Epub ahead of print]27(1):
    Subcellular Stress Markers in Epithelial Ovarian Cancer.
    Edina Amalia Wappler-Guzzetta, Eva Margittai, Krisztina Veszelyi, Shanel Pickard, Caroline Merwin, Attila Molvarec, Ibolya Czegle.
      Epithelial ovarian cancer is one of the most lethal gynecological malignancies worldwide. Its development strongly depends on several genetic and environmental factors, with metabolic components and cellular redox homeostasis alterations playing a significant a role in its development and disease progression. In this review, we summarize the contribution of mitochondrial and endoplasmic reticulum (ER) stress in the pathogenesis of epithelial ovarian cancer along with their role as potential biomarkers and therapeutic targets, including proteins of glucose metabolism, mitochondrial fission and fusion, mitophagy, membrane-associated ring-CH-type finger 5 (MARCH5), A-kinase anchoring proteins (AKAPs), proteins regulating mitochondrial Ca2+ homeostasis, mitochondrial unfolded protein response (UPRmt) proteins, activating transcription factors (ATFs), CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP), 'mitokines', GRP75, and GRP78. Although many of these potential targets are in preclinical phase, they have a high potential to become valuable alternative or additive treatments for epithelial ovarian cancers.
    Keywords:  endoplasmic reticulum stress; epithelial ovarian cancer; mitochondrial stress
    DOI:  https://doi.org/10.3390/ijms27010342
  16. bioRxiv. 2025 Dec 30. pii: 2025.12.30.693754. [Epub ahead of print]
    Characterizing the role of mitochondrial dynamics during Drosophila convergent extension using NADH fluorescence lifetime imaging.
    Maria Espana-Pena, Alan Woessner, Colten Nichols, Kyle P Quinn, Adam C Paré.
      Mitochondria are dynamic organelles that can fragment or fuse to support different bioenergetic demands (e.g., glycolysis vs. oxidative phosphorylation) and distinct cell behaviors (e.g., mitosis or migration). While the role of mitochondrial dynamics in wound healing and metabolic disorders has received significant attention, the role of mitochondrial fission and fusion during normal embryonic development is less well understood--in part due to the difficulty of studying such processes in vivo . Combined with the depth-resolved imaging capabilities of multiphoton microscopy, fluorescence lifetime imaging (FLIM) of the mitochondrial cofactor NADH can be used to simultaneously visualize mitochondrial network morphology and infer certain aspects of cellular bioenergetics (e.g., glycolysis vs. oxidative phosphorylation) in a label-free, non-invasive manner. Here we demonstrate that NADH FLIM can be used to accurately track the subcellular localization and topology of mitochondrial networks in live Drosophila embryos. We used this technique to assess whether cells show changes in NADH lifetime during convergent extension (CE)--a conserved process of tissue remodeling in which thousands of germband cells undergo coordinated intercalation to drive elongation of the head-to-tail axis. Contrary to our expectations, we did not observe significant changes in NADH lifetime or network appearance during CE in wild-type embryos, suggesting that germband cells do not need to alter their baseline metabolism to fuel cell intercalation during normal development. To directly assess the role of mitochondrial fission and fusion during CE, we used RNA interference to disrupt the fission mediator Drp1 and the fusion mediator Opa1 . Consistent with expectations, inhibiting mitochondrial fission in Drp1- knockdown embryos led to hyper-fused networks and significantly longer NADH lifetimes, indicating a shift towards oxidative phosphorylation. Conversely, inhibiting mitochondrial fusion in Opa1- knockdown embryos led to more hyper-fragmented networks and significantly shorter NADH lifetimes, indicating a shift towards glycolysis. Interestingly, inhibiting either fission or fusion altered tissue elongation and greatly increased the rate of cell intercalation errors, suggesting that a precise network topology is required for proper CE. We hypothesize that the CE defects in Drp1 -knockdown embryos are primarily due to incorrect basal subcellular localization of mitochondria, whereas the CE defects in Opa1 -knockdown embryos are due to deficient ATP and/or ROS production. These experiments demonstrate the utility of FLIM-based applications for characterizing the role of mitochondria during normal embryonic development, which could yield a better understanding of the metabolic underpinnings of various pathologies that involve epithelial remodeling, including spina bifida, defective wound healing, and cancer metastasis.
    DOI:  https://doi.org/10.64898/2025.12.30.693754
  17. Exp Cell Res. 2026 Jan 07. pii: S0014-4827(25)00477-X. [Epub ahead of print] 114875
    MiR-181c-5p-SIRT1 axis-driven Pink1/Parkin-mediated mitophagy prevents ferroptosis and vascular calcification in chronic kidney disease.
    Ruman Chen, Jiqing He, Na An, Mingzhi Xu, Liheng Wang, Yafei Bai.
       BACKGROUND: Vascular calcification (VC) is a severe cardiovascular complication of chronic kidney disease (CKD), driven by vascular smooth muscle cell (VSMC) osteogenic trans-differentiation and exacerbated by oxidative stress and cellular dysfunction. Despite its clinical relevance, the molecular mechanisms underlying CKD-associated VC remain incompletely understood. This study investigates the role of Sirtuin 1 (SIRT1) in modulating VC through ferroptosis inhibition and mitophagy activation and examines whether microRNA-181c-5p (miR-181c-5p) contributes to SIRT1 dysregulation in this context.
    METHODS: A CKD-associated VC model was induced in rats by 5/6 nephrectomy followed by high calcium/phosphate and calcitriol loading, and an in vitro calcification model was established in primary rat VSMCs. SIRT1 was manipulated using AAV9-mediated overexpression in vivo and plasmid overexpression or inhibition in vitro. Upstream regulation of SIRT1 by miR-181c-5p was predicted bioinformatically and validated by RNA pull-down and dual-luciferase assays. Ferroptosis was assessed by redox and Fe2+ indices, and mitophagy by Pink1/Parkin, LC3-II and p62 expression. Rescue experiments employed erastin, Mdivi-1 and Parkin knockdown.
    RESULTS: SIRT1 expression was markedly reduced in calcified aortic tissues and VSMCs. SIRT1 overexpression suppressed VC by reducing calcium deposition, downregulating osteogenic markers, and increasing fetuin-A levels. SIRT1 also suppressed ferroptosis by restoring the GSH/GPX4/SLC7A11 axis and limiting ROS and lipid peroxidation, whereas erastin abolished these effects. Mechanistically, miR-181c-5p was found to directly target SIRT1 and promote VSMC calcification by repressing SIRT1. Moreover, SIRT1 promoted mitophagy via the Pink1/Parkin pathway activation. Furthermore, inhibition of mitophagy reversed the anti-ferroptotic effects of SIRT1, confirming their functional interplay.
    CONCLUSIONS: SIRT1, negatively regulated by miR-181c-5p, mitigates CKD-associated VC by suppressing ferroptosis and activating Pink1/Parkin-dependent mitophagy in VSMCs, highlighting a potential therapeutic axis for vascular protection in CKD.
    CLINICAL TRIAL REGISTRATION NUMBER: Not applicable.
    Keywords:  Chronic kidney disease; Pink1/Parkin; SIRT1; ferroptosis; mitophagy; vascular calcification
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114875
  18. Zhongguo Zhong Yao Za Zhi. 2025 Nov;50(22): 6391-6399
    [Effect of Jiawei Duhuo Jisheng Mixture in improving mitophagy to treat knee osteoarthritis based on PINK1/Parkin pathway].
    Zi-Feng Ye, Yi-Wei Yuan, Zhi Wen, Xu-Yi Tan, Liang Ou, Xiao-Tong Xu, Gao-Yan Kuang, Min Lu.
      This study aims to investigate the effects of Jiawei Duhuo Jisheng Mixture on mitochondrial autophagy in the cartilage of rabbits with knee osteoarthritis(KOA) based on the PTEN-induced kinase 1(PINK1)/Parkinson protein(Parkin) pathway and explore its potential mechanism in improving cartilage lesions. A KOA model was established by fixing a high-molecular resin plaster bandage on the right hind limb of the rabbits for six weeks. After successful modeling, the modeling group was randomly divided into a model group, a celecoxib group, and low-and high-dose groups of Jiawei Duhuo Jisheng Mixture, with eight rabbits in each group. The celecoxib group was administered celecoxib by gavage at a single dose of 0.009 3 g·kg~(-1). The low-and high-dose groups of Jiawei Duhuo Jisheng Mixture were given Jiawei Duhuo Jisheng Mixture at single doses of 6.8 mL·kg~(-1)(4.515 2 g·kg~(-1)) and 27.2 mL·kg~(-1)(18.060 8 g·kg~(-1)), respectively. Administered once daily for six weeks, the rabbits in each group then underwent behavioral testing. After sample collection, the gross morphological changes of the knee articular cartilage were observed with the naked eye. Hematoxylin-eosin(HE) staining was used to detect pathological changes in cartilage tissue, which were quantitatively evaluated by using the Lequesne MG score, Pelletier score, and Mankin score. Transmission electron microscopy was used to observe the ultrastructural changes of chondrocyte mitochondria. Flow cytometry was used to detect the mitochondrial membrane potential(Δψm) and the average fluorescence intensity of reactive oxygen species(ROS) in chondrocytes and calculate the percentage of cells with low Δψm. Western blot was used to detect the expression level of mitochondrial autophagy-related proteins in cartilage tissue, including PINK1, Parkin, selective autophagy adapter protein 62(P62), light chain 3(LC3)Ⅱ/LCⅠ, mitochondrial outer membrane translocase 20(TOM20), collagen type Ⅱ alpha 1(COL2A1), aggrecan(ACAN), matrix metalloproteinase(MMP)-9, and MMP-13. Immunohistochemistry(IHC) was used to detect the expression of PINK1, Parkin, and LC3B in cartilage tissue. The results showed that, compared with the blank group, the model group exhibited marked knee joint swelling and damage, tissue fibrosis, sparse chondrocyte distribution, and indistinct and incomplete tide marks. The Lequesne MG, Pelletier, and Mankin scores increased significantly. Autophagosomes were reduced, and mitochondria were morphologically abnormal. The percentage of chondrocytes with low Δψm, ROS average fluorescence intensity, and the expression of P62, TOM20, MMP-9, and MMP-13 proteins in cartilage tissue rose significantly, while the expression of PINK1, Parkin, LC3Ⅱ/LCⅠ, COL2A1, and ACAN proteins in cartilage tissue decreased significantly. Compared with the model group, the celecoxib and both Jiawei Duhuo Jisheng Mixture groups showed improved knee articular cartilage surface, relatively intact tide marks, and denser chondrocytes. Their Lequesne MG, Pelletier, and Mankin scores dropped significantly. Autophagosomes increased, and mitochondrial swelling and damage eased. The percentage of chondrocytes with low Δψm, ROS average fluorescence intensity, and the expression of P62, TOM20, MMP-9, and MMP-13 proteins in cartilage tissue decreased significantly, while the expression of PINK1, Parkin, LC3Ⅱ/LCⅠ, COL2A1, and ACAN proteins in cartilage tissue increased significantly. In conclusion, Jiawei Duhuo Jisheng Mixture can effectively activate the PINK1/Parkin pathway to promote mitochondrial autophagy and alleviate articular cartilage damage in rabbits with KOA, thus slowing the progression of KOA.
    Keywords:  Jiawei Duhuo Jisheng Mixture; PINK1/Parkin signaling pathway; knee osteoarthritis; mitochondrial autophagy
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250730.401
  19. Mol Ther. 2026 Jan 02. pii: S1525-0016(25)01139-6. [Epub ahead of print]
    CTRP1 regulates skeletal muscle differentiation through quality control of mitochondrial dynamics and function.
    Sora Han, Youjeong Jang, Hyun Jeong Joo, Hye In Ka, Se Hwan Mun, Hai-Anh Nguyen, Doyeon Park, Yoohyun Jung, Doyeong Ko, Bo Ram Sohn, Seong Keun Sonn, Goo Taeg Oh, Young-Chul Choi, So-Young Park, Sung-Eun Kim, Young Yang.
