bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–12–28
67 papers selected by
Gavin McStay, Liverpool John Moores University
  1. The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity.
  2. Basic Science and Pathogenesis.
  3. Grass carp (Ctenopharyngodon idella) resist heat stress by maintaining mitochondrial quality and enhancing energy production.
  4. Mitochondrial fission and fusion in inflammatory diseases: mechanisms and therapeutic implications.
  5. Mitophagy in breast cancer: Regulatory mechanisms and therapeutic potential.
  6. [Resveratrol protects barrier function of mouse brain microvascular endothelial cell monolayers with oxygen/glucose deprivation and PM2.5 exposure by maintaining mitochondrial dynamics balance].
  7. α-Lipoic Acid Nanoparticles Functionalized with RVG29 Peptide Attenuate Seizure-Induced Neurotoxicity by Restoring Mitochondrial Homeostasis via the PINK1/Parkin Pathway.
  8. Targeting mitochondrial fission to ameliorate apoptosis of gingival fibroblasts: novel perspectives on inflammatory gingival recession prevention.
  9. Global trends and perspectives in mitophagy on neurodegenerative diseases: a scientometric analysis over 20 years.
  10. LncRNA H19 Upregulation Links Hypoplastic Left Heart Syndrome to Impaired PINK1/Parkin-Mediated Mitophagy and Ischemic Vulnerability.
  11. Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
  12. Mitofusin 2 is required for preventing deoxynivalenol-induced porcine intestinal epithelial cell damage.
  13. Astragaloside IV inhibits MAPK pathway and promotes mitochondrial autophagy in rats with heart failure.
  14. Benzo[a]pyrene induces an adaptive mitochondrial-dynamics response in endothelial cells, at human relevant concentration.
  15. Developing Topics.
  16. Basic Science and Pathogenesis.
  17. Ginsenoside Rg1 delays chronological aging in a yeast model via SSE1-Mediated mitophagy.
  18. Defective Mitochondrial Unfolded Protein Response in Cancer Acts as a Lifeline for Tumor Growth and Survival.
  19. Aldehyde dehydrogenase 9A1 promotes cisplatin resistance in laryngeal squamous cell carcinoma by enhancing PTEN-induced kinase 1-Parkin-mediated mitophagy.
  20. Developing Topics.
  21. High-Frequency rTMS can Improve Depressive Symptoms by Promoting Mitochondrial Fusion.
  22. Hypoxic BMSC-derived exosomes-induced mitophagy quenches intestinal inflammation via HIF-1α/BNIP3 pathway.
  23. Paeoniflorin mitigates myocardial hypertrophy by regulating mitophagy and ferroptosis mediated by mitochondria-associated AMPK-Parkin-ACSL4 pathway.
  24. Insights into PINK1/Parkin function and dysfunction from Drosophila models.
  25. Editorial: Insights in aging, metabolism and redox biology: 2024.
  26. A role for Fis1 in dendritic development.
  27. Correction: Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.
  28. Lipoteichoic Acid Stimulation of Macrophages Causes Mitochondrial Dysfunction.
  29. Shionone ameliorates pulmonary fibrosis by activating mitophagy via PINK1-Parkin pathway.
  30. Mitochondria in Developing Brain: Contribution of Deviations to Higher Susceptibility to Neurodegeneration in Latter Periods of Life.
  31. SUMO protease Pira induces autophagy-related cell death during Drosophila development.
  32. Pterostilbene mitigates the senescence of human dermal fibroblast cells by enhancing mitochondrial quality.
  33. Basic Science and Pathogenesis.
  34. Targeting mitochondrial autophagy for anti-aging.
  35. Turnover and Quality Control of Mitochondrial DNA.
  36. Correction: Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.
  37. DPEP1 mediates regulation of mitochondrial quality control via FOXO1/ALDH1L2 axis to attenuate ferroptosis in pulmonary endothelial cells to alleviate sepsis-associated acute lung injury.
  38. Gymconopin C exhibits anti-non-small cell lung cancer effect by regulating miR-6777-5p/ADRB2 pathway to promote mitophagy.
  39. Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.
  40. Injectable Magnolol-Peptide Hydrogel as a Minimally Invasive Treatment for Doxorubicin-Induced Cardiomyopathy via Inhibition of Aberrant Mitochondrial Fission.
  41. Deciphering the antitumor immune effects of succinate.
  42. Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
  43. ALDH3A2 negatively orchestrates gastric cancer progression through a synergistic induction of ferroptosis and ferroptosis-driven macrophage reprogramming.
  44. Drosophila as a model to study autophagy during oogenesis.
  45. Viral SAM-binding proteins nsp14 and NP868R reprogram ATG4A-dependent autophagy from antiviral LC3B activity to GABARAP-mediated mitophagy.
  46. Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.
  47. Placental-Derived Mesenchymal Stem Cells Triggers Lipid Metabolism in a Rat Model Thioacetamide-Induced Ovarian Disease via Increased CPT1A Expression for Mitochondrial Dynamics.
  48. The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
  49. New insight into the risk stratification and treatment priority of breast cancer: TMT scoring system.
  50. Trifloxystrobin induces oxidative stress-dependent activation of the OMA1-DELE1-HRI integrated stress response leading to apoptosis in human neuroblastoma cells.
  51. Prussian Blue Nanoparticles Promoting Diabetic Bone Regeneration via Mitochondrial Recovery.
  52. DCLRE1 downregulated by SYVN1-mediated ubiquitination and degradation, weakening mitochondrial homeostasis protection in ARC formation.
  53. Current perspectives and trends on the role of mitochondria in renal ischemia-reperfusion injury from 2005 to 2024: a bibliometric analysis and literature review.
  54. Atractylodes macrocephala Koidz. water extract alleviates exercise-induced fatigue by activating mitochondrial biogenesis via the PGC-1α/NRF1/TFAM axis.
  55. Fiscalin B exerts an anticancer effect through mitochondria-modulated apoptosis and cell cycle arrest in human hepatocellular carcinoma.
  56. PI3K/Akt/mTOR signaling pathway mediates energy metabolic reprogramming and regulates mitochondrial homeostasis in host cells exposed to Toxoplasma gondii.
  57. TRAF6 mediates vascular remodeling via endoplasmic reticulum stress-mitophagy in hypoxic pulmonary hypertension.
  58. Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.
  59. Mechanisms of Intracellular Selection of Mitochondrial DNA.
  60. A Cold Stress-Activated Endocrine Sentinel Chemical Hormone Promotes Insect Survival via Mitochondrial Adaptations Through the Adipokinetic Hormone Receptor.
  61. Mitochondrial Unfolded Protein Responsive Imaging and Surgical Navigation in Ovarian Cancer.
  62. Schwann cell Lrp1 deletion drives trigeminal neuron sensitization and orofacial pain by modulating mitochondrial function and TRPV1/TRPA1 activity.
  63. Basic Science and Pathogenesis.
  64. Prohibitin 2 ameliorates cisplatin-induced acute kidney injury by modulating mitochondrial homeostasis.
  65. Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.
  66. Xin-Ji-Er-Kang alleviates chronic heart failure by suppressing mtDNA/cGAS-STING signaling through NR3C1-mediated MFN2 upregulation.
  67. Drug Development.
  1. Neurotox Res. 2025 Dec 27. 44(1): 2
    The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity.
    Alexey A Tinkov, Hyunjin Kim, Anatoly V Skalny, Jung-Su Chang, Abel Santamaria, Rongzhu Lu, Ji-Chang Zhou, Aaron B Bowman, Eun-Sook Lee, Yousef Tizabi, Michael Aschner.
      The objective of the present review is to discuss the involvement of altered mitochondrial quality control in Mn-induced neurotoxicity. Existing data demonstrate that mitochondrial autophagy (mitophagy) and brain mitochondrial unfolded protein response (mtUPR) are activated in response to Mn exposure to counteract the Mn-induced mitochondrial dysfunction. Both mitophagy and mtUPR have significant overlap and mechanistic intersections with the integrated stress response (ISR). Increased Mn exposures impair mitochondrial dynamics, further aggravating Mn-induced mitochondrial dysfunction. Specifically, Mn suppresses PTEN-induced kinase 1 (PINK1)-Parkin-dependent mitophagy through a variety of mechanisms, including nitric oxide synthase 2 (NOS2)-dependent PINK1 S-nitrosylation, inhibition of transcription factor EB (TFEB) signaling, and mammalian target of rapamycin complex 1 (mTORC1) activation. In addition, Mn promotes mitochondrial fission by up-regulating dynamin-1-like protein (Drp1) expression and phosphorylation via the activation of c-Jun N-terminal kinase (JNK) and inhibition of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathways. Concomitantly, Mn impairs mitochondrial fusion by inhibiting mitofusin (Mfn) 1/2 and dynamin-like 120 kDa protein (Opa1) expression, leading to a reduction in mitochondrial size and disruption of the mitochondrial network. High-dose Mn exposure results in inhibition of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (NRF2)-dependent mitochondrial biogenesis. The latter may be mediated by inhibition of SIRT1/SIRT3 activity, as well as modulation of PINK1/ zinc finger protein 746 (ZNF746)/PGC-1α axis. Alterations in the mitochondrial quality control system may contribute to Mn-induced neuronal damage and neuroinflammation, indicating that dysregulation of the brain mitochondrial dynamics is an important mechanism by which Mn induces its neurotoxicity.
    DOI:  https://doi.org/10.1007/s12640-025-00776-w
  2. Alzheimers Dement. 2025 Dec;21 Suppl 1 e106561
    Basic Science and Pathogenesis.
    Dona P W Jayatunga, Eugene Hone, Ralph N Martins.
       BACKGROUND: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders that affects geriatric populations across the globe. Deposition of the Aβ peptide in the brain is considered a central event of AD pathology. Mitochondrial dysfunction is a characteristic feature of AD. The objective of the present study was to determine the time-dependent effects of Aβ1-42 toxicity in BE(2)-M17 and its role in mitochondrial quality control mechanisms namely, mitochondrial dynamics, selective autophagy and mitochondrial biogenesis.
    METHOD: Oligomeric Aβ1-42 was added to the cells for time points of 4, 8, 16, 24, 48 and 72 hours. At all these time points, cellular mitochondrial dehydrogenase activity, ATP and reactive oxygen species (ROS) levels were determined using MTS, CellTiter Glo and DCFDA assays, respectively. Western blots were used to quantify mitochondrial dynamics-related proteins: OPA1, MFN2 and FIS1, mitophagy related proteins: p62, NDP52, OPTN, PINK1 and TIMM23 and mitobiogenesis related protein, PGC-1α.
    RESULT: Increased ROS levels, attenuated ATP levels and fluctuations of mitochondrial quality control proteins in cells at the respective time intervals suggest altered mitochondrial quality control. Furthermore, compromised mitochondrial dynamics, mitophagy and mitobiogenesis suggest that chronic Aβ1-42 exposure promotes mitochondrial dysfunction.
    CONCLUSION: Further studies are required to determine if the time-dependent fluctuations of these mitochondrial mechanisms were due to adaptive cell responses against the Aβ1-42 cytotoxicity.
    DOI:  https://doi.org/10.1002/alz70855_106561
  3. J Fish Biol. 2025 Dec 26.
    Grass carp (Ctenopharyngodon idella) resist heat stress by maintaining mitochondrial quality and enhancing energy production.