      Mitochondrial dysfunction is a hallmark of myopathies and impaired skeletal muscle differentiation. Here, we demonstrate that C1q/TNF-related protein 1 (CTRP1) is essential for maintaining mitochondrial dynamics and supporting myogenic differentiation. Loss of CTRP1 in myoblasts and in skeletal muscle-specific knockout (CTRP1 KOΔACTA) mice led to impaired myotube formation, reduced muscle fiber cross-sectional area, and decreased muscle strength. CTRP1 deficiency also shifted the muscle fiber composition from oxidative Type IIA to glycolytic Type IIB fibers, indicating a compromised mitochondrial capacity. At the cellular level, CTRP1 loss resulted in elongated and disorganized mitochondria with diminished cristae density, membrane potential, and oxidative respiration. These mitochondrial abnormalities are associated with defective recruitment of dynamin-related protein 1 (DRP1), a central mediator of mitochondrial fission. Restoring CTRP1 expression or performing mitochondrial transplantation in CTRP1 KO myoblasts rescued mitochondrial function and re-established differentiation capacity. Furthermore, CTRP1 expression progressively decreased in accordance with disease severity in skeletal muscle biopsies from patients with polymyositis, dermatomyositis, and Duchenne muscular dystrophy, supporting its potential relevance to human myopathies. Together, these findings identify CTRP1 as a novel regulator of mitochondrial quality and myogenic differentiation, highlighting its potential as a therapeutic target for mitochondrial myopathies.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.063
  20. Circulation. 2026 Jan 06.
    Inhibition of Annexin A2 Facilitates PHB2-Mediated Mitophagy in Cardiomyocytes to Alleviate Cardiac Injury and Remodeling After Infarction.
    Ke-Qiong Deng, Zhendong Xu, Qiong-Xin Wang, Huan-Huan Cai, Di Fan, Qingqing Wu, Xiao-Jing Zhang, Peng Zhang, Zhi-Gang She, Xingguo Liu, Xianqing Li, Zhibing Lu.
       BACKGROUND: Mitophagy is critically involved in cardiac injury and repair after myocardial infarction (MI), whereas the annexin A family plays an important role in mitophagy. However, the intrinsic molecular underpinnings that orchestrate the homeostasis of mitophagy in the infarcted heart remain to be fully characterized. Here, we aimed to evaluate the role of ANXA2 (annexin A2) in cardiac mitophagy in response to MI.
    METHODS: Transcriptome analyses were conducted to identify differentially expressed genes and enriched pathways. Mitophagy, mitochondrial function, and cardiac injury and remodeling were analyzed in MI mice and neonatal rat ventricular myocytes with cardiomyocyte-specific ANXA2 knockdown or overexpression, as well as in models with ANXA2 knockdown combined with PHB2 (prohibitin 2) silencing. Immunoprecipitation, mass spectrometry, and glutathione S-transferase pull-down assays were used to identify the interacting proteins of ANXA2.
    RESULTS: We showed that ANXA2 was highly expressed in murine and human ischemic failing hearts, whereas increased circulating ANXA2 positively correlated with cardiac injury in patients with acute MI. Moreover, cardiomyocyte-specific ANXA2 depletion averted cardiac mitophagy inactivation, oxidative stress, cell death, and inflammatory cell infiltration, leading to significant improvements in infarct size, heart function, and cardiac remodeling after MI. Conversely, ANXA2 overexpression in cardiomyocytes suppressed mitophagy to exacerbate cardiac injury and deteriorate heart failure after MI. Moreover, ANXA2 silencing and overexpression, respectively, in neonatal rat ventricular myocytes under hypoxia in vitro recapitulated the in vivo findings on mitochondrial function and cell death. Mechanistically, we found that ANXA2 directly interacted with the mitophagy receptor PHB2 to competitively block the binding of LC3B with PHB2 and promote PHB2 proteasomal degradation through K48-linked polyubiquitination mediated by the E3 ligase TRIM29, resulting in mitophagy inhibition under hypoxia. Consequently, PHB2 knockdown abrogated the protective effects of ANXA2 deficiency on mitochondrial function, oxidative stress, and cell viability in stressed myocytes in vitro, as well as on heart function and remodeling under MI in vivo.
    CONCLUSIONS: These findings highlight the significance of ANXA2 inhibition as a molecular brake on mitophagy inactivation in cardiomyocytes under MI and uncover an ANXA2-mediated posttranslational mechanism essential for maintaining mitochondrial homeostasis and alleviating heart failure after MI.
    Keywords:  cardiomyocyte; mitochondrial function; mitophagy; myocardial infarction; proteasomal degradation
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.077780
  21. Sci Rep. 2026 Jan 06.
    Cancer cells surviving cisplatin chemotherapy increase stress-induced OMA1 activity and mitochondrial fragmentation.
    Melvin Li, Chenille A McCullum, Louis T A Rolle, Qin Ni, Zhuoxu Ge, Sean X Sun, Kenneth J Pienta, Sarah R Amend.
      Cancer is one of the leading causes of deaths worldwide. Once cancer cells acquire therapy resistance, they become the main driver of cancer lethality in patients. Thus, mechanisms of therapy resistance must be investigated to improve patient outcomes. Mitochondria are critical organelles in the cellular stress responses, undergoing dynamic morphological and functional changes in response to external stimuli. We and others have identified a chemotherapy-resistant cancer cell state where cells that survive treatment exhibit a dramatic increase in cell size and remain non-proliferative for weeks. In this study, we demonstrate that cancer cells that enter this resistant cell state in response to cisplatin increase OMA1 activity and decrease mitochondrial fusion and function to combat oxidative stress. These findings contribute to further understanding the role of the mitochondrial stress responses in therapy resistance in cancer and provide a potential therapeutic avenue to targeting cancer cells that enter this chemotherapy-resistant cell state.
    Keywords:  Cancer; Mitochondrial dynamics; Mitochondrial morphology; OMA1; OPA1; Oxidative stress
    DOI:  https://doi.org/10.1038/s41598-025-33677-1
  22. Cytoskeleton (Hoboken). 2026 Jan 08.
    Mitochondria and the Actin Cytoskeleton in Neurodegeneration.
    Shivani Tuli, Preet Patel, Aneri Shethji, David Gau.
      Mitochondrial dysfunction and cytoskeletal disorganization are widely recognized hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although these disorders differ in clinical presentation and etiology, accumulating evidence points to a shared cellular vulnerability at the intersection of mitochondrial dynamics and actin cytoskeletal regulation. In this review, we examine the emerging role of actin-mitochondria crosstalk as a convergent mechanism in neurodegeneration. We discuss how disruptions in actin filament remodeling, mitochondrial fission and fusion, organelle transport, and mitophagy contribute to neuronal dysfunction and loss across these diseases. Particular attention is given to disease-specific pathways, including cofilin-actin rod formation in AD, α-synuclein-driven actin disruption in PD, mutant huntingtin's effects on mitochondrial fragmentation in HD, and profilin-1-associated mitochondrial defects in ALS. By synthesizing findings from diverse models, we highlight how perturbations in the cytoskeleton-mitochondria interface may act as an upstream trigger and amplifier of neurodegenerative cascades. We also outline key knowledge gaps and propose future directions for research, with an emphasis on targeting actin-mitochondrial interactions as a potential therapeutic strategy across multiple neurodegenerative conditions.
    Keywords:  actin cytoskeleton; mitochondria dysfunction; mitochondria‐cytoskeleton crosstalk; neurodegeneration
    DOI:  https://doi.org/10.1002/cm.70095
  23. Zhongguo Zhong Yao Za Zhi. 2025 Sep;50(17): 4897-4905
    [Cajanolactone A ameliorates hepatocyte steatosis by regulating mitochondrial quality control via PGC-1α].
    Li-Zhen Gan, You-You Cao, Yu-Jia Guo, Ying-Jie Hu, Rui-Yi Yang.
      To explore the effects and mechanisms of cajanolactone A(CLA) on hepatocyte steatosis, with a focus on mitochondrial quality control(MQC) regulated by peroxisome proliferator-activated receptor-γ-coactivator-1α(PGC-1α). Human liver HHL-5 cells were induced with fatty acids(oleic acid-palmitic acid=2∶1) to develop steatosis, followed by exposure to different concentrations(2, 4, and 8 μmol·L~(-1)) of CLA. Lovastatin(LOV), the PGC-1α agonist ZLN005, and the PGC-1α inhibitor SR18292 served as control groups. Lipid accumulation was assessed by BODIPY staining, and flow cytometry. The levels of triglycerides(TG), total cholesterol(TC), and non-esterified fatty acids(NEFA) were measured by corresponding kits. The mitochondrial DNA(mtDNA) levels were determined by qPCR. The number and morphology of mitochondria(Mt) were observed by transmission electron microscopy. The mitochondrial quality was detected by Mt-specific fluorescent probe labeling. The functions of Mt were evaluated by JC-1 mitochondrial membrane potential and the ATP assay. The expression levels of PGC-1α and its associated transcription factors, including peroxisome proliferator-activated receptor α(PPARA), nuclear respiratory factor 1(NRF1), nuclear respiratory factor 2(NRF2), mitochondrial transcription factor A(TFAM), mitofusion 2(MFN2), optic atrophy 1(OPA1), autophagy receptor protein p62, beclin 1, and microtubule-associated protein 1 light chain 3β(LC3B), were quantified by RT-qPCR and Western blot. The results showed that CLA significantly reduced lipid accumulation, promoted lipolysis, increased Mt quantity, and improved the mitochondrial morphology, structure, and function in hepatocytes with steatosis. Furthermore, CLA up-regulated the expression of PGC-1α, PPARA, NRF1, NRF2, TFAM, MFN2, OPA1, p62, beclin 1, and LC3B. In conclusion, CLA may ameliorate hepatic steatosis by regulating the PGC-1α pathway and maintaining mitochondrial homeostasis.
    Keywords:  PGC-1α; cajanolactone A; lipid metabolism; mitochondrial function; mitochondrial quality control; steatosis
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250609.702
  24. Adv Sci (Weinh). 2026 Jan 04. e13442
    MDP25-VDAC3 Complex Orchestrates Actin Remodeling and Mitochondrial Dynamics to Modulate Innate Immunity in Arabidopsis.
    Junxiu Hou, Pengfei Lu, Xuan Cui, Liangfeng Luo, Qing Pan, Jiejie Li.
      Host actin remodeling is critical for plant defense against pathogen infection, yet its specific functions remain to be fully explored. This study characterizes the role of the actin cytoskeleton in regulating mitochondrial dynamics to enhance plant defense. We demonstrate that the perception of the bacterial flagellin epitope induces excessive mitochondrial elongation, which facilitates the exchange of mitochondrial components for the functional recovery of damaged mitochondria. This elongation also promotes ATP and mitochondrial ROS production. The formation of elongated mitochondria largely depends on actin bundles in the cortical array. The contribution of actin bundles involves providing structural support for mitochondrial fusion and preventing already elongated mitochondria from undergoing fission. We further identified the interaction between the actin-regulating protein MDP25 and the mitochondrial outer membrane protein VDAC3 in actin remodeling and mediating actin-mitochondria interaction essential for mitochondrial fusion and elongation. Collectively, this study presents a mechanistic model for actin-dependent mitochondrial elongation and its significance for plant immunity.
    Keywords:  Arabidopsis thaliana; MDP25‐VDAC3 complex; actin cytoskeleton remodeling; mitochondrial dynamics; plant innate immunity
    DOI:  https://doi.org/10.1002/advs.202513442
  25. Exp Neurol. 2026 Jan 01. pii: S0014-4886(25)00501-1. [Epub ahead of print]398 115636
    Biochanin A exerts neuroprotective effects in Parkinson's disease both in vivo and in vitro by improving mitochondrial dysfunction through the Sirt1 signaling pathway.
    Shuxiang Tian, Mingguang Niu, Qian Qian, Kexian Zhang, Han Yang, Yang Xiao, Xinyue Jin, Yanyan Yin.
      The accumulation of reactive oxygen species (ROS) leading to mitochondrial dysfunction is the pathological characteristics underlying the damage to dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD). Therefore, through improving mitochondrial dysfunction may be a potential strategy for PD treatment. Biochanin A (Bioch A), as a natural isoflavone phytoestrogen, has been implicated in studies for its therapeutic potential in neurodegenerative diseases. However, the precise molecular mechanisms by which it modulates PD-related neuronal damage remain unclear, limiting its clinical translational application. This study focuses on the neuroprotective mechanism of Bioch A, systematically revealing the key pathways and regulatory mechanisms through which it exerts its neuroprotective effects in PD by targeting mitochondrial dysfunction. By establishing lipopolysaccharide (LPS)-induced PD model mice and tumor necrosis factor-α (TNF-α)-induced SH-SY5Y cell models, combined with in vivo and in vitro experiments confirmed that Bioch A significantly alleviates dopaminergic neuronal damage by downregulating ROS levels, modulating adenosine triphosphate (ATP) production, promoting mitochondrial biogenesis, and improving abnormal mitochondrial dynamics. More importantly, this study has for the first time revealed that the Sirt1 pathway is a core target for Bioch A in regulating mitochondrial dysfunction. Furthermore, Bioch A promotes mitochondrial biogenesis by activating the Sirt1 pathway and reduces apoptosis levels by promoting mitochondrial fusion. In conclusion, this study provides novel experimental evidence for Bioch A's regulation of mitochondrial dysfunction, establishing the Sirt1 pathway as a key neuroprotective target. This discovery paves the way for Bioch A's clinical translation and targeted therapeutic research in PD.
    Keywords:  Biochanin A; Mitochondrial dysfunction; Neurons; Parkinson's disease; Sirt1
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115636
  26. Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2516471123
    USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy.
    Yanqi Xu, Keshuo Jin, Jiaqing Chen, Zhongding Li, Zhenhu Zhu, Xian Su, Jiangyun Shen, Bincheng Zhou, Zijun Cao, Liyan Lou, Deyu Deng, Jianzhao Zhang, Baohua Liu, Yangping Shentu, Xu Wang.
      Parkinson's disease (PD) is a progressive neurodegenerative disease that casts a significant shadow over global health and the identification of therapeutic targets for PD will empower more effective clinical treatment. The gene encoding the deubiquitinating enzyme USP25 has been identified as a susceptible locus for PD, but the role of USP25 in PD remains unknown. In this study, we found that USP25 exacerbated dopaminergic neuronal loss and motor deficits in murine models of PD by sabotaging the mitophagy machinery. USP25 physically interacted with the autophagy receptor optineurin and disrupted its linkage with K63-specific polyubiquitin chains, leading to impaired mitophagy and the accumulation of damaged mitochondria. Genetic ablation or pharmacological inhibition of USP25 significantly restored mitophagy and thereby impeded the neurodegenerative progression in PD model mice. Collectively, our results unravel a pivotal role of USP25 in PD and identify USP25 as a pharmacological target for the development of PD drugs.
    Keywords:  Parkinson’s disease; USP25; mitophagy; optineurin; ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2516471123
  27. Int J Mol Sci. 2026 Jan 02. pii: 485. [Epub ahead of print]27(1):
    Mitochondrial Health Through Nicotinamide Riboside and Berberine: Shared Pathways and Therapeutic Potential.
    Federico Visalli, Matteo Capobianco, Francesco Cappellani, Lorenzo Rapisarda, Alfonso Spinello, Alessandro Avitabile, Ludovica Cannizzaro, Caterina Gagliano, Marco Zeppieri.
      Mitochondrial dysfunction represents a central hallmark of aging and a broad spectrum of chronic diseases, ranging from metabolic to neurodegenerative and ocular disorders. Nicotinamide riboside (NR), a vitamin B3 derivative and efficient precursor of NAD+ (nicotinamide adenine dinucleotide), and berberine (BBR), an isoquinoline alkaloid widely investigated in metabolic regulation, have independently emerged as promising mitochondrial modulators. NR enhances cellular NAD+ pools, thereby activating sirtuin-dependent pathways, stimulating PGC-1α-mediated mitochondrial biogenesis, and triggering the mitochondrial unfolded protein response (UPRmt). BBR, by contrast, primarily activates AMPK (AMP-activated protein kinase) and interacts with respiratory complex I, improving bioenergetics, reducing mitochondrial reactive oxygen species, and promoting mitophagy and organelle quality control. Importantly, despite distinct upstream mechanisms, NR and BBR converge on shared signaling pathways that support mitochondrial health, including redox balance, metabolic flexibility, and immunometabolic regulation. Unlike previous reviews addressing these compounds separately, this article integrates current preclinical and clinical findings to provide a unified perspective on their converging actions. We critically discuss translational opportunities as well as limitations, including heterogeneous clinical outcomes and the need for robust biomarkers of mitochondrial function. By outlining overlapping and complementary mechanisms, we highlight NR and BBR as rational combinatorial strategies to restore mitochondrial resilience. This integrative perspective may guide the design of next-generation clinical trials and advance precision approaches in mitochondrial medicine.
    Keywords:  NAD+ metabolism; berberine; cardiometabolic disease; mitochondrial dysfunction; neuroprotection; nicotinamide; nicotinamide riboside; oxidative stress; retinal ganglion cells
    DOI:  https://doi.org/10.3390/ijms27010485
  28. Neuropharmacology. 2026 Jan 06. pii: S0028-3908(26)00004-3. [Epub ahead of print] 110831
    NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord.
    Xiaoyu Zhang, Jiale Sun, Fengtian Zhao, Ting Liu, Shangchen Yu, Wen Zhang, Xuebi Tian.
       OBJECTIVE: Neuropathic pain (NP) presents a significant clinical challenge due to its physical and psychological impact and the lack of effective treatments. While the pathogenesis of NP remains incompletely understood, emerging evidence suggests that Nod-like receptor pyrin domain-containing protein 10 (NLRP10) participates in neurological disorders via neuroinflammation and mitochondrial autophagy. This study investigates roles of NLRP10 in NP pathogenesis and elucidates its mechanism in triggering neuroinflammation-mediated NIX/LC3-dependent mitochondrial dysfunction.
    METHODS: A spared nerve injury (SNI) mouse model was established to investigate neuropathic pain (NP) mechanisms. Pain behaviors were assessed using the mechanical pain withdrawal threshold (MPWT). Adeno-associated virus (AAV) was administered to the spinal dorsal horn (SDH) to downregulate NLRP10 or overexpress NIX. Neuroinflammatory responses and alterations in mitophagy were subsequently evaluated using Western blotting, ELISA, immunofluorescence, and transmission electron microscopy.
    RESULTS: SNI mice exhibited upregulated NLRP10 inflammasome expression and enhanced activation of the downstream NLRP12/ASC/Caspase1 pathway in the SDH. This was accompanied by significant increases in NIX/LC3 protein concentrations and decreased mitochondrial-related protein levels after surgery. NLRP10 predominantly colocalized with neuronal marker NeuN in SDH. Transmission electron microscopy revealed characteristic mitochondrial damage. Knockdown of NLRP10 with mNLRP10 effectively suppressed inflammatory activation, attenuated excessive mitochondrial autophagy, and alleviated NP manifestations. Notably, NIX overexpression abolished the protective effects of NLRP10 reduction in SNI mice.
    CONCLUSION: In summary, our findings demonstrate that NLRP10 downregulation inhibit NLRP12/ASC/Caspase1 pathway activation and prevents pathological mitochondrial autophagy, ultimately alleviating NP. These results identify NLRP10 as a promising therapeutic target for NP management.
    Keywords:  Mitophagy; NIX/LC3; NLRP10; Neuroinflammation; Neuropathic pain
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110831
  29. NPJ Metab Health Dis. 2026 Jan 06. 4(1): 1
    Parkin-ACSL4 axis in ferroptosis regulation: a narrative review on therapeutic insights from exercise in aging cardiomyocytes.
    Negin Kordi, Behnam Bagherzadeh-Rahmani, Rezvan KheirAndish, Raheleh Rezaali, Brent R Stockwell.
      Ferroptosis, iron-dependent regulated cell death, drives age-related cardiac dysfunction. This review examines aerobic exercise modulation of ferroptosis in aging cardiomyocytes via Parkin-ACSL4 axis. Parkin promotes ACSL4 ubiquitination/degradation, reducing lipid peroxidation and ROS. Exercise activates PINK1/Parkin mitophagy and hepcidin, enhancing mitochondrial resilience and iron homeostasis. Despite promising preclinical evidence, molecular mechanisms remain unclear. Aerobic exercise offers non-pharmacological cardiac protection against ferroptosis in aging.
    DOI:  https://doi.org/10.1038/s44324-025-00092-z
  30. Peptides. 2026 Jan 02. pii: S0196-9781(25)00124-X. [Epub ahead of print]195 171463
    FGF9 drives mitochondrial biogenesis in glioblastoma by activating the CREB-PGC-1α axis.
    Kun Xue, Junmei Yang, Jia Hu, Lingwei Kong, Xinguo Cui, Yang Kong.
       BACKGROUND: Mitochondrial biogenesis is upregulated in glioblastoma to support tumor growth, invasion, and chemoresistance by meeting the heightened metabolic demands of cancer cells. Fibroblast growth factor 9 (FGF9) is a potent oncogenic driver in various cancers, promoting proliferation, survival, and angiogenesis. However, its role in regulating mitochondrial metabolism in glioblastoma remains unclear.
    METHODS: The activation of FGF9/fibroblast growth factor receptor 2 (FGFR2) signaling and expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) were examined in clinical glioblastoma samples and cell lines using real-time PCR, immunohistochemistry, and western blotting. Mitochondrial biogenesis and function in FGF9-treated U-87 cells were evaluated by measuring relative mtDNA/nDNA ratio, mitochondrial mass (MitoTracker), complex activity, membrane potential, and ATP production. The role of cAMP response element-binding protein (CREB) signaling was investigated using the specific inhibitor H89.
    RESULTS: We found activated FGF9/FGFR2 signaling in glioblastoma patients, with elevated serum FGF9 and tumor FGFR2. PGC-1α was upregulated in samples and cell lines. FGF9 boosted mitochondrial biogenesis and function in U-87 cells, increasing mtDNA, mass, complex activity, membrane potential, and ATP production. Mechanistically, FGF9 promoted the expression of PGC-1α and mitochondrial transcription factor A (TFAM) via activation of CREB signaling. Inhibition of CREB phosphorylation by H89 abolished FGF9-induced upregulation of PGC-1α/TFAM, mtDNA replication, and ATP production.
    CONCLUSION: These findings reveal that FGF9 enhances mitochondrial biogenesis in glioblastoma through the CREB-PGC-1α-TFAM axis, uncovering a novel metabolic mechanism underlying its pro-tumorigenic effects.
    Keywords:  CREB; FGF9; Glioblastoma; Mitochondrial biogenesis; PGC-1α
    DOI:  https://doi.org/10.1016/j.peptides.2025.171463
  31. Int J Mol Sci. 2025 Dec 22. pii: 107. [Epub ahead of print]27(1):
    Features of Mitochondrial Dynamics in Different Brain Parts of Patients with Alzheimer's Disease.
    Vladimir S Sukhorukov, Tatiana I Baranich, Olga V Velts, Dmitry N Voronkov, Ekaterina V Shcherbak, Dmitry S Lazarev, Dmitry A Kharlamov, Alexandr P Raksha.
      A number of recent studies have demonstrated the importance of investigating mitochondrial dynamics mechanisms in Alzheimer's disease (AD). This study involved an immunohistochemical analysis of mitochondrial dynamics markers Opa-1, Mfn-2, and Drp-1 in neurons of the middle frontal gyrus, anterior cingulate gyrus, head of the caudate nucleus, hippocampus, and inferior parietal lobule using autopsy material from AD patients. The comparison was made with similar brain regions in autopsy material from elderly and young patients. Additionally, changes in these markers in AD were correlated with the distribution of pathological amyloid aggregates in the corresponding regions. Our findings suggest specific features of metabolic process alterations in neurons in AD, which are not limited to a single brain region but involve multiple areas and exhibit a uniform pattern. Our data are significant for understanding the pathogenesis of this disease and aging in general, and may serve as a basis for developing targeted therapy for AD.