    Xiaotian Zhang, Xianfang Yan, Pengju Li, Chi Wang, Cheng Zhang, Hong Ji, Haibo Yu.
      This study aims to explore the resistance mechanism of grass carp (Ctenopharyngodon idella) to heat stress (HS). Grass carp were cultured at 28°C, and then exposed to 30°C, 32°C or 34°C with a heating rate of 1°C/d, respectively. The results show that serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and liver malondialdehyde (MDA) content significantly increased after HS. In contrast, liver total antioxidant capacity (T-AOC) was significantly reduced after HS. Additionally, serum triglyceride (TG) and free fatty acid (FFA) levels increased after HS. Notably, the hepatic adenosine triphosphate (ATP) content of grass carp exposed to 30°C and 32°C was significantly higher than that of those exposed to 28°C. However, the liver ATP content of grass carp exposed to 34°C was significantly reduced compared to other groups. Further, the liver mitochondrial DNA copies significantly increased after HS. The expression of mitochondrial biogenesis genes (pgc-1α, nrf1/2, tfam) and mitophagy genes (beclin1, atg5, atg7, pink1, parkin) was upregulated in grass carp after HS. However, the expression of mitochondrial fission gene (drp1) was significantly upregulated in grass carp exposed to 34°C compared to other groups, whereas no corresponding change was observed in the expression of mitochondrial fusion gene (mfn1/2) in grass carp exposed to 34°C. In conclusion, when grass carp were exposed to 30°C or 32°C, mitochondrial homoeostasis can be maintained via regulating mitochondrial quality, providing enough energy for grass carp to resist HS. However, when grass carp was exposed to 34°C, mitochondrial homoeostasis was impaired, leading to inadequate energy for grass carp to resist HS.
    Keywords:  energy supply; grass carp; heat stress; mitochondria quality control; mitochondrial homoeostasis; mitophagy
    DOI:  https://doi.org/10.1111/jfb.70320
  4. J Transl Med. 2025 Dec 24.
    Mitochondrial fission and fusion in inflammatory diseases: mechanisms and therapeutic implications.
    Wenjing Xu, Xinru Xu, Yaonan Zhang, Fenfen Li, Daozong Xia.
      
    Keywords:  Inflammatory diseases; Inflammatory pathways; Mitochondrial dynamics; Therapeutic targets; Translational medicine
    DOI:  https://doi.org/10.1186/s12967-025-07605-w
  5. Chin Med J (Engl). 2025 Dec 25.
    Mitophagy in breast cancer: Regulatory mechanisms and therapeutic potential.
    Yujing Chang, Yongjie Zhou, Libo Yang, Leyi Gao, Yu Zhang, Mengna Feng, Mengjia Shen, Bing Wei, Hong Bu, Zhang Zhang.
       ABSTRACT: Breast cancer (BC) is the most prevalent malignancy among women and presents significant challenges, such as drug resistance and relapse, particularly triple-negative breast cancer (TNBC). Mitophagy is the primary process by which damaged mitochondria are degraded via the autophagy-lysosomal pathway to maintain mitochondrial homeostasis. The regulatory mechanisms of mitophagy and its role in BC progression are crucial for the discovery of new biomarkers and therapeutic targets. This review provides a comprehensive summary of the current understanding of mitophagy in BC, highlighting the gaps in knowledge related to reliable biomarkers and personalized treatment strategies. The pathways and mechanisms of mitophagy and their importance in BC are also summarized. Key findings include the dual role of mitophagy in BC development, the association of mitophagy-related genes/proteins with BC pathogenesis, and the potential of mitophagy modulators in enhancing treatment outcomes. This review further discusses the design of biosensors for detecting mitophagy in BC metastasis and explores the potential of mitophagy-related genes as biomarkers and prognostic factors. The unique value of this manuscript lies in its in-depth exploration of the regulatory mechanisms of mitophagy in BC, providing a scientific basis for clinical management and treatment while offering guidance for future research directions.
    Keywords:  Biomarkers; Breast cancer; Mitochondria; Mitophagy; Tumor therapy
    DOI:  https://doi.org/10.1097/CM9.0000000000003949
  6. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Dec 20. pii: 1673-4254(2025)12-2690-09. [Epub ahead of print]45(12): 2690-2698
    [Resveratrol protects barrier function of mouse brain microvascular endothelial cell monolayers with oxygen/glucose deprivation and PM2.5 exposure by maintaining mitochondrial dynamics balance].
    Meng Qin, Siyu Sun, Jiaqi Liu, Yujiao Gao, Hao Wang, Youkun Wang, Ao Sun, Jiachun Yan, Jinbao Wang, Ying Yu.
       OBJECTIVES: To evaluate the effect of resveratrol (RES) on barrier function of mouse brain microvascular endothelial cell monolayers exposed to oxygen/glucose deprivation/reoxygenation (OGD/R) and PM2.5 and explore the role of mitochondrial fission and fusion in protecting endothelial barrier function.
    METHODS: Cultured mouse brain microvascular endothelial cells were exposed to OGD/R, treated with PM2.5 (100 μg/mL) before OGD/R, or pretreated with RES (40 mg/mL) prior to OGD/R+PM2.5 exposures. The changes in cell viability were examined with CCK-8 assay, and cell permeability was assessed by measuring transendothelial electrical resistance (TEER) and FITC-dextran permeation. Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured, and intracellular and mitochondrial ROS levels were detected using fluorescent probes. Mitochondrial morphology in the treated cells was observed using Mito-Tracker Red CMXRos. Western blotting was performed to detect the changes in cellular expressions of the tight junction proteins (ZO-1, occludin, and claudin-5) and mitochondrial dynamics-associated proteins (Drp1, Fis1, Mfn2, and OPA1).
    RESULTS: Compared with the normal control cells, the cells exposed to OGD/R or both OGD/R and PM2.5 showed significantly decreased TEER levels, increased permeability, elevated oxidative stress, and increased ROS fluorescence intensities. Obvious mitochondrial fragmentation and morphological changes in the mitochondria were observed in the exposed cells, which also showed decreased expressions of tight junction proteins and mitochondrial fusion proteins with increased expressions of mitochondrial fission proteins. RES pretreatment of the endothelial cells before the exposures significantly reduced membrane permeability, lowered ROS levels, improved mitochondrial morphology, increased expressions of tight junction and fusion proteins, and decreased fission protein expressions.
    CONCLUSIONS: RES can protect barrier function of mouse brain microvascular endothelial cell monolayers exposed to OGD/R and PM2.5 by modulating mitochondrial dynamics, potentially through promoting mitochondrial fusion and inhibiting mitochondrial fission.
    Keywords:  Blood-brain barrier; PM 2.5; cerebral ischemia-reperfusion injury; mitochondrial fission and fusion; resveratrol
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.12.16
  7. Free Radic Biol Med. 2025 Dec 23. pii: S0891-5849(25)01454-6. [Epub ahead of print]
    α-Lipoic Acid Nanoparticles Functionalized with RVG29 Peptide Attenuate Seizure-Induced Neurotoxicity by Restoring Mitochondrial Homeostasis via the PINK1/Parkin Pathway.
    Jianxun Hou, Lei Hao, Wei Du, Qiuyu Su, Qijiang Xiong, Wang Zhao, Zhao Yang.
      This study developed a novel nanotherapeutic approach for epilepsy treatment using Rabies Virus Glycoprotein Peptide 29 (RVG29) peptide-functionalized Polyethylene Glycol-Poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles encapsulating the potent antioxidant α-lipoic acid (designated RPP@A). The platform was designed to correct mitochondrial dysfunction by regulating the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway. The engineered nanoparticles exhibited strong brain-targeting capability and efficiently crossed the blood-brain barrier, enabling precise delivery of α-lipoic acid to vulnerable neuronal populations. Comprehensive in vitro and in vivo analyses demonstrated that RPP@A treatment markedly attenuated seizure-induced neurotoxicity by restoring mitochondrial homeostasis and suppressing excessive mitophagy. The antioxidant function of α-lipoic acid, combined with targeted delivery, reduced oxidative stress and neuroinflammation and decreased neuronal apoptosis associated with epileptic pathology. Multi-omics analyses confirmed the central role of PINK1/Parkin signaling in mediating these protective effects. Comparative studies showed that RPP@A outperformed both free α-lipoic acid and non-targeted nanoparticles in reducing seizure frequency and preserving cognitive function, indicating the critical importance of the targeted delivery system. The nanoplatform represents a significant advancement in antioxidant-based therapy for neurological disorders, offering a promising strategy for clinical translation by specifically addressing mitochondrial quality control mechanisms in epilepsy.
    Keywords:  Mitophagy; Oxidative Stress; PINK1/Parkin Pathway; Targeted Nanoparticles; α-Lipoic Acid
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.037
  8. Int Immunopharmacol. 2025 Dec 24. pii: S1567-5769(25)02068-5. [Epub ahead of print]170 116079
    Targeting mitochondrial fission to ameliorate apoptosis of gingival fibroblasts: novel perspectives on inflammatory gingival recession prevention.
    Wenjia Cai, Ping He, Zhangmin He, Yi Yang, Jingsong Ren, Jia Wang, Wenjie Zhong, Xiang Gao, Jinlin Song.
      Gingival recession currently lacks effective strategies for prevention and treatment. Excessive apoptosis of gingival fibroblasts (GFs) compromises the biosynthetic capacity of periodontal tissues, thereby accelerating the progression of gingival recession. Mitochondria play a critical role in the apoptotic pathway and mitochondrial dynamics are essential for maintaining mitochondrial function. However, the specific role of mitochondrial dynamics in regulating GFs apoptosis and its contribution to gingival recession remains unclear. Emerging evidence suggests that mitochondrial dynamics, specifically the balance between mitochondrial fission and fusion, are essential for maintaining mitochondrial function. Excessive mitochondrial fission may lead to mitochondrial fragmentation, loss of mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) accumulation, ultimately resulting in cellular damage. We utilized lipopolysaccharide (LPS) to mimic the inflammatory stimulation of GFs in vitro and established a novel in vivo model that integrates a bone defect with ligature-induced inflammation to recapitulate and study gingival recession. LPS not only induced significant inflammation and apoptosis in GFs but also triggered an imbalance in mitochondrial dynamics, characterized by enhanced fission, decreased MMP, and impaired ATP production. Notably, Mdivi-1 treatment reversed these detrimental effects. Consistently, in animal models, Mdivi-1 alleviated gingival inflammation, enhanced gingival connective tissue fiber density, and suppressed mitochondrial fission and apoptosis of fibroblasts, ultimately mitigating the severity of gingival recession. In conclusion, this study investigates the role of mitochondrial dynamics in inflammatory gingival recession and provides its inhibition as a potential strategy for prevention.
    Keywords:  Apoptosis; Gingival fibroblasts; Gingival recession; Mitochondria; Mitochondrial dynamics; Periodontitis
    DOI:  https://doi.org/10.1016/j.intimp.2025.116079
  9. Front Med (Lausanne). 2025 ;12 1666909
    Global trends and perspectives in mitophagy on neurodegenerative diseases: a scientometric analysis over 20 years.
    Haiyan Wu, Minheng Zhang, Lei Zhang, Hongwei Liu, Haixia Fan.
       Background: The investigation of mitophagy in neurodegenerative diseases has grown significantly, yet a comprehensive global insight remains limited. This study conducts a scientometric analysis to map the research landscape related to mitophagy in neurodegenerative diseases.
    Methods: We conducted a bibliometric analysis of 2,566 publications (2004 to 11 June 2025) from Web of Science Core Collection and Scopus. To mitigate bias in trend analyses, incomplete 2025 data were excluded from publication growth and curve fitting but retained for other analyses. Data were analyzed via Bibliometrix R package, VOSviewer, Scimago Graphica, and CiteSpace to map mitophagy research evolution.
    Results: The field showed exponential growth with peak productivity in 2021. The United States led publication output, with institutions from the USA, UK, and China forming the core of robust international collaborations, while maintaining the highest citation impact. Influential researchers included Tavernarakis, Nektarios and Reddy, P. Hemachandra, with prominent journals such as International Journal of Molecular Sciences, Cells and Autophagy, serving as key publication venues. Cluster analysis revealed thematic structures centered on "Parkinson's disease," "mitochondrial dysfunction," "oxidative stress," and "fission/fusion mechanisms", with additional focus on "Parkin-mediated mitophagy" and "neurodegenerative diseases." Research evolved from foundational studies through mechanistic exploration to translational applications. Emerging trends include "post-translational modifications (PTMs)," "chaperone-mediated autophagy," "gut microbiota," "mitochondrial quality control," and therapeutic investigations of compounds like "curcumin" and "melatonin."
    Conclusion: This first comprehensive scientometric analysis underscores the expanding interest in mitophagy as a crucial molecular mechanism in neurodegenerative diseases. Our findings establish a framework for developing novel therapeutic interventions such as mitochondrial quality control modulators and compounds like curcumin and melatonin targeting mitophagy dysfunction in neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; PINK1/Parkin; mitochondrial dysfunction; mitophagy; neurodegenerative diseases; oxidative stress
    DOI:  https://doi.org/10.3389/fmed.2025.1666909
  10. bioRxiv. 2025 Dec 19. pii: 2025.12.16.694773. [Epub ahead of print]
    LncRNA H19 Upregulation Links Hypoplastic Left Heart Syndrome to Impaired PINK1/Parkin-Mediated Mitophagy and Ischemic Vulnerability.
    Xuebin Fu, Conrad L Epting, Anshuman Sinha, Michael C Mongé, Ming Zhao, Kristofor E Glinton, Swetha Thirukannamangai Krishnan, My Linh Thi Nguyen, Vincent Joseph Dudley, Gregory B Waypa, Pedro G Lara, Tarek Kishawi, Connor W Lantz, David Winlaw, Paul T Schumacker, Edward B Thorp, Zhi-Dong Ge.
       BACKGROUND: The myocardium in hypoplastic left heart syndrome (HLHS) exhibits immature metabolic programming, impaired mitochondrial quality control, and heightened susceptibility to ischemic and hypoxic injury during palliative surgery. The long non-coding RNA H19 suppresses translation of PTEN-induced putative kinase 1 (PINK1) mRNA and modulates mitochondrial quality control and ischemia/reperfusion injury (IRI) in adult hearts. Whether-and how-H19 regulates mitophagy and IRI in HLHS or in immature animals remains unknown.
    METHODS: We investigated H19 regulation and its role in mitophagy and ischemia/reperfusion or hypoxia/reoxygenation injury in myocardial tissue from HLHS patients, HLHS-specific induced pluripotent stem cell-derived cardiomyocytes (HLHS-iPSC-CMs), and immature rat hearts. Mechanistic interactions among H19, PINK1/Parkin signaling, and mitophagosome formation were assessed using loss-of-function approaches.
    RESULTS: HLHS myocardium exhibited markedly elevated H19 expression, accompanied by reduced PINK1 and Parkin protein abundance and diminished mitophagosome formation. Similar findings were observed in HLHS-iPSC-CMs exposed to hypoxia/reoxygenation and in immature rat hearts subjected to myocardial IRI. H19 knockdown in HLHS-iPSC-CMs attenuated hypoxia/reoxygenation-induced lactate dehydrogenase release and restored PINK1 and Parkin protein levels. In immature rats, myocardial H19 silencing reduced infarct size, enhanced mitochondrial PINK1 and Parkin expression, and improved post-reperfusion cardiac function for up to 28 days. Conversely, knockdown of PINK1 or Parkin reduced mitophagosome formation and exacerbated functional deterioration during IRI.
    CONCLUSIONS: H19 upregulation impairs PINK1/Parkin-dependent mitophagy and increases susceptibility to ischemic and hypoxic injury in HLHS and the immature heart. These findings identify H19 as a key regulator of mitochondrial quality control and a potential therapeutic target for mitigating IRI in early-life cardiac disease.
    Abstract Figure:
    Novelty and Significance: What Is Known?: The myocardium in hypoplastic left heart syndrome (HLHS) exhibits immature metabolic programming, abnormal coronary perfusion, and impaired mitochondrial quality control, rendering it highly susceptible to ischemic and hypoxic injury.Both structural limitations and intrinsic mitochondrial dysfunction contribute to the reduced ischemic tolerance of the HLHS heart, particularly during surgical and hemodynamic stress.The long noncoding RNA H19 regulates mitochondrial quality control and modulates myocardial ischemia/reperfusion injury (IRI) in adult hearts.H19 inhibits the binding of the translation initiation factor eIF4A2 to PTEN-induced putative kinase 1 (PINK1) mRNA, thereby suppressing PINK1 protein synthesis and influencing PINK1-dependent mitophagy in adult mice.What New Information Does This Article Contribute?: This study identifies robust upregulation of H19 in HLHS myocardium, HLHS-specific induced pluripotent stem cell-derived cardiomyocytes (HLHS-iPSC-CMs) exposed to hypoxia/reoxygenation, and in immature rats subjected to myocardial IRI.Elevated H19 is associated with suppressed PINK1/Parkin-dependent mitophagy, exacerbated IRI, and adverse post-injury remodeling.Knockdown of H19 restores mitochondrial PINK1 and Parkin protein levels, enhances mitophagy, reduces infarct size, and improves long-term recovery of cardiac function-demonstrating a previously unrecognized pathogenic role for H19 in the immature heart under stress.Knockdown of PINK1 or Parkin decreases mitophagosomes and exacerbates myocardial IRI in immature rats.
    DOI:  https://doi.org/10.64898/2025.12.16.694773
  11. Autophagy. 2025 Dec 26.
    Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
    Ang Li, Shu-Qin Cao, Evandro F Fang, Huanxing Su.
      Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.
    Keywords:  ALS; PINK1-Parkin; isoginkgetin; mitophagy; motor neurons
    DOI:  https://doi.org/10.1080/15548627.2025.2610450
  12. J Anim Sci Biotechnol. 2025 Dec 23. 16(1): 178
    Mitofusin 2 is required for preventing deoxynivalenol-induced porcine intestinal epithelial cell damage.
    Kan Xiao, Minfang Zhang, Qingqing Lv, Feifei Huang, Qilong Xu, Junjie Guo, Jiangchao Zhao, Huiling Zhu, Shaokui Chen, Yulan Liu.
       BACKGROUNDS: Deoxynivalenol (DON) is an abundant environmental pollutant in feed, posing serious health hazards to animals. However, whether DON triggers an imbalance in mitochondrial fission/fusion and the underlying mechanisms involved remain poorly understood. Our aim was to clarify whether mitochondrial fission or fusion proteins participated in DON-caused intestinal damage in pigs.
    METHODS: Firstly, two groups of weaning pigs were fed a basal diet, or basal diet supplemented with 4 mg DON/kg for 3 weeks. Additionally, another two groups of weaning pigs were given an oral gavage with 2 mg/kg body weight DON or an equivalent amount of normal saline. In addition, the involvement of mitochondrial fission or fusion proteins in DON-induced intestinal damage was further verified in intestinal porcine epithelial cell line (IPEC-1) by overexpressed plasmids of dynamin related protein 1 (Drp1) and mitofusin 2 (Mfn2) which were determined by animal studies. Finally, a mitochondrial fusion promotor M1 was used in IPEC-1 cells to explore the role of Mfn2 in DON-induced intestinal damage.
    RESULTS: Dietary DON caused jejunal damage and inflammation, reduced intestinal Drp1, mitofusin 1 (Mfn1) and Mfn2, and induced cell apoptosis. DON gavage also impaired jejunal structure and led to decreased Drp1 and Mfn2, and increased cell apoptosis. Moreover, DON challenge also resulted in cell damage and mitochondrial dysfunction, accompanied by abnormal protein expression of mitochondrial fission/fusion proteins and increased cell apoptosis in IPEC-1 cells. Subsequently, Mfn2, but not Drp1 overexpression plasmid restored mitochondrial fission/fusion protein expression, suppressed cell apoptosis, mitigated cell damage and mitochondrial dysfunction in IPEC-1 cells after DON challenge. Finally, M1 alleviated DON-induced reduction of Mfn2 protein and cell apoptosis, rescued mitochondrial dysfunction, barrier function impairment and cell damage.
    CONCLUSIONS: Overall, our study demonstrates that DON exposure triggers Mfn2 protein dysregulation, which in turn mediates DON-induced intestinal epithelial damage in piglets.
    Keywords:  Deoxynivalenol; Intestinal injury; Mfn2; Mitochondrial homeostasis; Piglets
    DOI:  https://doi.org/10.1186/s40104-025-01306-6
  13. Korean J Physiol Pharmacol. 2026 Jan 01. 30(1): 61-69
    Astragaloside IV inhibits MAPK pathway and promotes mitochondrial autophagy in rats with heart failure.
    Yaoyao Wang, Yujiang Chen, Tengxian Li, Peng Zhong, Qinsha Wang.
      Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with mitochondrial dysfunction and impaired mitophagy recognized as key contributors to its progression. Astragaloside IV (AS-IV), a major active component of Astragalus membranaceus, has shown multiple biological effects, but its role in mitochondrial homeostasis in HF remains unclear. In this study, a rat model of HF was induced by abdominal aortic constriction, and AS-IV was administered at doses of 20 mg/kg and 80 mg/kg. We found AS-IV treatment significantly reduced myocardial fibrosis and hypertrophy, improved mitochondrial function by increasing ATP and manganese superoxide dismutase levels, reducing reactive oxygen species, and upregulating PGC-1α and TFAM. It also enhanced mitochondrial autophagy. Moreover, AS-IV markedly inhibited the activation of the p38 MAPK pathway. AS-IV suppresses autophagy and mitochondrial function via targeting MAPK pathway in H9c2 cells. These findings suggest that AS-IV alleviates HF by promoting mitophagy and preserving mitochondrial function through suppression of the MAPK pathway, highlighting its potential as a novel therapeutic agent for HF.
    Keywords:  ATP; Autophagy; Heart failure; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.4196/kjpp.25.113
  14. Environ Pollut. 2025 Dec 18. pii: S0269-7491(25)01912-8. [Epub ahead of print]391 127538
    Benzo[a]pyrene induces an adaptive mitochondrial-dynamics response in endothelial cells, at human relevant concentration.