    Keywords:  Alzheimer’s disease; aging; amyloid; hippocampus; mitochondrial dynamics; neuron
    DOI:  https://doi.org/10.3390/ijms27010107
  32. Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Jan 06. pii: S1388-1981(26)00002-8. [Epub ahead of print] 159716
    Neuroprotective effect of berberine-loaded niosomes against brain injury in dyslipidemic rats: The interplay between oxidative stress, mitochondrial dysfunction and apoptotic signals.
    Mohamed Fouad Mansour, Amany Behairy, Tarek Khamis, Haiam A Mohammed, Amira Ebrahim Alsemeh, Asmaa Monir Eltaweel, Mahran Mohamed Abd El-Emam.
      Dyslipidemia is a major risk factor for the development of atherosclerosis, cardiovascular diseases, and brain injury. Berberine (BER), a type of isoquinoline alkaloid, has the potential to enhance mitochondrial performance owing to its remarkable antioxidant properties. This study aimed to explore how berberine-loaded niosomes (BER-NIO) would alleviate the adverse effects of brain injury in dyslipidemic rats. Hence, for this purpose, the genes of electron transport chain, mitochondrial dynamics, mitophagy, and apoptosis were assessed in brain tissue. Moreover, molecular docking analysis was done to predict this target pathway.
    METHODS: Thirty-five male Sprague Dawley rats were separated into five groups: (I) Control (Ctl), (II) Poloxamer 407 (Plx), (III) Plx + BER-NIO, (IV) Plx + NC, and (V) Plx + BER-NIO + NC.
    RESULTS: BER-NIO improved lipid profile, brain MDA, and brain total antioxidant capacity (TAC) compared to Plx group. Moreover, BER-NIO was able to notably restore the activity of mitochondrial respiratory chain complexes through upregulation of the mRNA expression levels of Ndufs1, Sdhc, Coq8a, Cox6a2 and Atp5f1a. It also enhanced the mitochondrial dynamics via modulation of the transcriptional level of DRP-1, MFN-1, and MFN-2. In addition, administration of BER-NIO to dyslipidemic rats regulated the mitophagy pathway through alteration of PINK-1/Prkn pathway within brain tissue. Furthermore, BER-NIO notably enhanced neurological function through reduction of brain pathological alterations, suppression of apoptosis and decrease of the biomarker for brain injury (GFAP). Interestingly, molecular docking analysis revealed a strong binding affinity between BER and MFN-2, PINK-1 and caspase-3.
    CONCLUSION: The findings suggested that the BER-NIO is effective in the reduction of brain injury in dyslipidemic rats via modulation of brain oxidant/antioxidant status and mitochondrial functions.
    Keywords:  Apoptosis; Berberine-loaded niosomes; Dyslipidemia; Mitochondrial function; Mitophagy; Niacin
    DOI:  https://doi.org/10.1016/j.bbalip.2026.159716
  33. J Pharm Anal. 2025 Dec;15(12): 101333
    Naringenin boosts Parkin-mediated mitophagy via estrogen receptor alpha to maintain mitochondrial quality control and heal diabetic foot ulcer.
    Xin-Meng Zhou, Ying Yang, Dao-Jiang Yu, Teng Xie, Xi-Lu Sun, Ying-Xuan Han, Hai-Ying Tian, Qing-Qing Liao, Yu-Jie Zhao, Yih-Cherng Liou, Wei Huang, Yong Xu, Xi Kuang, Xiao-Dong Sun, Yuan-Yuan Zhang.
      Diabetic foot ulcer (DFU) is an increasing global burden due to the rising prevalence of diabetes, and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment. In this study, naringenin (NAR) was found to accelerate diabetic wound healing in diabetic C57BL/6J wild-type (WT) mice by reducing oxidative stress, as assessed through histological assay. NAR also alleviated the inhibition of proliferation, inflammation, cell senescence, and apoptosis in HaCaT cells induced by high glucose (HG). Mechanistically, the beneficial effects of NAR on wound healing are dependent on the E3 ubiquitin-protein ligase parkin (Parkin/PRKN/Prkn). NAR upregulated the expression level of Parkin and promoted its mitochondrial translocation, thereby activating Parkin-mediated mitophagy and maintaining mitochondrial quality control (MQC). Moreover, the wound healing-promoting effects of NAR were significantly diminished in Parkin knockdown HaCaT cells and Prkn knockout (Prkn -/-) DFU mice. Inhibition of NAR binding to estrogen receptors (ERs) using tamoxifen (TAM) abolished the protective effects of NAR in HG-induced HaCaT cells. The luciferase reporter assay confirmed that NAR enhanced ERs binding to the estrogen response element (ERE), thereby upregulating Parkin transcription. Additionally, the cellular thermal shift assay (CETSA) revealed that NAR specifically bound to ERα. In conclusion, NAR promoted DFU wound healing by enhancing Parkin-mediated mitophagy via binding to ERα, highlighting its potential as a promising therapeutic candidate.
    Keywords:  Diabetic foot ulcer; E3 ubiquitin-protein ligase parkin; Estrogen receptor α; Mitochondrial quality control; Mitophagy; Naringenin
    DOI:  https://doi.org/10.1016/j.jpha.2025.101333
  34. Mol Neurobiol. 2026 Jan 03. 63(1): 338
    Cannabidiol Alleviates LPS-Induced Depressive-Like Behaviors Via Improving Mitochondria Function.
    Junning Zhao, Qian Liu, Xin Wang, Yusen Xiao, Baiyi Yao, Jiale Liu, Cailin Wang, Gongping Liu, Xiaoyue Hong.
      Mitochondrial autophagy has been regarded as a new signaling pathway for the action of antidepressant drugs. The neuroprotective properties of the non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated in different animal models of neurological disorders. However, the therapeutic effect of cannabidiol on neuroinflammation-induced depression and its underlying molecular mechanisms involved has not been comprehensively studied. In this study, depressive-like behaviors were induced in male C57BL/6 mice by LPS injection, with intragastric administration of CBD (70 or 140 mg/kg/day) for 6 days. Our results demonstrated that CBD treatment significantly attenuated lipopolysaccharide (LPS)-induced depressive-like behaviors, accompanied by a marked amelioration of synaptic healthiness in the hippocampal region. CBD effectively inhibited reactive oxygen species production, normalized the levels of oxidative stress markers, and restored superoxide dismutase activity, involving a mechanism that promotes mitochondrial biogenesis and mitophagy. In addition, LPS-induced neuroinflammation was reduced by CBD, as evidenced by a marked decrease in neuroinflammatory activation markers. CBD also inhibited LPS-activated inflammasome activation by targeting NLRP3/IL-1β/Caspase-1 signaling pathway. These findings suggest that CBD may be a potential therapeutic drug for managing major depressive disorder.
    Keywords:  Cannabidiol; Depression; Mitochondria; Mitophagy; NLRP3; Neuroinflammation
    DOI:  https://doi.org/10.1007/s12035-025-05614-w
  35. Cells. 2025 Dec 26. pii: 48. [Epub ahead of print]15(1):
    AUF1 Restrains Hepatocyte Senescence by Maintaining Mitochondrial Homeostasis in AML12 Hepatocyte Model.
    Myeongwoo Jung, Sukyoung Han, Seungyeon Ryu, Seongho Cha, Ye Eun Sim, Se Hoon Jung, Hyosun Tak, Wook Kim, Eun Kyung Lee.
      Cellular senescence, a hallmark of aging, involves irreversible growth arrest and an enhanced senescence-associated secretory phenotype (SASP). It is often accompanied by mitochondrial dysfunction and altered inter-organelle communication. Using a chronic oxidative stress model in AML12 hepatocytes, we confirmed senescence by canonical assays (e.g., SA β-gal positivity and proliferation arrest) and observed a decline in the RNA-binding protein AUF1 (hnRNP D). AUF1 knockdown further amplified senescent phenotypes, including elongation of mitochondrial network, loss of mitochondrial membrane potential, reduced ATP level, and elevated mitochondrial reactive oxygen species (ROS). In addition, AUF1 knockdown weakened mitochondria-endoplasmic reticulum coupling and reduced mitochondrial Ca2+ load. At the molecular level, AUF1 binds to the 3' untranslated regions (3'UTRs) of Opa1 and Mfn2 and limits their abundance, thereby coupling post-transcriptional control to mitochondrial dynamics. In gain-of-function experiments, ectopic expression of AUF1 attenuated Opa1/Mfn2 induction, restored mitochondrial network architecture, and preserved bioenergetic function under pro-senescent stimuli. Collectively, these findings support a model in which AUF1 preserves mitochondrial homeostasis and thereby restrains the mitochondria-senescence axis in hepatocytes.
    Keywords:  AUF1; fusion; mitochondria; reactive oxygen species; senescence
    DOI:  https://doi.org/10.3390/cells15010048
  36. Nanomaterials (Basel). 2025 Dec 25. pii: 34. [Epub ahead of print]16(1):
    Promoting Drp1-Mediated Mitochondrial Division in Nickel Nanoparticles-Induced Reproductive Toxicity in GC-2 Cells.
    Liya Qiao, Zhimin Tong, Yabing Xu, Chunliu Guan, Geyu Liang, Lu Kong.
      Male reproductive disorders and declining fertility rates play an important role in birth rates, and their impact on future populations makes them one of the most serious public health issues of this century. Defects in spermatogenesis are the most common manifestation of male infertility, and exposure to environmental pollutants has been suggested as a potential cause. Nanomaterials, due to their unique physicochemical properties and widespread application, have raised growing concerns about their potential reproductive toxicity. Studies have shown that nickel nanoparticles (Ni NPs) have reproductive toxicity in male rats and mice, especially sperm damage. This study aimed to explore the male reproductive toxicity of Ni NPs and the role of mitochondrial fission in mouse spermatocytes (GC-2). Our results showed that Ni NPs induced the damage of mitochondrial structure and function in GC-2 cells and disrupted intramitochondrial homeostasis, thereby resulting in enhanced Dynamin-related protein 1(Drp1)-mediated mitochondrial fission and cell apoptosis, along with aggravated cytotoxicity and obvious reproductive toxicity. The mitochondrial division inhibitor 1(Mdivi-1) and lentiviral-transfected low expression of Dnm1l can significantly alleviate the germ cell toxicity caused by Ni NPs, suggesting a certain therapeutic effect. The novelty of this study lies in its systematic demonstration that Drp1-mediated mitochondrial division is a core pathogenic mechanism of Ni NP-induced male reproductive toxicity, and the validation of both pharmacological inhibition and genetic silencing as effective intervention strategies. Therefore, this study offers a reference for expanding the reproductive toxicity effect of Ni NPs and potential molecular mechanisms and provides an important basis for finding potential targets and treatment of Ni NPs.
    Keywords:  Drp1; apoptosis; mitochondrial division; nickel nanoparticles; reproductive toxicity
    DOI:  https://doi.org/10.3390/nano16010034
  37. Cell Death Discov. 2026 Jan 06.
    Mitochondrial retrograde signaling initiates HIF-1α/BNIP3/NIX-mediated mitophagy in Tibetan high-altitude adaptation.
    Yang Wei, Dayan Sun, Fei Wu, Shixuan Zhang, Bowen Cai, Yanyun Ma, Hongxiang Zheng, Xiangguang Shi, Yi Li, Shiguan Le, Xiang Zhou, Li Jin, Jiucun Wang.
      Genome-wide studies have identified the nuclear gene EPAS1 and the mitochondrial M9a haplogroup as pivotal contributors to hypoxia adaptation in Tibetans. However, the interaction between these two genetic components is not yet clear. In this study, we demonstrate that cells harboring the Tibetan-specific M9a haplogroup with downregulated EPAS1 (M9a+shEPAS1) exhibit enhanced cellular function under hypoxic conditions. These cells display improved mitochondrial function and proliferation, alongside reduced apoptosis and mtDNA-mediated inflammation, driven by the activation of HIF-1α-BNIP3/NIX-mediated mitophagy and an increase in reactive oxygen species (ROS) levels. Furthermore, treatment with N-acetylcysteine (NAC), PX-478, or Mdivi-1 significantly attenuated BNIP3/NIX-mediated mitophagy, leading to an aggravation of mtDNA-mediated inflammation and apoptosis in M9a+shEPAS1 cells during hypoxia. This study first reveals that ROS-driven HIF-1α-BNIP3/NIX-mediated mitophagy mitigates hypoxia-induced inflammation and apoptosis, contributing to the enhanced hypoxia adaptation observed in Tibetans. HIF-1α-BNIP3/NIX-mediated mitophagy may offer potential therapeutic targets for high-altitude illnesses by regulating cellular energy metabolism and inflammation.