    Joan Guillouzouic, Camille Chauvin, Valentine Genet, Simon Martarello, Agnes Burel, Lydie Sparfel, Normand Podechard, Dominique Lagadic-Gossmann, Catherine Lavau, Eric Le Ferrec.
      Although polycyclic aromatic hydrocarbons (PAHs) are a public health concern in many countries, the cellular response at concentrations representative of human exposure remains poorly defined. At the cellular level, because of their function and composition, mitochondria are privileged targets of these contaminants. PAHs such as benzo[a]pyrene (B[a]P) can compromise mitochondrial functions. Using an integrated approach, we examined how low-dose B[a]P disrupts the three determinants of mitochondrial homeostasis (biogenesis, mitophagy, and dynamics) and triggers apoptosis. We assessed the cellular response to a low-dose of B[a]P (100 nM) in the human microvascular endothelial cell line HMEC-1. Endothelial cells are sensitive to PAHs and display marked reactivity to effectors of B[a]P toxicity, such as oxidative stress. We show that B[a]P doesn't modify mRNA expression of mitochondrial biogenesis markers but causes a blockage of autophagic flux. In parallel, we observe early and transient mitochondrial elongation accompanied by decreased expression of the fission factors DRP1 and MFF, and increased intracellular concentration of ATP. These events constitute cellular signatures of stress-induced mitochondrial hyperfusion (SIMH), a mechanism of resistance to apoptosis. B[a]P eventually causes apoptosis of HMEC-1 cells, which is mitochondria-dependent, caspase-independent, requires B[a]P bioactivation by CYP1 family enzymes, and is only detectable after 24 h of exposure when SIMH markers decline. Our results show that endothelial cells can mobilize SIMH to delay and limit B[a]P-induced apoptosis. We confirm that mitochondria, at human-relevant doses, are early sensitive targets of B[a]P and show that changes in mitochondrial dynamics constitute an early readout of cellular responses to B[a]P.
    Keywords:  Aryl hydrocarbon receptor; Endothelial cells; Mitochondria; Mitochondrial dynamics (fusion/fission); Polycyclic aromatic hydrocarbons; Stress-induced mitochondrial hyperfusion
    DOI:  https://doi.org/10.1016/j.envpol.2025.127538
  15. Alzheimers Dement. 2025 Dec;21 Suppl 7 e108430
    Developing Topics.
    Fanpeng Zhao.
       BACKGROUND: Mitochondrial dysfunction is a major pathological event of neurodegeneration including Alzheimer's disease (AD). Expanding evidence demonstrate that an altered balance in mitochondrial dynamics is an important mechanism leading to mitochondrial and neuronal dysfunction during neurodegeneration. Thus, it is of great interest to test if restoration of mitochondrial dynamics has beneficial role in AD treatment.
    METHOD: 5xFAD mouse model of AD was used to test whether MFN2 OE or MFN2 activator rescues mitochondrial dysfunctions and neurodegeneration. Behavioral tests, mitochondrial analysis, electrophysiological study, RNA-seq and biochemical analysis were applied to examine the brain pathology in the AD mouse model.
    RESULT: In this study, we observed fragmented and damaged mitochondria in 5xFAD mouse brains, along with impaired mitochondrial respiration of synaptosome at 6 months. Restoration of mitochondrial dynamics by conditional overexpression (OE) of mitofusin-2 (MFN2) in forebrain neurons rescues mitochondrial fragmentation and dysfunction in 5xFAD mouse brains. Importantly, MFN2 OE protects against long-term potential reduction, synaptic loss, oxidative stress damage, amyloid plaque size, neuroinflammation and cognitive deficits in 5xFAD mice at 6 months. Amyloid plaque burden and neuronal death in plaque-enriched layer V cortical regions can be alleviated in 5xFAD mice by MFN2 OE at 10 months. RNA sequencing (RNA-seq) reveals disturbed transcriptomic profiles including increased inflammatory responses in 5xFAD mice, which is reversed by MFN2 OE. Specifically, MFN2 OE inhibits microglial activation, proinflammatory cytokine production, and NLRP3 inflammasome activation in 5xFAD mice. Lastly, intraperitoneal injection of compound BAY2402234, a brain penetrant MFN2 activator, rescues mitochondrial fragmentation, oxidative damage, and memory deficits in 5xFAD mice.
    CONCLUSION: Overall, our study demonstrated that the restoration of mitochondrial dynamics by inhibition of mitochondrial fragmentation can protect against neurodegeneration in 5xFAD mouse model and mitochondrial dynamic could be a promising therapeutic target for AD.
    DOI:  https://doi.org/10.1002/alz70861_108430
  16. Alzheimers Dement. 2025 Dec;21 Suppl 1 e105239
    Basic Science and Pathogenesis.
    Vivien Csikos, Brittany M Hauger, Taylor A Strope, Colton R Lysaker, Edziu M Franczak, Colin S McCoin, John P Thyfault, Heather M Wilkins.
       BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. A key contributor to AD pathology is metabolic dysfunction, including impaired mitophagy, a specialized form of autophagy targeting damaged mitochondria. We hypothesize that exercise and fasting, known to enhance metabolic health, can synergistically stimulate autophagy and mitophagy, offering a potential therapeutic strategy for AD.
    METHOD: To investigate the cellular mechanisms underlying the potential benefits of exercise on mitochondrial health, we cultured primary mouse neurons and treated them with serum (1% for 24h) from sedentary or exercised mice. We measured mitochondrial biogenesis using a MitoTimer reporter and mitophagy using an EGFP-mCherry COX8 reporter. We also measured p62 and LC3B protein levels following treatment with the autophagy inhibitor chloroquine (CQ). We also investigated the impact of exercise and fasting on autophagy in vivo using proteomics combined with CQ inhibition of autophagic flux in 5xFAD AD mice and their WT littermates (n = 48, 12-15 weeks of age). The animals were divided into control (Sed, n = 6) and combined fasting with exercise (FEx, n = 6) groups. Post-intervention, the animals received unilateral intrahippocampal CQ or PBS injections, and 4 hours post-injection, the hippocampi were collected for analysis.
    RESULT: Exercise serum increased mitochondrial biogenesis and mitophagy in primary neurons. We observed increased autophagic flux in exercise serum treated neurons by increased LC3-II and p62 content following CQ treatment. Proteomic analysis revealed distinct mitochondrial adaptations between WT and 5xFAD mice. While both strains showed upregulated metabolic pathways (TCA cycle and ETC) following an acute bout of FEx, 5xFAD mice exhibited a blunted response. Antioxidant defense adaptations to acute FEx were prominent in WT mice but absent in 5xFAD animals. Additionally, acute FEx robustly upregulated lysosomal proteins in WT mice but not in 5xFAD mice. Autophagy and mitophagy were differentially modulated by FEx, suggesting impaired adaptive responses in 5xFAD mice.
    CONCLUSION: These findings highlight the potential of exercise and fasting to enhance mitochondrial and lysosomal function, though their efficacy may be compromised in the context of AD pathology.
    DOI:  https://doi.org/10.1002/alz70855_105239
  17. Gene. 2025 Dec 24. pii: S0378-1119(25)00776-0. [Epub ahead of print] 149986
    Ginsenoside Rg1 delays chronological aging in a yeast model via SSE1-Mediated mitophagy.
    Ze Yao, Ming Lu, Chunshuang Li, Xiang Li, Hui Shang, Songtao Bie.
      Ginsenoside Rg1 (Rg1), an active compound in Panax ginseng C. A. Meyer (ginseng), has shown potential to ameliorate age-related cell damage and extend lifespan in multiple model organisms. However, the precise molecular mechanisms of its anti-aging effects remain unclear. In this study, we explore the anti-aging mechanisms of ginsenoside Rg1, focusing on its impact on mitophagy in Saccharomyces cerevisiae. Using propidium iodide staining, we found that Rg1 extends the chronological lifespan (CLS) of yeast cells. Further analyses revealed that Rg1 enhances mitochondrial function and antioxidant capacity in yeast cells by inducing mitophagy. Moreover, RNA-Seq and bioinformatics analyses identified the molecular chaperone SSE1 as a key target of Rg1. SSE1 knockout strain demonstrated that Rg1 enhances mitochondrial function and antioxidant capacity through SSE1-dependent mitophagy, thereby extending cell lifespan. Collectively, we concluded that Rg1 exerts its anti-aging effects through SSE1-mediated mitophagy. This study advances our understanding of Rg1-mediated mitophagy and mitochondrial regulation via SSE1, offering a foundation for the rational design of targeted anti-aging treatments.
    Keywords:  Anti-aging; Autophagy; Bioinformatics Analyses; Ginsenoside Rg1; SSE1
    DOI:  https://doi.org/10.1016/j.gene.2025.149986
  18. Cell Stress Chaperones. 2025 Dec 19. pii: S1355-8145(25)00088-4. [Epub ahead of print] 100143
    Defective Mitochondrial Unfolded Protein Response in Cancer Acts as a Lifeline for Tumor Growth and Survival.
    Uttam Sharma, Vaishnavi Vishwas, Rajiv Ranjan Kumar, Nikita Agarwal, Akshi Shree, Jaya Kanta Gorain, Archana Sasi, Surender K Sharawat, Archna Singh, Jayanth Kumar Palanichamy, Sameer Bakhshi.
      Defective mitochondrial unfolded protein response (UPRmt plays an important role in driving tumor growth and treatment resistance. Under physiological conditions, UPRmt preserves mitochondrial protein homeostasis and structure by inducing chaperones such as heat shock proteins (HSP60, HSP70, HSP10) and proteases like caseinolytic peptidase ATP-dependent, proteolytic subunit (ClpP), and Lon peptidase 1 (LONP1). However, dysfunctional UPRmt in cancer cells may allow them to tolerate mitochondrial damage and metabolic dysregulation, and avoid cell death, thus promoting therapy resistance. Our current understanding of how transcriptional regulators such as activating transcription factor 5 (ATF5), C/EBP homologous protein (CHOP), and forkhead box protein O3a (FOXO3a), along with signaling circuits including ATF5-ATF4-CHOP, SIRT3-FOXO3a and AKT-ERα, coordinate detrimental forms of UPRmt activation in cancer cells remains limited. This review describes known interactions among mediators of the UPRmt pathway and how they may be dysregulated in cancer cells. We also explore how this altered stress response may provide avenues for therapeutic targeting.
    Keywords:  Cancer; Chaperones; Mitochondrial unfolded protein response; Proteases; UPRmt
    DOI:  https://doi.org/10.1016/j.cstres.2025.100143
  19. Anticancer Drugs. 2025 Dec 24.
    Aldehyde dehydrogenase 9A1 promotes cisplatin resistance in laryngeal squamous cell carcinoma by enhancing PTEN-induced kinase 1-Parkin-mediated mitophagy.
    Jiawei Gui, Bo Wu, Yutong Fan, Xiaotong Liu, Yuzhe Liu, Haiying Wang, Jun An, Hao Wang, Ruoqing Wu, Liang Li, Jingchun Ge, Hui Xiao.