    DOI:  https://doi.org/10.1038/s41420-025-02933-8
  38. Cell Rep. 2026 Jan 05. pii: S2211-1247(25)01565-7. [Epub ahead of print]45(1): 116793
    METTL3 regulates α-KG-dependent mitophagy and apoptosis in nucleus pulposus cells through the MALAT1/miR-23c/IDH1 axis.
    Ouqiang Wu, Yuxin Jin, Shoutao Weng, Zhiguang Zhang, Keyu Tu, Jing Sun, Linjie Chen, Qizhu Chen, Zhihua Chen, Morgan Jones, Xinzhou Wang, Zhenyu Guo, Yan Michael Li, Yangli Xie, Min Wu, Shuying Shen, Aimin Wu.
      Alpha-ketoglutarate (α-KG), a key intermediate in the tricarboxylic acid (TCA) cycle, was found to be significantly decreased in nucleus pulposus (NP) tissues of patients with intervertebral disc degeneration (IVDD). Supplementation with α-KG restored nucleus pulposus cell (NPC) proliferation, reduced apoptosis, and reestablished extracellular matrix (ECM) metabolic homeostasis. Mechanistically, α-KG enhanced mitophagy and suppressed reactive oxygen species (ROS) accumulation, effects that were abolished by the mitophagy inhibitor Mdivi-1. Further investigation identified isocitrate dehydrogenase 1 (IDH1) as essential for α-KG production and mitochondrial maintenance, with its expression controlled by the METTL3/MALAT1/miR-23c axis. Specifically, METTL3-mediated m6A modification destabilized MALAT1, attenuating its sponging of miR-23c and ultimately leading to IDH1 suppression. These findings reveal a novel regulatory pathway governing mitophagy and oxidative stress in NPCs, highlighting potential therapeutic targets for IVDD.
    Keywords:  CP: cell biology; METTL3; ROS; alpha-ketoglutarate; apoptosis; intervertebral disc degeneration; m(6)A modification; mitophagy; nucleus pulposus cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.116793
  39. Vet Microbiol. 2025 Dec 31. pii: S0378-1135(25)00501-2. [Epub ahead of print]313 110865
    ENTR1 stabilizes MAVS by inhibiting NIX-mediated mitophagy to restrict BPIV3 and VSV replication.
    Xiaoyang Yao, Xingyu Li, Lixiang Shi, Hongmei Wang, Hongbin He.
      Endosome-associated trafficking regulator 1 (ENTR1) is implicated in cell apoptosis, cytokinesis, and adipogenesis, but its role in antiviral innate immunity has not been elucidated. In this study, we identify ENTR1 as a positive regulatory factor for type I interferon (IFN-I) signaling pathway, which suppresses bovine parainfluenza virus type 3 (BPIV3) and vesicular stomatitis virus (VSV) replication. Further investigations revealed that ENTR1 deficiency enhanced Nip3-like protein X (NIX)-mediated mitophagy, leading to accelerated degradation of mitochondrial antiviral signaling protein (MAVS) during viral infection. Mechanistically, ENTR1 knockout resulted in increased accumulation of NIX on mitochondria, which promoted the autophagic degradation of MAVS. Importantly, silencing NIX rescued MAVS protein levels and significantly reduced viral titers in ENTR1-deficient cells. Moreover, NIX silencing prevented the degradation of MAVS and consequently reduced viral titers in ENTR1-deficient cells. Consequently, our findings reveal a novel regulatory axis in which ENTR1 stabilizes MAVS by suppressing NIX-dependent mitophagy, thereby enhancing antiviral IFN-I responses. This study not only uncovers a previously unrecognized function of ENTR1 in antiviral immunity but also identifies ENTR1 as a potential target for developing broad-spectrum antiviral therapeutics against RNA viruses.
    Keywords:  Bovine parainfluenza virus type 3 (BPIV3); Endosome-associated trafficking regulator 1 (ENTR1); Mitochondrial antiviral signaling protein (MAVS); Mitophagy; Vesicular stomatitis virus (VSV)
    DOI:  https://doi.org/10.1016/j.vetmic.2025.110865
  40. Nutrients. 2025 Dec 25. pii: 68. [Epub ahead of print]18(1):
    Melatonin Alleviates High-Fructose-Induced Renal Injury in Male Mice, Which Might Be Associated with the Regulation of Mitophagy and Fatty Acid Oxidation.
    Yanzhen Ma, Dan Sun, Yixian Bai, Weiheng Liu, Xue Bai, Zhikang Liu, Tian Kong, Peng Wang, Xi Liang, Zhe Zhang, Hui Liang, Huaqi Zhang.
      Objective: To explore the preventive effect and mechanism of melatonin on high-fructose-induced renal injury in mice. Methods: A total of forty male C57BL/6J mice aged six weeks were randomly assigned to four groups: control group (CON), melatonin group (MLT), fructose group (FRU), and fructose + melatonin group (FRU + MLT). The concentration of the fructose solution was 30%, and the dose of melatonin was 10 mg/kg/day by intragastric administration. The experiment lasts for 10 weeks. Results: Liquid intake and energy intake were comparable between the FRU and FRU + MLT, both of which were significantly higher than that in the CON and MLT. MLT inhibited fructose-induced increased levels in serum creatinine (Cre), serum urea nitrogen (BUN), serum uric acid (UA), serum triglyceride (TG), renal kidney injury molecule-1 (KIM-1), and renal TG. Hematoxylin and Eosin (H&E) staining and Oil Red O (ORO) staining showed that MLT alleviated renal tubular dilatation, loss of brush border, epithelial cell detachment and lipid accumulation. Transmission electron microscope (TEM) observations showed that MLT increased autophagic vacuoles among mitochondria. Western blot analysis showed that, compared with the FRU, the FRU + MLT had elevated expression of AMP-activated protein kinase (AMPK) phosphorylation, along with a significant increase in the expression of its downstream mitophagy-related proteins (including PINK1, Parkin, LC3 II, and Beclin1), whereas the expression of p62 was markedly decreased. Furthermore, the expression levels of FAO-related proteins (including PPARα and CPT1A) in the FRU + MLT were significantly upregulated. Conclusions: MLT alleviates renal injury caused by high-fructose exposure in male mice and its mechanism might be associated with the regulation of mitophagy and fatty acid oxidation.
    Keywords:  fatty acid oxidation; high fructose; melatonin; mitophagy; renal injury
    DOI:  https://doi.org/10.3390/nu18010068
  41. Free Radic Biol Med. 2026 Jan 05. pii: S0891-5849(26)00001-8. [Epub ahead of print]
    Corrigendum to "BL-918 alleviates oxidative stress in rats after subarachnoid hemorrhage by promoting mitophagy through the ULK1/PINK1/Parkin pathway" [Free Radic. Biol. Med. 224 (2024) 846-861].
    Jinshuo Yang, Qiaowei Wu, Yuchen Li, Yongzhi Zhang, Shuai Lan, Kaikun Yuan, Jiaxing Dai, Bowen Sun, Yuxiao Meng, Shancai Xu, Huaizhang Shi.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.001
  42. Phytomedicine. 2025 Dec 10. pii: S0944-7113(25)01327-3. [Epub ahead of print]150 157692
    Anwulignan mitigates UVB-induced skin photodamage by dual activation of the Nrf2/PINK1/Parkin and Nrf2/SLC7A11/GPX4 signaling pathways.
    Yuxin Jiang, Danfeng Wang, Xiaoran Lin, Zihao Yuan, Xinyu Xing, Qingzhuo Gao, Tianshuo Zhang, Shu Jing, He Li.
       BACKGROUND: Skin photoaging (SP) is a major contributor to skin aging. Anwulignan (AN) has been confirmed to possess diverse biological activities. This study investigated the protective effect of AN against SP and explored its underlying mechanisms.
    METHODS: A UVB-induced SP model in mice was established to evaluate skin erythema index (EI), transepidermal water loss (TEWL), and skin hydration. Histopathological assessments were performed using hematoxylin and eosin (HE), Masson, and Sirius red staining. Transmission electron microscopy examined the morphology and quantity of mitochondria in epidermal cells. ELISA measured levels of hydroxyproline (HYP), hyaluronic acid (HA), oxidative stress markers, and inflammation indicators. Molecular docking predicted the potential targets of AN on UVB-induced SP. Western blot and immunofluorescence staining assessed the expression of proteins related to oxidation, inflammation, aging, ferroptosis, and autophagy. Zebrafish experiments further validated the effects.
    RESULTS: AN significantly alleviated SP, evidenced by increased levels of HA and HYP, suppressed pro-inflammatory cytokine expression, reduced reactive oxygen species (ROS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and malondialdehyde (MDA), while enhancing activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). It also regulated the expression of proteins involved in the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis. Significant differences were observed among groups in tail fin area, β-galactosidase staining fluorescence intensity, yolk sac fluorescence, and mitochondrial fluorescence in muscle.
    CONCLUSION: AN may exert protective effects against SP by targeting Nrf2 and subsequently activating both the Nrf2/PINK1/Parkin mitophagy axis and the Nrf2/SLC7A11/GPX4 ferroptosis regulatory axis.
    Keywords:  Antioxidant; Anwulignan; Ferroptosis; Mitophagy; Skin photoaging
    DOI:  https://doi.org/10.1016/j.phymed.2025.157692
  43. Chem Biol Interact. 2026 Jan 06. pii: S0009-2797(26)00014-1. [Epub ahead of print]425 111906
    Cadmium exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission.
    Yin-Fei Xing, Liang Yue, Chen-Hao Wang, Cai-Jiao Zhou, Jia-Qi Ye, Shi-Jie Li, Bin Guo.
      Cadmium (Cd), a widespread environmental pollutant, has toxic effects on spermatogenesis and sperm motility, but its role in uterine decidualization remains unknown. This study revealed that Cd exposure during early pregnancy might impair the uterine decidualization along with the disordered proliferation and apoptosis of stromal cells, resulting in the reduction of mouse neonatal number and birth weight. After disrupting the binding of Ca2+ and LNR-C, Cd exposure ligand-independently activated the NOTCH1 signaling and then restrained the expression of nuclear TAZ via RBPJ-targeting LATS. Further analysis suggested that Cd exposure contributed to the depletion of glutathione via Gclc that was identified as a direct downstream target of TAZ/TEAD, resulting in intracellular ROS accumulation and subsequent mitochondrial dysfunction. Meanwhile, Cd exposure prevented mitochondrial fusion and facilitated mitochondrial fission together with the fragmented mitochondria, whereas attenuation of intracellular ROS alleviated the imbalance between mitochondrial fusion and fission by Cd exposure. Moreover, improvement of mitochondrial fusion insufficiency and excessive fission rescued the impairment of Cd on decidualization. Collectively, Cd exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission. These findings reveal the toxic effect of Cd on female reproduction and serve as a risk factor for adverse pregnancy outcomes.
    Keywords:  Cadmium; Mitochondria; NOTCH1 signaling; TAZ; Uterine decidualization
    DOI:  https://doi.org/10.1016/j.cbi.2026.111906
  44. iScience. 2026 Jan 16. 29(1): 114279
    Mitochondrial integrity modulates mTOR signaling and podocyte function.
    Cem Özel, Khawla Abualia, Duc Nguyen-Minh, Mahsa Matin, David Unnersjö-Jess, Martin Höhne, Wilhelm Bloch, Henning Hagmann, Richard J M Coward, Sebastian Brähler, Bernhard Schermer, Thomas Benzing, Philipp Antczak, Paul T Brinkkötter.