      Cisplatin resistance remains a major challenge in laryngeal squamous cell carcinoma (LSCC) treatment. Aldehyde dehydrogenase 9A1 (ALDH9A1), a mitochondrial matrix protein, is dysregulated in various cancers, but its role in LSCC is unclear. This study demonstrates that ALDH9A1 is significantly downregulated in LSCC tissues, and low ALDH9A1 expression correlates with poor patient prognosis. Functionally, ALDH9A1 overexpression inhibits LSCC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, ALDH9A1 interacts with and stabilizes PTEN-induced kinase 1 (PINK1), leading to activation of PINK1-Parkin-mediated mitophagy. Under cisplatin treatment, ALDH9A1 is upregulated and induces protective mitophagy, contributing to cisplatin resistance. Inhibition of mitophagy with chloroquine sensitizes LSCC cells to cisplatin. These findings identify ALDH9A1 as a key regulator of mitophagy and cisplatin resistance in LSCC, suggesting that targeting the ALDH9A1/PINK1 axis could provide a novel therapeutic strategy for overcoming cisplatin resistance.
    Keywords:  PTEN-induced kinase 1–Parkin; aldehyde dehydrogenase 9A1; cisplatin resistance; laryngeal squamous cell carcinoma; mitophagy
    DOI:  https://doi.org/10.1097/CAD.0000000000001799
  20. Alzheimers Dement. 2025 Dec;21 Suppl 7 e108879
    Developing Topics.
    Xu Hou, Hannah Hompesch, Savannah J Tiemann, Julian Rubiano, Shunsuke Koga, Taylor Hsuan-Yu Chen, Melissa E Murray, Dennis W Dickson, Fabienne C Fiesel, Wolfdieter Springer.
       BACKGROUND: Mitophagy constitutes a crucial cellular pathway in mitochondrial quality control, in which the enzymatic pair PINK1 and PRKN selectively decorates damaged mitochondria with phosphorylated-ubiquitin (pS65-Ub), facilitating their autophagic-lysosomal removal. We previously demonstrated significant accumulation of pS65-Ub labeled damaged mitochondria in Lewy body and Alzheimer's disease autopsy brain. This mitophagy alteration was strongly associated with pre-tangle tau pathology in neurons. The effects of distinct tau species on mitophagy across different cell types however remain largely unknown. We therefore expanded our analyses to primary tauopathies, exploring how specific tau forms and their aggregation influence mitophagy in selectively vulnerable brain regions and cell types.
    METHOD: This study included 92 control and tauopathy cases with primary age-related tauopathy (PART), Pick's disease (PiD), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). Immunohistochemistry for the mitophagy marker pS65-Ub and phospho-tau was performed in vulnerable brain regions (hippocampus for PART and PiD, primary motor cortex for PSP and CBD). A deep learning-based image identification model was used to identify and quantify distinct tau inclusions. pS65-Ub-positive cells were manually counted and grouped based on signal intensity and morphology. Immunofluorescence co-staining of pS65-Ub and phospho-tau was conducted to study their spatial relationship at single-cell level.
    RESULT: We observed marked increases in pS65-Ub-positive cells in the hippocampus of PART and PiD cases compared to controls. Although less prominent, significant increases were also found in the primary motor cortex of PSP, whereas only minor changes were observed in CBD. Single-cell analyses revealed that the accumulation of pS65-Ub was most abundant in hippocampal neurons from PART. Cells with lower signal intensity contained mostly granular pS65-Ub deposits, while those with higher intensity harbored rather vacuolar inclusions. Across tau aggregate subtypes, pS65-Ub levels were strongly correlated and often co-resided with neurofibrillary tangles and Pick bodies. Such correlations were weaker for coiled bodies and tufted astrocytes, and absent for astrocytic plaques.
    CONCLUSION: Our study highlights distinct mitophagy alterations in primary tauopathies that are associated with specific tau inclusions in neurons, oligodendrocytes, and astrocytes. The observed pathological heterogeneity and complex mitophagy disruption underscores the need for future studies to elucidate pathogenic mechanisms and advance targeted therapeutics for each tauopathy.
    DOI:  https://doi.org/10.1002/alz70861_108879
  21. Actas Esp Psiquiatr. 2025 Dec;53(6): 1252-1264
    High-Frequency rTMS can Improve Depressive Symptoms by Promoting Mitochondrial Fusion.
    Jingmei Song, Yaru Wang, Simeng Li, Jingyu Yuan, Zhenhui Zhang, Yifeng Pan, Jing Lu, Yuyan Zhang.
       BACKGROUND: Depression is a common and highly prevalent disabling mental disorder. Recent clinical data have shown that repetitive transcranial magnetic stimulation (rTMS) effectively improves depressive symptoms. Mitochondrial quality control (MQC) plays a central role in various psychiatric disorders. However, the relationship between the therapeutic mechanisms underlying rTMS and MQC remains unclear. This study aimed to evaluate the therapeutic effect of rTMS on depression and to investigate the relationship between rTMS and MQC.
    METHODS: A depression model was established using chronic unpredictable mild stress (CUMS). The rTMS treatment protocol was administered daily for 4 weeks at a frequency of 10 Hz (17 trains of 4 s each, with 15 s intervals), totaling 1000 pulses per day. Each session involved 10 s of stimulation followed by 50 s of rest and was divided into four groups: control, CUMS, CUMS + 10 Hz rTMS, and fluoxetine (FlX)-treated groups (six mice in each group). In this study, we used the open field test (OFT), tail suspension test (TST), sucrose preference test (SPT), and forced swimming test (FST) to assess depression in mice; immunohistochemical staining to observe changes in the prefrontal cortex (PFC), hippocampal neurons, and glial cells; and transmission electron microscopy to detect changes in mitochondrial morphology in the hippocampus.
    RESULTS: Our findings suggest that mitochondrial pre-autophagy increased after treatment (LC3Ⅰ/II, F = 34.31, p < 0.0001; FIS1, F = 6.666, p = 0.0272), hippocampal mitochondrial fusion was enhanced after treatment (NeuN, p < 0.0001; c-Fos, p < 0.001; MFN1, p = 0.0006), and that treatment significantly improved the depression-like behavior of mice in the SPT (p = 0.0024) and FST (p = 0.0025).
    CONCLUSION: The present study demonstrates that rTMS improves depression-like behavior in mice by promoting mitochondrial fusion and enhancing autophagy.
    DOI:  https://doi.org/10.62641/aep.v53i6.1934
  22. Sci Rep. 2025 Dec 21.
    Hypoxic BMSC-derived exosomes-induced mitophagy quenches intestinal inflammation via HIF-1α/BNIP3 pathway.
    Feng Zhu, Jingbo Wang, Yuyi Yuan, Chunzhu Wei, Fei Gao, Xingxing Liu, Jingjing Li, Zaifeng Yi, Lijuan Zhang, Heng Fan.
      The use of hypoxia-preconditioned exosomes (HP-Exos) to modulate intestinal immunity in ulcerative colitis (UC) represents a promising therapeutic strategy. However, the effects of hypoxic preconditioning on exosomes derived from bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanisms in UC treatment remain inadequately understood. This study sought to elucidate the regulatory roles and molecular mechanisms of HP-Exos in the context of UC. HP-Exos were isolated from BMSCs and characterized. We employed hypoxia-inducible factor 1α (HIF-1α)-silenced lentivirus-interfered HP-Exos to assess their effects in both in vivo and in vitro models. A series of experiments were conducted to evaluate the effects of HP-Exos on mitophagy, oxidative stress, and apoptosis in HT-29 cells and colonic tissues and to comprehensively analyze the immunoprotective mechanisms of HP-Exos. The results demonstrated that HP-Exos enhanced mitophagy, inhibited reactive oxygen species (ROS) accumulation and apoptosis in HT-29 cells and colon tissues, and upregulated the expression of Bcl-2 19-kDa interacting protein 3 (BNIP3), a downstream effector of HIF-1α. Conversely, HIF-1α knockdown markedly reversed the increase in mitophagy and the inhibition of apoptosis. Our findings indicate that HP-Exos protect against DSS-induced colitis by mitigating apoptosis and ROS production through HIF-1α-BNIP3-mediated mitophagy.
    Keywords:  Exosomes; Hypoxia; Hypoxia-inducible factor 1α; Mitophagy; Ulcerative colitis
    DOI:  https://doi.org/10.1038/s41598-025-32293-3
  23. Free Radic Biol Med. 2025 Dec 22. pii: S0891-5849(25)01453-4. [Epub ahead of print]
    Paeoniflorin mitigates myocardial hypertrophy by regulating mitophagy and ferroptosis mediated by mitochondria-associated AMPK-Parkin-ACSL4 pathway.
    Yingwanqi Wang, Song Lin, Jianing Liu, Shudi Hu, Jiawen Zeng, Mengyang Wang, Xue Li, Yuhui He, Shan Ren, Ying Lyu, Weiwei Jia, Yu Zhao, Yan Lin.
       BACKGROUND: Pathological cardiac hypertrophy plays a significant role in the development of heart failure, involving mitochondrial dysfunction and metabolic dysregulation. Paeoniflorin (PF) is a monoterpene glycoside derived from Paeonia lactiflora. It has demonstrated cardioprotective potential, although its precise mechanisms are still unclear.
    PURPOSE: This study aimed to investigate the therapeutic effect of PF on cardiac hypertrophy induced by isoproterenol (ISO) and to uncover the underlying mechanisms, focusing on AMPK/Parkin/ACSL4-mediated mitophagy and ferroptosis.
    METHODS: A mouse model of cardiac hypertrophy was established using subcutaneous ISO injections. PF was administered at low, medium, and high doses, and Fosinopril (FOS) was used as a positive control. Cardiac function and morphology were evaluated using echocardiography, hemodynamic measurements, and histological staining. In vitro validation was performed in ISO-treated H9c2 cardiomyocytes. Western blotting, PCR, mitochondrial isolation, immunofluorescence, and targeted lipidomics were employed to assess molecular changes. Pharmacological inhibition of AMPK using Compound C and siRNA targeting Parkin was used to confirm the specificity of the AMPK/Parkin pathway involvement.
    RESULTS: PF significantly attenuated ISO-induced cardiac hypertrophy and improved cardiac function in vivo by activating AMPK and promoting Parkin-dependent mitophagy. PF also reduced mitochondrial accumulation of ACSL4, thereby limiting ferroptotic injury. Targeted lipidomics identified seven PF-responsive metabolites linked to lipid peroxidation, while parallel analyses demonstrated coordinated modulation of key pathway proteins involved in mitophagy and ferroptosis. Pharmacological inhibition of AMPK or knockdown of Parkin abolished these protective actions of PF. Moreover, PF decreased mitochondrial ROS generation and iron overload, further supporting its regulatory role in ferroptosis signaling.
    CONCLUSION: PF attenuates ISO-induced cardiac hypertrophy by stimulating AMPK-dependent mitophagy and suppressing ferroptosis through the Parkin/ACSL4 pathway. These findings elucidate the molecular basis of PF's cardioprotective function and support its prospective application in addressing abnormal heart remodeling.
    Keywords:  AMPK/Parkin/ACSL4; Cardiac hypertrophy; Energy metabolism; Ferroptosis; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.036
  24. Biochem J. 2025 Dec 23. pii: BCJ20253459. [Epub ahead of print]483(1):
    Insights into PINK1/Parkin function and dysfunction from Drosophila models.
    Seoyoung Park, Nikita Kozhushko, Thomas H Wight, Alexander J Whitworth.