      Mitochondrial dysfunction has emerged as a key contributor to the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) and genetic focal-segmental glomerulosclerosis (FSGS). This study explores the role of mitochondrial integrity in podocyte biology, focusing on the impact of OMA1, a critical regulator of mitochondrial morphology. Using a model of disrupted mitochondrial homeostasis, we show that mitochondrial dysfunction sensitizes podocytes to insulin, triggering the overactivation of mTOR signaling. Disruption of OMA1 function was achieved through the deletion of Oma1 or a podocyte-specific knockout of its regulator Phb2. Remarkably, simultaneous Oma1 deletion extended the lifespan of severely affected Phb2 pko mice, alleviated proteinuria, and restored mitochondrial morphology. Increased mTOR activity was observed in Phb2 pko , Oma1 del , and Phb2/Oma1 double-knockout mice. Our findings highlight the critical role of mitochondrial integrity in podocyte function and disease mitigation, providing potential therapeutic insights for mitochondrial dysfunction-associated nephropathies.
    Keywords:  cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.114279
  45. Zhongguo Zhong Yao Za Zhi. 2025 Nov;50(22): 6439-6449
    [Mechanisms of Danggui Buxue Decoction in alleviating myocardial injury caused by chronic intermittent hypoxia by activating AMPK/mTOR signaling pathway].
    Jie Chen, Hao Zhang, Dong-Li Li, Ji-Xian Song, Ya-Jing Guo, En-Sheng Ji.
      This study aimed to explore the molecular mechanism underlying the protective effect of Danggui Buxue Decoction(DBD) against myocardial injury induced by chronic intermittent hypoxia(CIH). A CIH model was established in Sprague-Dawley(SD) rats, and DBD was administered via intragastric gavage at low, medium, and high doses(3.6, 7.2, and 14.4 g·kg~(-1)·d~(-1)). An intermittent hypoxia(IH) model was established in H9c2 cells. Cells were treated with DBD-containing serum, DBD-containing serum combined with the AMPK inhibitor Compound C, or the AMPK activator A769662. Molecular docking was used to analyze the binding affinity and interaction between the main active components of DBD and the AMPK protein. Cardiac function, myocardial histopathological changes, and mitochondrial morphological alterations were detected in SD rats. In myocardial tissue and H9c2 cells, mitochondrial membrane potential(JC-1), the activity of mitochondrial respiratory complexes Ⅰ and Ⅱ, ATP content, and MDC fluorescence staining intensity were measured. The expression levels of mitophagy-related proteins(Beclin-1, LC3-Ⅱ, LC3-Ⅰ, Parkin, PINK1, P62), apoptosis-related proteins(Bcl-2, BAX, cleaved caspase-3, caspase-3, p-p70S6K, p70S6K, Cyt C), and proteins related to the AMPK/mTOR signaling pathway(p-AMPK, AMPK, p-mTOR, mTOR, p-ULK1, ULK1) were also detected. The results showed that DBD significantly improved cardiac function and alleviated myocardial injury in CIH rats. DBD and its medicated serum upregulated the expression of Beclin-1, LC3-Ⅱ/LC3-Ⅰ, Parkin, PINK1, Bcl-2/BAX, mitochondrial Cyt C, p-AMPK/AMPK, and p-ULK1/ULK1, while downregulating the expression of P62, cleaved caspase-3/caspase-3, and p-p70S6K/p70S6K, p-mTOR/mTOR. Additionally, DBD increased mitochondrial membrane potential, the activity of respiratory complexes I and Ⅱ, ATP levels, and MDC fluorescence intensity. The AMPK activator A769662 exerted therapeutic effects similar to those of DBD, whereas the AMPK inhibitor compound C significantly suppressed the therapeutic effect of DBD-containing serum. These findings suggest that DBD alleviates CIH-induced myocardial injury by activating the AMPK/mTOR signaling pathway, thereby promoting mitophagy and inhibiting mitochondria-mediated apoptosis.
    Keywords:  AMPK/mTOR signaling pathway; Danggui Buxue Decoction; apoptosis; chronic intermittent hypoxia; mitophagy
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250617.703
  46. Biomaterials. 2026 Jan 03. pii: S0142-9612(26)00005-0. [Epub ahead of print]329 123981
    Mitochondria-targeted co-assembled nanosystem with multimodal mitochondrial DNA level control to alleviate inflammation and promote chronic wound healing.
    Xueyan Mao, Chuanwen Wang, Shufan Yu, Kai Zhang, Zheng Wang, Jing Du, Ying Kong, Alberto Bianco, Shaohua Ge, Baojin Ma.
      Mitochondrial dysfunction, particularly when associated with the mitochondrial DNA (mtDNA) activated cGAS-STING signaling pathway, represents a key pathogenic mechanism contributing to excessive inflammation. Therapeutic targeting of mitochondrial homeostasis coupled with precise modulation of mtDNA release emerges as a promising yet underexplored strategy to suppress pathological inflammation and promote chronic wound healing. Herein, epigallocatechin gallate-quercetin co-assembled nanoparticles (EQ NPs) were engineered to inhibit mtDNA-mediated inflammatory cascades through mitochondria-targeted multimodal mtDNA level control. Primarily, EQ NPs reduced the formation of oxidized mtDNA fragments (Ox-mtDNA). Then, EQ NPs inhibited the excessive opening of the mitochondrial permeability transition pore, preventing Ox-mtDNA cytoplasmic leakage. Subsequently, the escaped mtDNA fragments were neutralized by EQ NPs through polyphenol-mediated adsorption. Finally, mitophagy was upregulated to selectively eliminate damaged mitochondria. This well-designed strategy significantly inhibited the activation of the mtDNA-mediated cGAS-STING pathway, relieved the release of inflammatory factors, and promoted anti-inflammatory phenotype polarization of macrophages. In vivo, EQ NPs promoted chronic wound healing by bacteriostasis, anti-inflammation, immunomodulation, and accelerated angiogenesis. Overall, the study establishes a sequential mitochondrial quality control paradigm in which the inflammatory cascade is interrupted by multimodal and full-chain mtDNA scavenging, providing a promising candidate for the treatment of inflammatory diseases and chronic wound healing.
    Keywords:  Co-assembly; Immunomodulation; Mitochondrial homeostasis; Oxidative stress; Polyphenol
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.123981
  47. Cell Oncol (Dordr). 2026 Jan 08. 49(1): 21
    Targeting VCP with V8 suppresses glioblastoma development via formation of aggregates and disruption of mitophagy flux.
    Xuejun Cao, Yishen Li, Bin Guo, Yan Liu, Baoshuai Wang, Hao Wang, Jingbo Lu, Libin Wei, Yuan Gao, Yongjian Guo, Tao Wu.
      
    Keywords:  Aggregates; Autolysosome; Mitophagy; PRKN; VCP
    DOI:  https://doi.org/10.1007/s13402-025-01149-3
  48. Nat Aging. 2026 Jan 05.
    Author Correction: Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
    Dominic Denk, Anurag Singh, Herbert G Kasler, Davide D'Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R Greten.
      
    DOI:  https://doi.org/10.1038/s43587-025-01060-4
  49. Redox Biol. 2025 Dec 25. pii: S2213-2317(25)00509-9. [Epub ahead of print]89 103996
    Islet regeneration protein Reg3g promotes macrophage clearance of β cell-derived dysfunctional mitochondria-rich vesicles to mitigate T2DM.
    Senlin Li, Mengheng Wang, Hong Zhou, Jia Liu, Mengxuan Wang, Huimin Yuan, Mengzhu Zheng, Xin Li, Xiangling Zhu, Ming Xiang.
      Under metabolic stress in type 2 diabetes mellitus (T2DM), β cells accumulate damaged mitochondria, and proinflammatory macrophages infiltrate pancreatic islets. In several tissues, mitochondrial transfer between macrophages and parenchymal cells has been shown to alleviate inflammation and sustain cellular function reponse to stress. However, whether a similar process occurs between pancreatic β cells and macrophages remains unclear. Here, we identified a form of intercellular communication mediated by damaged mitochondrial-rich extracellular vesicles (mEVs) from β cells to macrophages within the inflammatory islets, promoted by Reg3g. Using time-lapse confocal microscopy, flow cytometry and split-GFP mitochondrial fusion assays, we demonstrated that stressed β cells release damaged mitochondria via mEVs, which were internalized by macrophages through a heparan sulfate (HS)-dependent mechanism and subsequently degraded through mitophagy. Under metabolic stress, β cells increased mEVs release, but macrophage uptake was impaired due to reduced HS biosynthesis. The protein Reg3g restored this process by binding macrophage exostosin-like glycosyltransferase 3 (EXTL3) receptors, promoting HS synthesis. Mechanically, increased HS enhanced mEVs uptake and strengthened the heparan sulfate proteoglycan (HSPG)-NF-κB interaction, sequestering NF-κB in the cytoplasm and suppressing purinergic receptor P2X7 (P2RX7) expression. P2RX7 downregulation subsequently promoted metabolic remodeling and an anti-inflammatory shift in macrophages. Collectively, our study identifies a Reg3g-orchestrated transcellular mitophagy pathway, wherein macrophages clear mEVs from β cells, promoting islet homeostasis. Targeting this axis may offer new therapeutic strategies for T2DM.
    Keywords:  Heparan sulfate; Macrophage; Mitochondria-rich extracellular vesicles; Reg3g; Transcellular mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2025.103996
  50. Biochim Biophys Acta Mol Cell Res. 2026 Jan;pii: S0167-4889(25)00177-6. [Epub ahead of print]1873(1): 120072
    Loss of Sugen Kinase 495 in macrophages alleviates chronic colitis by improving mitochondrial stress.
    Jikai He, Yuanmei Lou, Pingan Yao, Shiguang Yang, Jinliang Dong, Qifeng Yu.
      Inflammatory bowel disease (IBD), highlighted by chronic intestinal inflammation, is an escalating global health concern. The pathogenesis of IBD is not fully understood, with DSS-induced chronic colitis in mice serving as a prevalent model, characterized by an increase in Ly6Chigh macrophages-a signature of IBD. Sugen Kinase 495 (Sgk495), also known as serine/threonine kinase 40 (STK40), is known to influence cell differentiation, has an obscure role in mitochondrial in macrophage and its molecular mechanisms. Our research demonstrates that Sgk495 exacerbates chronic colitis in mice by disrupting colon structure and function and enhancing colonic pathology. The absence of Sgk495 in macrophage cells resulted in a reduction in the proportion of Ly6Chigh macrophage. Mechanistically, Sgk495 silencing also improved mitochondrial stress by upregulated PINK1, Parkin, TOMM20 and DRP1, while reducing FOXO3a phosphorylation. Knockout of Sgk495 downregulates FOXO3a phosphorylation and improves mitochondrial stress, inhibits Ly6Chigh macrophage polarization, and alleviates chronic colonic inflammation. Sgk495 may serve as a new potential therapeutic target for IBD.
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120072
  51. J Cell Mol Med. 2026 Jan;30(1): e70965
    HIF1α Attenuated the Lung Ischemia-Reperfusion Injury by Activating the miR-485/Notch1 Signalling.
    Shaohua Dai, Xuemei Wan, Lingchun Xia, Lei Xu, Chunfan Xie, Guohui Wang, Jian Tang.
      Lung ischemia-reperfusion (I/R) injury is a common complication following lung transplantation and cardiac surgery. This study aimed to investigate the role and underlying mechanisms involving Neurogenic locus notch homologue protein 1 (Notch1) signalling and microRNA-485 (miR-485) of hypoxia-inducible factor 1-alpha (HIF1α) in protecting pulmonary microvascular endothelial cells (PMVECs) against I/R-induced injury. We found that overexpression of HIF1α significantly increased cell viability and decreased apoptosis in hypoxia/reoxygenation (H/R)-treated PMVECs, while knockdown or inhibition of HIF1α had the opposite effects. Moreover, HIF1α overexpression activated the Notch1 signalling pathway by upregulating Hes1 mRNA expression and Hes1 promoter activity. Conversely, HIF1α knockdown or inhibition inhibited Notch1 signalling. Furthermore, HIF1α overexpression alleviated H/R-induced mitophagy and mitochondrial dysfunction. On the other hand, HIF1α knockdown or inhibition aggravated mitophagy and mitochondrial dysfunction. We also found that HIF1α transcriptionally activated the expression of miR-485. Overexpression of miR-485 reversed the detrimental effects of HIF1α knockdown or inhibition on cell viability, apoptosis, Hes1 expression and mitophagy levels in H/R-treated PMVECs. Additionally, we identified NUMB endocytic adaptor protein (Numb) mRNA as a direct target of miR-485, and miR-485 overexpression suppressed Numb expression in PMVECs. In conclusion, these results suggest that targeting the HIF1α-miR-485-Numb axis may be a potential therapeutic strategy for attenuating lung I/R injury.