      Loss-of-function mutations in PINK1 and PRKN cause familial forms of Parkinson's disease (PD). In vitro studies have revealed incredible insights into the molecular and cell-biological function of these genes, which have focused predominantly on mitophagy - the autophagic degradation of damaged mitochondria. The mechanisms of PINK1/Parkin function ultimately require investigation in an in vivo context using classic genetic approaches in animal models. In this context, Drosophila models have proven to be remarkably informative, in part due to robust phenotypes arising from null mutations. They have revealed important insights into the function of the Pink1 and parkin orthologues, much of which has proven to be conserved in humans. The simplicity, speed and genetic tractability make Drosophila an excellent in vivo model to interrogate the physiological functions of Pink1 and parkin and to rapidly test emerging hypotheses arising from in vitro work. They also represent a powerful model with which to explore the pathological consequences of Pink1/parkin loss in a whole-organism context. In this regard, several themes have emerged from recent studies that likely have significance for the neurodegenerative process in humans, including aberrant activation of immune signalling and consequent inflammation, disruptions to gut integrity and disturbed mitochondrial calcium handling. In this review, we evaluate the current evidence regarding the mechanism(s) of Pink1/parkin-mediated mitochondrial turnover in Drosophila, and discuss the potential implications of recent developments on the consequences of Pink1/parkin mutations and how these may inform the pathogenesis of PD.
    Keywords:   Drosophila ; PINK1; Parkin; Parkinson’s disease; autophagy; calcium signalling; immune signalling; mitochondria; mitophagy; mtDNA; neurodegeneration
    DOI:  https://doi.org/10.1042/BCJ20253459
  25. Front Aging. 2025 ;6 1750125
    Editorial: Insights in aging, metabolism and redox biology: 2024.
    Ruben K Dagda, Jianhua Zhang.
      
    Keywords:  NAD+; ROCK inhibitor; autophagy and mitophagy; lactate; lifestyles including sleep/fasting/exercise; mitochondria and mitochondrial DNA; neurodegeneration; rapamycin
    DOI:  https://doi.org/10.3389/fragi.2025.1750125
  26. Sci Rep. 2025 Dec 23.
    A role for Fis1 in dendritic development.
    Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis.
      Mitochondrial ATP production and calcium handling are critical for metabolic regulation and neurotransmission. Thus, the formation and maintenance of the mitochondrial network is a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously revealed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Therefore, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo, and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 activity regulates mitochondrial morphological and functional features that influence dendritic tree arborization and connectivity.
    DOI:  https://doi.org/10.1038/s41598-025-33557-8
  27. Cell Death Dis. 2025 Dec 23. 16(1): 912
    Correction: Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.
    Ananth Ponneri Babuharisankar, Cheng-Liang Kuo, Han-Yu Chou, Vidhya Tangeda, Chi-Chen Fan, Chung-Hsing Chen, Yung-Hsi Kao, Alan Yueh-Luen Lee.
      
    DOI:  https://doi.org/10.1038/s41419-025-08273-w
  28. Int Dent J. 2025 Dec 19. pii: S0020-6539(25)08573-9. [Epub ahead of print]76(1): 109290
    Lipoteichoic Acid Stimulation of Macrophages Causes Mitochondrial Dysfunction.
    Siyao Liu, Xin Liu, Guixin Li, Huan Liu, Weiwei Zhang, Shuang Pan.
       OBJECTIVES: This study aimed to investigate the role of mitochondrial dysfunction in the pathogenesis of Enterococcus faecalis and its lipoteichoic acid (LTA)-induced refractory apical periodontitis, and then to evaluate whether the modulation of mitochondrial dynamics with Mdivi-1 could alleviate the ensuing inflammatory response..
    METHODS: An LTA-induced macrophage model was established to simulate the inflammatory environment of apical periodontitis. Changes in inflammatory factors, mitochondrial morphology, dynamics-related proteins, autophagy markers, and reactive oxygen species (ROS) were analysed. The mitochondrial division inhibitor Mdivi-1 was applied to assess its effects on mitochondrial and inflammatory parameters.
    RESULTS: In the in vivo model, E. faecalis infection successfully induced apical periodontitis, as confirmed by radiographic evidence of periapical bone loss and histological observation of inflammatory cell infiltration. These lesions exhibited a significant upregulation of the pro-inflammatory marker iNOS, concurrently with a downregulation of the mitochondrial protein MFN-2. Consistent with the in vivo findings, LTA stimulation in a cellular model significantly increased the expression of inflammatory mediators (NLRC4, iNOS, NF-κB, Caspase-1) and induced mitochondrial dysfunction, characterised by morphological disruption, dysregulated dynamics, impaired autophagy and elevated ROS levels. Critically, Mdivi-1 treatment mitigated these abnormalities by improving mitochondrial structure and function, normalising dynamics-related protein expression and consequently reducing the inflammatory response.
    CONCLUSIONS: Mitochondrial dysfunction plays a central role in LTA-driven inflammatory processes in apical periodontitis. Targeting mitochondrial dynamics with Mdivi-1 can restore mitochondrial function and mitigate macrophage-mediated inflammation, revealing a key mechanism underlying refractory apical periodontitis.
    CLINICAL SIGNIFICANCE: This study suggests that enhancing mitochondrial function with agents such as Mdivi-1 could serve as a novel therapeutic strategy for refractory apical periodontitis by modulating immune responses and reducing chronic inflammation, potentially improving treatment outcomes in clinically challenging cases.
    Keywords:  Apical periodontitis; Lipoteichoic acid; Macrophage; Mitochondrial
    DOI:  https://doi.org/10.1016/j.identj.2025.109290
  29. Toxicol Appl Pharmacol. 2025 Dec 18. pii: S0041-008X(25)00469-7. [Epub ahead of print]507 117693
    Shionone ameliorates pulmonary fibrosis by activating mitophagy via PINK1-Parkin pathway.
    Yijia Su, Qiang Fu, Xilin Wu, Xianhua Che, Zhe Jiang, Xuezheng Li.
      Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited clinical treatment options. Shionone (SHI), a major active compound derived from Ligularia fischeri Turcz (LF), has shown pharmacological potential; however, its mechanism of action against PF remains unclear. This study investigates the anti-fibrotic effects and underlying pathways of SHI using a bleomycin (BLM)-induced PF mouse model and a Transforming Growth Factor-β (TGF-β)-stimulated A549 cell model. The results demonstrate that SHI treatment markedly alleviates BLM-induced alveolar damage, collagen accumulation, and inflammatory responses, while significantly improving survival rates in mice. At the molecular level, SHI activates the PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy pathway, leading to increased expression of autophagy-related proteins such as LC3II/LC3I and Beclin1, decreased levels of p62 and pro-fibrotic markers, enhanced clearance of dysfunctional mitochondria, restoration of mitochondrial membrane potential (MMP), and reduction of reactive oxygen species (ROS) accumulation. In vitro experiments further confirm that SHI inhibits fibrosis in TGF-β-challenged A549 cells through the same mechanism. This study is the first to elucidate that SHI mitigates PF by regulating mitophagy, offering a promising therapeutic target and potential drug candidate for PF. Future research may focus on optimizing the clinical application strategies of SHI.
    Keywords:  Mitophagy; PINK1-Parkin; Pulmonary fibrosis; Shionone
    DOI:  https://doi.org/10.1016/j.taap.2025.117693
  30. Biochemistry (Mosc). 2025 Dec;90(12): 2027-2040
    Mitochondria in Developing Brain: Contribution of Deviations to Higher Susceptibility to Neurodegeneration in Latter Periods of Life.
    Natalia A Stefanova, Natalia A Muraleva, Diana V Sityaeva, Mikhail A Tyumentsev, Nataliya G Kolosova.
      It has been proven that the preclinical period of the sporadic (&gt;95% of cases) form of Alzheimer's disease (AD) can last for decades, but the question of when the disease begins to develop and what contributes to it remains open. It is hypothesized that vulnerabilities to AD may be influenced by anatomical and functional brain parameters formed early in life. This is supported by our research on the senescence-accelerated OXYS rats - a unique model of AD. The delayed brain maturation observed in these rats is associated with insufficient glial support, a key regulator of neural network function, and the development of AD signs in the OXYS rats is preceded and accompanied by the mitochondrial dysfunction. This raises the question of whether the structural and functional features of mitochondria could influence brain maturation and thus determine predisposition to the later development of AD signs. In this study, we compared mitochondrial biogenesis, their trafficking, and structural state in the neuronal cell bodies, axonal and dendritic processes, as well as activity of the mitochondrial dynamics processes in the prefrontal cortex and hippocampus of OXYS and Wistar rats (control) during the period of brain maturation completion (from birth to 20 days of age). Changes in the number and ultrastructural parameters of mitochondria were compared with the parameters of dynamics processes, assessed by the frequency of mitochondria undergoing fusion or fission, the content of the key biogenesis protein PGC-1α, and proteins mediating mitochondrial dynamics (mitofusins Mfn1 and Mfn2, dynamin-1-like protein DRP1). In OXYS rats, deviations in formation of the mitochondrial apparatus in the early postnatal period were identified, which may contribute to the delayed brain maturation of these rats, promote mitochondrial dysfunction, reduce synaptic density, and ultimately lead to the neuronal death and development of the early neurodegenerative changes.
    Keywords:  Alzheimer’s disease; early postnatal period; mitochondria; neurodegeneration; senescence-accelerated OXYS rats
    DOI:  https://doi.org/10.1134/S0006297925602874
  31. Genetics. 2025 Dec 24. pii: iyaf277. [Epub ahead of print]
    SUMO protease Pira induces autophagy-related cell death during Drosophila development.
    Tian Gan, Qiaoling Su, Yue Zhang, Long Zhao, Ying Su.
      Autophagy is a major intracellular degradative process required for maintaining homeostasis in multicellular organisms. Aberrant autophagy is considered to induce internal environmental disturbance and cell death. Therefore, it is of great significance to explore the regulatory mechanism of autophagy. Here, we report a positive role of protein Pira, a SUMO protease, in inducing autophagy and autophagy-dependent cell death during Drosophila development. We found that overexpression of pira in wing imaginal discs was able to induce selective autophagy (mitophagy) and autophagic cell death, resulting in wing loss. Moreover, Pira-induced mitophagy and cell death were dependent on the accumulation of Sima, the sole Drosophila homolog of mammalian HIF-1α. Disrupting the sima expression was adequate to inhibit the Pira effects for cell survival and wing development. In addition, the biomarkers of aging were activated in wing discs upon pira overexpression, and excessive Pira shortened fly lifespan, suggesting that Pira may be associated with aging. Together, we provided evidence demonstrating that ectopic Pira can activate the Sima/HIF-1α-mediated mitophagy and cell death, thereby leading to developmental defects in Drosophila.
    Keywords:  Autophagy; Cell death; Pira; SUMO protease; Sima/HIF-1α
    DOI:  https://doi.org/10.1093/genetics/iyaf277
  32. Front Pharmacol. 2025 ;16 1732154
    Pterostilbene mitigates the senescence of human dermal fibroblast cells by enhancing mitochondrial quality.
    Xinyu Zhou, Ning Wang, Jihua Wei, Guizhi Li, Zhengwei Lue, Chang Liu, Qi Bao, Zhe Feng, Minjie Zhang, Hu Huang, Yue Li, Jing Wang, Xiangnan Zhang.
       Introduction: Pterostilbene (PT), a natural polyphenol found in blueberries and several grape varieties, exhibits pleotropic pharmacological effects. PT reduced the makers of aging caused by either ultraviolet (UV) light exposure or chemical stress in keratinocytes, whereas its potential anti-aging effects and underlying mechanisms in the dermis have not been elucidated.
    Methods: The anti-senescence effects of PT were investigated in human dermal fibroblasts (HDFs) using models of UVB-induced acute oxidative stress and replicative senescence. Key assays included senescence-associated beta-galactosidase (SA-β-gal) activity, RT-PCR, western blotting, immunofluorescence, live-cell confocal imaging with fluorescent probes, flow cytometry and mitochondrial respiration analysis. A mouse model of UVB-induced skin damage was used to evaluate PT's anti-aging effects in vivo through histopathological examination and western blot analysis.
    Results: PT treatment mitigated senescence in HDFs, as shown by reduced SA-β-gal activity, p16, and p21, along with increased collagen expression. It restored mitochondrial morphology, MMP, and reduced mitochondrial reactive oxygen species in both senescent models. Furthermore, PT improved mitochondrial basal respiration, ATP production, and maximal respiration. Mechanistically, PT promoted mitophagy, indicated by enhanced TOM20/LC3 colocalization. In vivo, topical PT restored collagen, dermal thickness, and LC3, while reducing p21 levels in UVB-exposed mice.
    Discussion: Our findings demonstrate that PT delays dermal senescence by enhancing mitochondrial quality via enhancing mitophagy. These results highlight PT as a promising anti-aging agent capable of countering both intrinsic and extrinsic aging in the dermis.
    Keywords:  human dermal fibroblasts cells (HDFs); mitochondria; mitophagy; pterostilbene; senescent; skin aging
    DOI:  https://doi.org/10.3389/fphar.2025.1732154
  33. Alzheimers Dement. 2025 Dec;21 Suppl 1 e106610
    Basic Science and Pathogenesis.
    Maggie N Benson, Keith P Smith, Vivien Csikos, Heather M Wilkins.
       BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder marked by amyloid beta (Aβ) plaques and neurofibrillary tangles. Studies have revealed that damaged mitochondria accumulate across various AD disease models, suggesting disrupted mitochondrial quality control pathways. Mitophagy-the cellular process that removes dysfunctional mitochondria-has been shown to be impaired in AD, though its exact relationship to disease mechanisms remains unclear. This study investigates the relationship between mitophagy mechanisms and AD pathophysiology.
    METHODS: Whole brain from 5xFAD and wild-type (WT) mice was use to collect whole cell, mitochondrial, and autophagosome components (AP). Mitochondrial DNA (mtDNA) copy number was measured from whole brain and AP fractions using qPCR. iPSC-derived cerebral organoid models were generated from both non-AD and sporadic AD (sAD) sources. These models were then separated into AP fractions and mtDNA copy number was measured using qPCR. Postmortem human brain was fractionated to collect whole cell, mitochondrial, and AP fractions from non-demented (ND) and sAD subjects. Aβ levels were measured in fractions using ELISA kits. iPSCs where used to derive neurons from ND and sAD subjects and lysosome number and autophagosome events were measured using LysoTracker and DAPRed fluorescent dyes.
    RESULTS: We observed a significant reduction in AP mtDNA content from 5xFAD mice from 2 months of age, while whole brain mtDNA was elevated in 5xFAD mice at 2 months of age but reduced at 12 months of age. Organoids derived from sAD iPSC donors also had reduced AP mtDNA content. Aβ levels were increased in whole and AP fractions in 5xFAD mouse samples, cerebral organoid models, and human postmortem brain. iPSC derived neurons from sAD donors had reduced lysosome content and autophagy events.
    CONCLUSIONS: Overall mitophagy is impaired across mouse and iPSC models of AD. Associations with Aβ pathology and other underlying mechanisms requires further investigation.
    DOI:  https://doi.org/10.1002/alz70855_106610
  34. Cell Death Discov. 2025 Dec 24.
    Targeting mitochondrial autophagy for anti-aging.
    Wenjun Shan, Yuling Liu, Ruying Tang, Longfei Lin, Hui Li, Hongjun Yang.
      Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.
    DOI:  https://doi.org/10.1038/s41420-025-02913-y
  35. Biochemistry (Mosc). 2025 Dec;90(12): 1849-1861
    Turnover and Quality Control of Mitochondrial DNA.
    Wolfram S Kunz.
      The quantitative content of mitochondrial DNA (mtDNA) - a multicopy circular genome - is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).
    Keywords:  determinants of cellular mtDNA content; mtDNA degradation; mtDNA maintenance; mtDNA maintenance disorders; mtDNA replication
    DOI:  https://doi.org/10.1134/S0006297925602485
  36. Cell Death Dis. 2025 Dec 23. 16(1): 906
    Correction: Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.
    Yanling Chen, Xun Liu, Yixuan Liu, Yujia Li, Dingxiang Li, Zhigang Mei, Yihui Deng.
      
    DOI:  https://doi.org/10.1038/s41419-025-08078-x
  37. Int Immunopharmacol. 2025 Dec 19. pii: S1567-5769(25)02038-7. [Epub ahead of print]170 116049
    DPEP1 mediates regulation of mitochondrial quality control via FOXO1/ALDH1L2 axis to attenuate ferroptosis in pulmonary endothelial cells to alleviate sepsis-associated acute lung injury.
    Xin Yao, Ziang Wen, Junjie Liao, Yaling Meng, Peng Lu, Xiaopei Li, Zihao Shen, Ao Wang, Minchao Wu, Xiangyu Li, Wanjun Jin, Xiao Zhang, Yuanpu Qi, Jia Feng, Mingyu Chu, Jialin Zhang, Yixuan Dai, Xiaotian Qin, Faliang Zhan, Xiaowei Wang, Meijuan Song.
      Sepsis is a leading cause of acute lung injury worldwide; however, the contribution of ferroptosis, an iron-dependent form of regulated cell death, to sepsis-associated acute lung injury (SALI) remains poorly understood. In this study, we established in vitro and in vivo models of SALI using lipopolysaccharide (LPS) to explore the underlying cellular and molecular mechanisms. Human pulmonary microvascular endothelial cells or mice were treated according to experimental groupings with the mitochondrial division inhibitor 1 (Mdivi-1), the autophagy inhibitor 3-methyladenine (3-MA), the specific forkhead box O1 (FOXO1) inhibitor AS1842856 (AS18), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway activator Insulin-like Growth Factor I (IGF-1) or dipeptidase 1 (DPEP1) short hairpin RNA. Ferroptosis, mitochondrial quality control (MQC), and inflammatory responses were evaluated using hematoxylin and eosin staining, immunofluorescence, lung wet/dry weight ratio, enzyme-linked immunosorbent assay, western blotting, reverse transcription quantitative polymerase chain reaction, chromatin immunoprecipitation quantitative polymerase chain reaction, and RNA sequencing. DPEP1 knockdown significantly attenuated LPS-induced inflammation, oxidative stress, and ferroptosis in pulmonary endothelial cells. In LPS-treated human pulmonary microvascular endothelial cells, DPEP1 knockdown preserved MQC, as demonstrated by a shift from mitochondrial fission to fusion, reduced mitophagy, and improved fatty acid β-oxidation. Mechanistically, RNA sequencing analysis revealed that DPEP1 knockdown inhibited the phosphoinositide 3-kinase/protein kinase B signaling pathway, decreasing FOXO1 phosphorylation and promoting its nuclear translocation. This led to upregulation of aldehyde dehydrogenase 1 family member L2 transcription, improvement of fatty acid β-oxidation, stabilization of mitochondrial quality, and reduction of ferroptosis. Inhibition of FOXO1 with AS18 reversed these protective effects. Furthermore, combining DPEP1 knockdown with Mdivi-1 or 3-MA synergistically suppressed ferroptosis and oxidative stress. Overall, the results of this study demonstrate that DPEP1 modulates MQC likely through the FOXO1/ALDH1L2 axis to counteract ferroptosis. Targeting DPEP1 via knockdown offers a promising therapeutic approach for SALI, and when combined with Mdivi-1 and 3-MA, this strategy produces a synergistic protective effect against ferroptosis.
    Keywords:  DPEP1; Forkhead box O1; Mitochondrial quality control; Sepsis-associated acute lung injury
    DOI:  https://doi.org/10.1016/j.intimp.2025.116049
  38. J Adv Res. 2025 Dec 19. pii: S2090-1232(25)01014-8. [Epub ahead of print]
    Gymconopin C exhibits anti-non-small cell lung cancer effect by regulating miR-6777-5p/ADRB2 pathway to promote mitophagy.
    Xue Li, Mingyu Han, Limei Zhang, Xiaofang Xie, Chenying Li, Heng Zhang, Junsha An, Jianning Yang, Shuang Pu, Yue Duan, Changnian Yang, Cheng Peng, Hailin Tang, Fu Peng.
       INTRODUCTION: Non-small cell lung cancer (NSCLC) remains the leading cause of morbidity and mortality from malignant tumors in China with therapeutic limitations. Developing novel therapeutic agents and innovative treatment strategies is critical for advancing NSCLC management. Gymconopin C, a compound isolated from Bletilla striata, has demonstrated potential anti-NSCLC activity; However, the underlying mechanism remains elusive.
    OBJECTIVES: This study aimed to decipher the anti-NSCLC mechanism of Gymconopin C by demonstrating its induction of PINK1/Parkin-mediated mitophagy via the miR-6777-5p/ADRB2 pathway, and to establish the fundamental regulatory role of miRNA/mRNA axis in NSCLC suppression. This study establishes a novel therapeutically targetable pathway and offers a mechanistically grounded candidate for NSCLC therapy.
    METHODS: Integrated in vitro and in vivo strategies were used to elucidate the anti-NSCLC mechanism of Gymconopin C. Inhibitory effects on two NSCLC cell lines were assessed using CCK-8 proliferation, transwell migration and invasion assays. Subsequently, transmission electron microscopy and mitochondrial functional analyses were conducted to assess mitophagy. Transcriptomic profiling revealed dysregulation of the miR-6777-5p/ADRB2 axis, and gain/loss-of-function experiments were performed to investigate its functional role in mitophagy. Finally, the therapeutic efficacy and pathway modulation were evaluated in vivo using zebrafish xenograft and murine ectopic tumor models.
    RESULTS: Gymconopin C significantly inhibited the proliferation, migration and invasion of NSCLC cells; induced cell cycle arrest and enhanced apoptosis of A549 cells. Mechanistically, it modulated the miR-6777/ADRB2 axis to promote PINK/Parkin-mediated mitophagy, ultimately leading to NSCLC growth arrest in both in vivo and in vitro experiments.
    CONCLUSION: Gymconopin C exerts tumor-suppressive effects by activating PINK1/Parkin-mediated mitophagy via the miR-6777-5p/ADRB2 axis, highlighting its potential as a therapeutic agent for NSCLC.
    Keywords:  Gymconopin C; Mitophagy; Non-small cell lung cancer; Zebrafish xenograft and murine ectopic tumor models; miR-6777-5p/ADRB2 axis
    DOI:  https://doi.org/10.1016/j.jare.2025.12.023
  39. Mol Neurobiol. 2025 Dec 27. 63(1): 329
    Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.