    Keywords:  Notch1 signalling; hypoxia‐inducible factor 1‐alpha; lung ischemia–reperfusion injury; mitophagy; pulmonary microvascular endothelial cells
    DOI:  https://doi.org/10.1111/jcmm.70965
  52. Basic Clin Pharmacol Toxicol. 2026 Feb;138(2): e70188
    Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.
    Luling Li, Xiuting Huang, Pei Li.
      Metformin alleviates oxidized low-density lipoprotein (ox-LDL)-induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox-LDL-induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin-1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin-1 was shown to reverse metformin-mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1-mitophagy pathway, with Caveolin-1 serving as an essential modulator. This NR4A1-mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.
    Keywords:  atherosclerosis; inflammation; macrophage senescence; metformin; ox‐LDL
    DOI:  https://doi.org/10.1111/bcpt.70188
  53. Front Pharmacol. 2025 ;16 1736086
    Mitophagy-related gene TRIP13 predicts prognosis and immune response and promotes proliferation and migration in vitro and in vivo of clear cell renal cell carcinoma.
    Zhongjun Jiang, Lanlan Wang, Zhongrun He, Lian Guo, Wen Luo, Ying Fu, Qiyu Xiao, Guanglan Chen, Yinzi Liu.
       Background: The incidence of clear cell renal cell carcinoma (ccRCC) is increasing every year. Mitophagy is a unique form of autophagy that plays a crucial role in cancer development and invasion. However, its role in ccRCC remains to be fully elucidated.
    Methods: After extracting mitophagy-related genes (MRGs), differential expression analysis was performed to screen differentially expressed genes (DEGs). Univariate Cox regression analysis was used to screen prognostic-related DEGs, CNV mutation frequencies were compared, and consensus cluster analysis was constructed to evaluate the survival and functional enrichment status among different subtypes. LASSO Cox regression analysis was used to identify key prognostic genes and construct risk models to evaluate the prognostic value and immune contribution. The protein and mRNA expression levels of independent prognostic genes and their effects on ccRCC function were verified by in vitro and in vivo experiments.
    Results: The study found 174 DEGs, including 9 prognosis-related DEGs. These 9 DEGs were used to cluster ccRCC patients into two subtypes. Significant differences existed between the two subtypes in the survival status and KEGG functions. Finally, three core genes (JUP, TRIP13, and ACAD11) were identified for constructing a risk model, which can accurately predict the prognosis of ccRCC patients and evaluate the immune status. TRIP13 was identified as a key independent prognostic gene for ccRCC, and its protein and mRNA expression levels were highly expressed in ccRCC. ccRCC growth and motility can be markedly inhibited by TRIP13 knockdown, which also increases their susceptibility to destruction by CD8+ T cells.
    Conclusion: The prognosis and immune response of patients with ccRCC could be reliably estimated by the model in our cohorts created using MRGs in this research. The development of ccRCC is significantly influenced by MRGs, particularly TRIP13. This study can assist in offering ccRCC patients individualized treatment options.
    Keywords:  TRIP13; clear cell renal cell carcinoma; immune response; mitophagy; prognosis
    DOI:  https://doi.org/10.3389/fphar.2025.1736086
  54. ACS Nano. 2026 Jan 08.
    Piezoelectric Nanofibers Synchronize Mitochondrial Dynamics and Immune Responses for Regeneration of Infected Wounds.
    Hongying Fu, Liping Wu, Jingrong Cheng, Le Hu, Weijia Wang, Yanhui Lu, Xuehui Zhang, Yang Liu, Xuliang Deng.
      Mitochondria play a central role in coordinating wound repair by integrating bioenergetic activity with immune-metabolic signaling. Although electrical cues are known to influence mitochondrial behavior, most existing methods depend on implanted electrodes. Besides, how electrical stimulation precisely regulates the fate of mitochondrial function during infection remains incompletely defined. In this study, we use piezoelectric poly(L-lactic acid) (PLLA) nanofibers upon ultrasound stimulation to act as a wireless interface for spatiotemporally precise mitochondrial regulation during infected wound repair. During the inflammatory stage, piezoelectric activation led to a rapid mitochondrial Ca2+ influx and membrane depolarization within seconds, followed by a minute-scale rise in mitochondrial reactive oxygen species (ROS). This sequence initiated the Ca2+-ROS-mtDNA-STING cascade, enhancing antimicrobial activity via cytosolic DNA sensing and promoting mitochondrial fission associated with proinflammatory defense. As healing progressed to the proliferative phase, electrical cues from the nanofibers shifted cellular metabolism and drove macrophage polarization toward a regenerative phenotype, as indicated by a higher Arg1/iNOS ratio and lower IL-6 and TNF-α expression, while promoting mitochondrial fusion and tissue remodeling. In vivo experiments confirmed that these time-scaled mitochondrial responses facilitated the immune response, angiogenesis, and epithelial regeneration, resulting in markedly accelerated closure of infected wounds. Collectively, this work demonstrates how piezoelectric charges regulate mitochondrial Ca2+, ROS, and mtDNA, identifying mitochondria as spatiotemporal mediators of electrostimulation-driven immune reprogramming, offering a wireless bioelectronic strategy to overcome chronic infection barriers and promote functional tissue regeneration.
    Keywords:  electrical stimulation; immune responses; mitochondrial dynamics; mtDNA; piezoelectrics; wound repair
    DOI:  https://doi.org/10.1021/acsnano.5c19373
  55. FASEB J. 2026 Jan 15. 40(1): e71430
    Silencing GADD45B Ameliorates Epilepsy by Inhibiting Ferroptosis and Maintaining Mitochondrial Homeostasis Through the HIF-1 Signaling Pathway.
    Jiaomei Jiang, Yongmin Ding, Fen Wang.
      Epilepsy is a chronic brain disorder with unclear pathogenesis and no effective biomarkers. This study aims to identify potential biomarkers and elucidate the regulatory pathways in epilepsy. Epilepsy-associated differentially expressed genes (DEGs) were discovered from the GSE60772, GSE88992, and GSE100202 datasets. Hub genes were determined from a protein-protein interaction (PPI) network, followed by screening of downstream pathways of growth arrest and DNA damage inducible beta (GADD45B). GADD45B was silenced in lithium-pilocarpine-induced epileptic rats and glutamate-treated HT22 cells to investigate its effects on hippocampal neuron injury, ferroptosis, mitochondrial homeostasis, and its downstream signaling pathway. GADD45B as an epilepsy-associated hub gene was highly expressed in the hippocampal tissues of epileptic rats. Silencing GADD45B in epileptic rats suppressed neuronal injury and death. It also decreased Fe2+, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), reactive oxygen species (ROS), and hypoxia-inducible factor-1α (HIF-1α) but increased glutathione (GSH) in epileptic rats and HT22 cells, as well as suppressed acyl-CoA synthetase long chain family member 4 (ACSL4) expression and increased glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression. Mitochondrial homeostasis was maintained after silencing GADD45B via suppressing mitofusin 1 (MFN1) and mitofilin. The HIF-1 signaling pathway was a downstream pathway of GADD45B, and its activation reversed the protective effects of GADD45B silencing on glutamate-induced neuronal death, ferroptosis, and mitochondrial homeostasis. Silencing GADD45B attenuates epileptic neuronal death by inhibiting ferroptosis and maintaining mitochondrial homeostasis via inhibiting the HIF-1 signaling pathway, which provides novel insights into epilepsy pathogenesis and potential biomarkers.
    Keywords:  GADD45B; HIF‐1 signaling pathway; epilepsy; ferroptosis; mitochondrial homeostasis
    DOI:  https://doi.org/10.1096/fj.202503717R
  56. Sci Rep. 2026 Jan 06.
    RhoA accelerates atherosclerosis progression by interacting with Hspa5.
    Ruoyu Dong, Can Cao, Jikuan Li, Guangwei Jiang, Yunjie Tian, Xiaoming Shi.
      RhoA has been demonstrated to play a role in atherosclerosis (AS); however, its regulatory mechanisms remain poorly characterized. This study aimed to investigate the function of RhoA in AS and elucidate its underlying mechanisms. An AS mouse model was established via a high-fat diet, and the role of RhoA was assessed by administering adeno-associated viruses. Mouse aortic vascular smooth muscle cells (MOVAS) were exposed to oxidized low-density lipoprotein (ox-LDL), and cellular phenotypes were analyzed using cell counting kit-8 assays, Transwell migration assays, transmission electron microscopy, and western blotting. The interaction between RhoA and Hspa5 was investigated through bioinformatic analysis, co-immunoprecipitation, and immunofluorescence. Results revealed that RhoA was highly upregulated in AS mice and predominantly localized in the smooth muscle layer of the aortic root. Knockdown of RhoA or inhibit its activity suppressed the viability, migration, invasion, and mitophagy of ox-LDL-treated MOVAS cells in vitro, and reduced plaque formation and inflammatory responses in AS mice. Furthermore, Hspa5 was found to interact with RhoA, with its expression positively correlated to RhoA levels. Overexpression of Hspa5 counteracted the inhibitory effects of RhoA silencing on cellular behaviors in ox-LDL-stimulated cells in vitro and plaque lesions and inflammation responses in vivo. Collectively, RhoA promotes vascular smooth muscle cell migration, invasion, and mitophagy via interaction with Hspa5, thereby exacerbating AS progression. These findings highlight RhoA as a potential therapeutic target for AS treatment.
    Keywords:  Atherosclerosis; Hspa5; Mitophagy; RhoA; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1038/s41598-025-33741-w
  57. bioRxiv. 2025 Dec 23. pii: 2025.12.19.695597. [Epub ahead of print]
    Methionine synthase reductase regulates heterochromatin independently of methionine synthesis through mitochondrial homeostasis.
    Fernanda Rezende Pabst, Andrey Tvardovskiy, Iratxe Estibariz, Veronica Finazzi, Pauline Couacault, Anna Artati, Michael Witting, Antonio Scialdone, Till Bartke, Daphne Selvaggia Cabianca.
      Metabolic enzymes can influence chromatin organization by modulating the availability of key metabolites, yet how specific metabolic reactions affect chromatin function remains poorly understood. Here, we show that in Caenorhabditis elegans, the methionine-cycle enzyme methionine synthase reductase (MTRR-1/MSR) regulates heterochromatin independently of methionine synthesis. Loss of MTRR-1, but not of the methionine synthase METR-1/MS, specifically reduces heterochromatic histone methylation, derepresses repetitive elements, and causes developmental delay. Multi-omics profiling revealed that mtrr-1 mutants activate transcriptional programs associated with mitochondrial stress and accumulate long-chain acylcarnitines, indicating disrupted mitochondrial homeostasis. Functional assays confirmed altered mitochondrial respiration in mtrr-1 mutants, while direct perturbation of mitochondrial function was sufficient to induce heterochromatin defects. Together, our results reveal a previously unrecognized mitochondria-to-chromatin axis controlled by the methionine-cycle enzyme MTRR-1/MSR.
    DOI:  https://doi.org/10.64898/2025.12.19.695597
  58. ACS Nano. 2026 Jan 08.
    Frequency-Selective Terahertz Irradiation Activates Mitochondrial Biogenesis.
    Fengsu Wu, Zhiqiang Mu, Wenyu Peng, Hongkang Qu, Yuchen Tian, Yiyi Yang, Yuanming Wu, Zhi Zhu.
      Mitochondria play a central role in cellular energy metabolism, survival, and apoptosis, with their dysfunction implicated in numerous diseases, including neurodegenerative and age-related disorders. Modulating mitochondrial function therefore represents a promising therapeutic strategy. In this study, we demonstrate that high-frequency terahertz (THz) irradiation elicits frequency-specific effects on mitochondrial biogenesis. Through MitoTimer and MitoTracker assays, we observed that irradiation at 34.5 THz significantly enhanced mitochondrial biogenesis, an effect not observed at 36.1 THz. Electrophysiological and molecular analyses revealed that 34.5 THz irradiation elevates intracellular calcium flux and activates the calcium-mediated PGC-1α-NRF1/2-TFAM pathway, leading to increased cellular energy production and oxygen consumption. Computational modeling suggested a resonant coupling mechanism in which 34.5 THz irradiation interacts with the bending vibration of the glutamate C-C-C bond at the narrowest region of the calcium ion channel pore, thereby lowering the energy barrier for calcium influx. Our findings reveal a noninvasive, frequency-specific mitochondrial modulation by THz irradiation, which may offer a promising therapeutic avenue for addressing mitochondrial dysfunction.
    Keywords:  PGC-1α pathway; calcium signaling; frequency-selective modulation; mitochondrial biogenesis; terahertz irradiation
    DOI:  https://doi.org/10.1021/acsnano.5c16791
  59. J Cell Biol. 2026 Apr 06. pii: e202507116. [Epub ahead of print]225(4):
    Mitochondrial presequences harbor variable strengths to maintain organellar function.
    Youmian Yan, Baigalmaa Erdenepurev, Thiago N Menezes, Ian Collinson, Natalie M Niemi.
      Hundreds of mitochondrial proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphiphilic helices, presequences lack a consensus motif and thus likely promote protein import into mitochondria with variable efficiencies. Indeed, the concept of presequence strength underlies biological models such as stress sensing, yet a quantitative analysis of what dictates strong versus weak presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the MitoLuc protein import assay to define multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPRmt), impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those associated with stress signaling promote highly variable import efficiency in vitro, suggesting presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust in vitro import can fully rescue defects in respiratory growth in complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as weak or strong requires more nuanced characterization than typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202507116
  60. Metabol Open. 2026 Mar;29 100433
    No effect of pyrroloquinoline quinone on mouse body weight and energy metabolism with the concomitant increase in mitochondrial biogenesis and antioxidant ability.
    Lijun Zhang, Yimin Xu, Yanyan Zhao, Xiaochun Zhang, Xiangyan Liang, Zhuo Sun, Ying Zhou, Huan Liu, Jinrui Chang, Man Shi, Yufeng Zhao.
      Pyrroloquinoline quinone (PQQ) stimulates mitochondrial biogenesis and exhibits antioxidant properties. Since mitochondria play a crucial role in energy generation and metabolism, the present study aims to clarify whether PQQ is able to modulate energy expenditure and the development of obesity by regulating mitochondrial biogenesis. Male mice fed normal chow diet (NCD) or high fat diet (HFD) were supplemented with PQQ through drinking water for three months. Throughout this period, food and water intake, body weight, energy metabolic rate and the autonomous activity of the mice were measured. Then, the mice were sacrificed and the tissues were collected. Mitochondrial biogenesis, antioxidant capacity, and changes in gene expression were measured in liver tissue. The results showed that PQQ supplementation did not result in significant alterations in the food and water intake, body weight, and energy metabolic rate of the mice fed NCD or HFD although it significantly enhanced mitochondrial biogenesis and antioxidant capabilities of liver and promoted autonomous activity in NCD mice. Moreover, it had no impact on the adipose tissue mass in mice fed NCD or HFD. While PQQ supplementation induced the changes in metabolism-related genes such as CPT1a, SCD1, FABP1, HK2, HK3 and PGK1 in liver, it is suggested PQQ supplementation may influence lipid and glucose metabolism. However, PQQ-induced changes in hepatic gene expression and mitochondrial biogenesis are unable to alter systemic energy metabolism and adipose tissue accumulation in male mice.
    Keywords:  Body weight; Energy metabolism; Pyrroloquinoline quinone
    DOI:  https://doi.org/10.1016/j.metop.2025.100433
  61. Biomater Adv. 2025 Dec 30. pii: S2772-9508(25)00524-2. [Epub ahead of print]182 214697
    Nanoplatform for renal ischemia-reperfusion injury repair: Modulating macrophage polarization, oxidative stress, and mitophagy.
    Mu He, Ting Liu, Hongchao Zhao, Tianran Zheng, Maonan Chen, Hengcheng Zhu, Kang Yang.
      Acute kidney injury (AKI) is a common clinical condition characterized by high morbidity and mortality rates, with a notable lack of effective therapeutic drugs. Complex pathological processes-such as oxidative stress overload, aberrant macrophage polarization, mitochondrial dysfunction, and renal tubular epithelial cell apoptosis-contribute to the current absence of effective clinical treatments for AKI. Although mesoporous cerium dioxide nanospheres have been widely applied in various diseases due to their remarkable ROS-scavenging and drug-loading capabilities, their poor targeting ability limits their use in ischemia-reperfusion injury models. To address this, we developed a multifunctional nanoplatform RGD-CeO₂@Que. based on mesoporous hollow cerium dioxide (AhCeO₂). This system achieves targeted accumulation in injured kidneys by binding to integrin αvβ3 receptors, which are overexpressed under oxidative stress. Through the Nrf2/HO-1/GPX4/SOD1 pathway, it alleviates oxidative stress and reduces apoptosis. Moreover, the platform is loaded with the bioactive molecule quercetin to promote mitophagy in renal tubular epithelial cells (HK-2). In vivo studies demonstrated that RGD-CeO₂@Que. improves renal function, ameliorates pathological damage, and reduces inflammatory infiltration in AKI mice. In summary, this integrated nanoplatform combines multiple restorative mechanisms, offering a novel and targeted therapeutic strategy for AKI induced by renal ischemia-reperfusion injury.
    Keywords:  Acute kidney injury; Mitophagy; Oxidative stress; Quercetin; Targeted nanomaterial
    DOI:  https://doi.org/10.1016/j.bioadv.2025.214697
  62. Cell Death Dis. 2026 Jan 08. 17(1): 9
    Aberrant mitochondrial hsp60 expression affects mitochondria homeostasis and results in muscle dystrophy and premature death.
    Tsung-Hsien Chen, Chu-Kuang Chou, Kurt Ming-Chao Lin.
      Heat shock protein 60 (HSP60) plays a vital role in maintaining mitochondrial homeostasis and essential functions and requires ATP for its assembly into chaperone complexes. This study aimed to investigate the long-term effects of HSP60 induction on mitochondrial homeostasis at varying doses and durations using HSP60 transgenic mice. In this study, we generated transgenic mice with elevated levels of native HSP60 using the LoxP-Cre system. These mice exhibited impaired postnatal development, skeletal muscle dystrophy, and increased mortality. Initially, excess HSP60 enhanced the mitochondrial oxidative respiratory capacity, which was later compensated for by increased glycolysis. Surplus HSP60 primarily accumulated in the mitochondria, likely due to insufficient ATP availability, leading to the buildup of HSP60 heptamers. Consequently, mitochondrial number and morphology were altered, protein levels in electron transport chain complexes were reduced, and oxidative phosphorylation was impaired. Additionally, reactive oxygen species accumulated, contributing to mitochondrial dysfunction in skeletal muscles. The upregulation of Pink-1/Parkin triggered enhanced autophagy, while increased Bax and poly (ADP-ribose) polymerase (PARP) cleavage mediated heightened apoptosis; both mechanisms aimed at eliminating damaged mitochondria. However, prolonged HSP60 accumulation overwhelmed these protective processes, ultimately leading to skeletal muscle dystrophy and premature death. Our findings demonstrated that excessive mitochondrial HSP60 initially boosts oxidative respiration; however, over time, it contributes to mitochondrial dysregulation and myopathy. This study provides novel insights into how excessive HSP60 affects mitochondrial oxidative respiration and glycolysis, with potential links to certain mitochondria-related diseases.
    DOI:  https://doi.org/10.1038/s41419-025-08260-1
  63. Mater Today Bio. 2026 Feb;36 102687
    Immunomodulatory microneedles restore mitochondrial homeostasis and balance TGF-β/TNF-α signaling to accelerate diabetic wound repair.
    Minjian Liao, Xinmin Guo, Longbao Feng, Qing Peng, Jianhao Liang, Aleh Kuzniatsou, Rui Guo, Pan Yu, Shuqin Zhou.
      Diabetic infected wounds bring great physical and psychological burden to patients. To solve this problem, removing bacteria and regulating the local immune microenvironment have become effective measures. However, traditional wound repair materials are difficult to break through the bacterial biofilm covering the wound site and thus cannot effectively regulate the internal immune environment of the wound. A bilayer multifunctional sulfonated chitosan (SCS)/methacrylated hyaluronic acid (HAMA)/methacrylated collagen III (ColIIIMA) (SCS/HAMA/ColIIIMA, SHC) microneedle loaded with MXene@Zn-MOF (MXZ) composite was designed for diabetic infected wound repair. The MXZ composite achieved more than 99 % bacterial inhibition against both E. coli and S. aureus, and was able to effectively remove the bacterial biofilm. In addition, SHC + MXZ microneedles were able to promote angiogenesis by activating the Transforming Growth Factor-β (TGF-β) signaling pathway. It also regulated macrophage polarization towards the M2 phenotype and inhibited the Tumor Necrosis Factor-α (TNF-α) signaling pathway to reduce the level of inflammation. Further studies on mitochondrial membrane potential showed that SHC + MXZ microneedles were able to restore the decrease in mitochondrial membrane potential caused by ROS and then restore mitochondrial function. In diabetic infected wound repair results showed that SHC + MXZ microneedles effectively promoted diabetic infected wound repair by promoting angiogenesis and reducing the inflammation level of the wound tissue. Finally, the regulation of related gene expression was explored by transcriptome sequencing, and the intrinsic mechanism of SHC MXZ microneedles in promoting the repair of diabetic infected wounds by regulating the TGF-β and TNF-α signaling pathways was elucidated.
    Keywords:  Diabetic wound; Dual-layer microneedles; MXene@Zn-MOF; TGF-β signaling pathways
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102687
  64. Mol Biol Evol. 2026 Jan 09. pii: msag005. [Epub ahead of print]
    Mitochondrial Retrograde Control of Transcription Evolves with Respiratory Stress, Metabolic Adaptation, and Virulence in Budding Yeasts.
    Karolina Łabędzka-Dmoch, Thi Hoang Diu Bui, Jakub Piątkowski, Marta Dilling, Paulina Jagiełło, Wiktoria Kabza, Paweł Golik.
      The pathway involving the paralogous transcription factors Rtg1 and Rtg3 was first described in Saccharomyces cerevisiae as the retrograde regulation that adapts cellular metabolism in response to the state of mitochondrial respiration. We investigated the evolution of this pathway by studying its target genes in respiratory-deficient mutants of Candida albicans - a phylogenetically distant and metabolically distinct yeast species. We show that in C. albicans the Rtg pathway is also responsible for adaptation to cellular stresses related to respiratory dysfunction, but the repertoire of its target genes is different than in S. cerevisiae, and includes genes encoding proteins involved in alternative respiration, oxidative stress, mitophagy, and other aspects of metabolism. We also traced the evolution of the main components of the Rtg pathway and its target genes in the budding yeast (Saccharomycotina) subphylum. We show that the system originated within this clade following a single duplication of the gene encoding the ancestor of Rtg1 and Rtg3, but employs other factors, like the regulatory proteins Rtg2 and Mks1 that were likely present in the last common ancestor of budding yeasts. The regulation of the Rtg transcription factors in C. albicans is different than in S. cerevisiae, as both Rtg2 and Mks1 were lost in the majority of Serinales. Among the target genes, of particular interest is the evolution of the alternative oxidase (Aox), which was either lost or duplicated in multiple independent events. The presence of Aox strongly correlates with the mitochondrially encoded Complex I - a major source of oxidative stress.
    DOI:  https://doi.org/10.1093/molbev/msag005
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