    Mahalaxmi Iyer, Masako Kinoshita, Dibbanti HariKrishna Reddy, Harysh Winster Suresh Babu, Vikas Lakhanpal, Mukesh Kumar Yadav, Jayalakshmi Krishnan, Vignesh Palanivel, Salmanul Faris, Khushboo Chauhan, Balachandar Vellingiri.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in dopamine depletion and impaired motor function. Growing evidence implicates mitochondrial dysfunction as a central driver of PD pathogenesis with many PD-associated genes and proteins localized are localized near mitochondria and they also have major functions in proper functioning of mitochondria. Among mitochondrial regulators, the transcriptional co-activator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) orchestrates oxidative stress response, mitochondrial biogenesis and inflammatory pathways whereas mitochondrial transcription factor A (TFAM) is essential for maintaining mitochondrial DNA (mtDNA) integrity and copy number variations. Dysregulation of TFAM contributes to mtDNA stress mediated oxidative stress and neurodegeneration whereas experimental studies demonstrate that TFAM overexpression or enzyme replacement enhances neuronal survival and functions. Therefore, in this review we have highlighted the PGC-1α-TFAM regulatory axis as a central hub linking mitochondrial dysfunction, neuroinflammation and oxidative stress in PD. We further discuss therapeutic opportunities aimed at modulating PGC-1α and TFAM to restore mitochondrial homeostasis, underscoring their potential as promising yet underexplored targets for slowing or halting PD progression.
    Keywords:  Mitochondria; PGC-1α; Parkinson’s Disease; TFAM; Therapeutics
    DOI:  https://doi.org/10.1007/s12035-025-05611-z
  40. ACS Appl Mater Interfaces. 2025 Dec 26.
    Injectable Magnolol-Peptide Hydrogel as a Minimally Invasive Treatment for Doxorubicin-Induced Cardiomyopathy via Inhibition of Aberrant Mitochondrial Fission.
    Yongquan Hua, Huiming Chen, Yuanyuan Wu, Yajie Wu, Chenyazhuo Hu, Yinghua Zeng, Mingzhi Shen, Jie Zhan, Rongsen Meng, Yanbin Cai.
      Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, faces clinical limitations due to dose-dependent cardiotoxicity that can progress to irreversible DOX-induced cardiomyopathy (DIC). This pathology is driven by mitochondrial dysfunction, with the DOX-induced hyperactivation of mitochondrial fission as a central pathological event in DIC, leading to oxidative stress and cardiomyocyte apoptosis. To address this, we developed an injectable, self-assembling peptide-drug conjugate hydrogel, Mag-Gel, for mitochondrial targeted therapy. This system enables precise intramyocardial delivery via ultrasound-guided percutaneous injection, overcoming the translational barrier of conventional invasive hydrogels by eliminating the need for invasive surgery. In vitro, Mag-Gel attenuated aberrant mitochondrial fission by upregulating Sirt3 expression 5.76-fold and enhancing inhibitory phosphorylation of DRP1 at Ser637 2.33-fold, thereby reducing reactive oxygen species (ROS) accumulation and suppressing apoptosis in cardiomyocytes. In a murine DIC model, Mag-Gel ensured sustained myocardial retention and significantly improved cardiac function, enhancing the ejection fraction and reducing fibrosis compared to free drug treatment. This work presents a clinically feasible, minimally invasive strategy for treating DIC by targeting mitochondrial homeostasis, offering a practical approach to mitigating DOX-related myocardial injury.
    Keywords:  cardiac injury treatment; doxorubicin cardiotoxicity; mitochondrial fission; peptide–drug conjugate; self-assembly hydrogel
    DOI:  https://doi.org/10.1021/acsami.5c20219
  41. Trends Endocrinol Metab. 2025 Dec 22. pii: S1043-2760(25)00265-6. [Epub ahead of print]
    Deciphering the antitumor immune effects of succinate.
    Ziyan Xia, Zhaoyi Li, Peng Jiang.
      Through metabolic remodeling, tumor cells can modulate neighboring CD8+ T cell function via metabolites. A recent study by Ma et al., published in Immunity, reveals that tumor-cell-derived succinate exhibits an antitumor immune effect, promoting the survival and stemness of CD8+ T cells by enhancing mitochondrial fitness and inducing epigenetic reprogramming.
    Keywords:  CD8(+) T cell stemness; ICB therapy; epigenetic regulation; mitochondrial homeostasis; succinate
    DOI:  https://doi.org/10.1016/j.tem.2025.12.001
  42. Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01499-8. [Epub ahead of print]45(1): 116727
    Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
    Lilia Colina-Tenorio, Patrick Horten, Enzo Scifo, Susanne E Horvath, Rhena F U Klar, Chantal Priesnitz, Fabian den Brave, Martin van der Laan, Thomas Becker, Kuo Song, Heike Rampelt.
      Mitochondrial cytochrome c oxidase, complex IV (CIV) of the respiratory chain, is assembled in a modular fashion from mitochondrial as well as nuclear-encoded subunits, guided by numerous assembly factors. This intricate process is further complicated by the characteristic architecture of the inner mitochondrial membrane. The mitochondrial contact site and cristae organizing system (MICOS) maintains the stability of crista junctions that connect the cristae, the site of mitochondrial respiration, with the inner boundary membrane, where newly imported respiratory subunits first arrive. Here, we report that MICOS facilitates specific assembly steps of CIV and associates with intermediates of the Cox1 and Cox3 modules. Moreover, MICOS recruits a variety of assembly factors even in the absence of ongoing CIV biogenesis, directly or via the mitochondrial multifunctional assembly (MIMAS). Our results establish MICOS as an important agent in efficient respiratory chain assembly that promotes CIV biogenesis within the compartmentalized inner membrane architecture.
    Keywords:  CP: Cell biology; CP: Metabolism; MICOS; MIMAS; Mic60; cristae; cytochrome c oxidase; mitochondria; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2025.116727
  43. Cell Death Dis. 2025 Dec 24.
    ALDH3A2 negatively orchestrates gastric cancer progression through a synergistic induction of ferroptosis and ferroptosis-driven macrophage reprogramming.
    Yuanyuan Ren, Yue Cui, Zhen Wang, Yizhi Luo, Junchang Jin, Yiyi Yuan, Xuan Li, Yaning Zhang, Nan Cao, Xiaofang Li, Yi Yu, Yuyan Xiong.
      Gastric cancer (GC) is a prevalent gastrointestinal malignancy in which ferroptosis, mitochondrial dysfunction, and macrophage reprogramming remarkably contribute to disease progression. However, the molecular interplay among these processes in contributing to GC remains poorly understood. In this study, we identified ferroptosis- and mitochondrial dysfunction-related genes (FMDRGs) implicated in GC through bioinformatics analyses. Among them, aldehyde dehydrogenase 3 family member A2 (ALDH3A2) was identified as a key FMDRG significantly downregulated in GC tissues and cell lines. Functional assays revealed that ALDH3A2 overexpression in GC cell lines suppressed proliferation, migration, and invasion while enhancing ferroptosis, effects that were reversed by GPX4 overexpression. ALDH3A2 also impaired the mitochondrial unfolded protein response (UPRmt) and induced mitochondrial dysfunction. Restoration of UPRmt ameliorated ALDH3A2-induced mitochondrial dysfunction and ferroptosis. Mechanistically, ALDH3A2 impaired UPRmt by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and subsequent ferroptosis. Synergistically, ALDH3A2-induced ferroptosis promoted IL-6 release, which drove macrophage polarization toward the M1 phenotype with elevated IL-1β production. This macrophage reprogramming, in turn, inhibited GC cell progression by downregulating PD-L1 expression. Therapeutically, both genistein treatment and ALDH3A2 overexpression significantly attenuated GC progression in vitro and in vivo. These findings elucidate ALDH3A2 as a dual regulator of tumor-intrinsic ferroptosis and tumor-extrinsic immune remodeling in contributing to GC pathogenesis, highlighting its potential as a promising therapeutic target in GC.
    DOI:  https://doi.org/10.1038/s41419-025-08364-8
  44. Dev Biol. 2025 Dec 23. pii: S0012-1606(25)00344-6. [Epub ahead of print]
    Drosophila as a model to study autophagy during oogenesis.
    Mrunmayee Kulkarni, Nidhi Murmu, Minal Ayachit, Karan Selarka, Kiran Nilangekar, Bhupendra V Shravage.
      Autophagy is an evolutionarily conserved catabolic process that is essential for maintaining cellular and developmental homeostasis in eukaryotes. Drosophila oogenesis offers a robust model for investigating the spatial and temporal regulation of autophagy within a complex developmental framework that involves cells from both germline and somatic lineages. This tightly regulated cascade of events enables the differentiation of a germline stem cell into a mature oocyte. Autophagy contributes to cellular quality control, nutrient sensing, and the regulation of developmental cell death, all of which are critical for proper egg development and maturation. Disruption of autophagy influences oogenesis, resulting in defective egg chamber development, altered apoptotic dynamics, abnormally shaped mitochondria and compromised mitophagy. Methodological advances, including immunofluorescence-based detection, live imaging using fluorescent reporters, and ultrastructural analysis via transmission electron microscopy, have significantly enhanced the ability to monitor autophagic activity in the ovary. This review summarizes current evidence that establishes autophagy as a key regulatory mechanism during oogenesis. Additionally, it offers an opportunity to investigate the role of autophagy in various cellular processes, including cell division, gene amplification, endocycling, collective cell migration, and cytoplasmic streaming for embryonic polarity, nurse cell dumping, and programmed cell death during Drosophila oogenesis.
    Keywords:  Drosophila; aging; autophagy; cell death; germarium; germline stem cells; mitophagy; nurse cells; oogenesis; starvation; vitellogenesis
    DOI:  https://doi.org/10.1016/j.ydbio.2025.12.013
  45. Autophagy. 2025 Dec 23.
    Viral SAM-binding proteins nsp14 and NP868R reprogram ATG4A-dependent autophagy from antiviral LC3B activity to GABARAP-mediated mitophagy.
    Yahui Li, Ya Zhu, Fei Wang, Xuezhi Ying, Chenchen Zhao, Wei Si, Jiepeng Zhong, Wei Yin, Lulu Lin, Jian Li, Yan Yan, Jiyong Zhou, Boli Hu.
      Members of the mammalian Atg8-protein family (ATG8), including the MAP1LC3/LC3 and GABARAP subfamilies, play essential roles in selective macroautophagy/autophagy. However, their functional distinctions during viral infection remain poorly understood. Here, we show that S-adenosyl-L-methionine (SAM)-binding viral proteins, such as nsp14 from coronavirus and NP868R from African swine fever virus (ASFV), reprogram autophagy by shifting antiviral LC3B activity toward GABARAP-mediated mitophagy in an ATG4A-dependent manner. Mechanistically, the SAM-binding motif allows these viral proteins to stabilize ATG4A mRNA, thereby increasing ATG4A expression and redirecting autophagic flux from LC3B-mediated virophagy to GABARAP-dependent mitophagy. This shift suppresses innate immune responses by targeting both MAVS-dependent interferon signaling and virophagy, ultimately enhancing viral replication. Collectively, our findings uncover a previously unrecognized immune evasion strategy in which SAM-binding viral proteins rewire autophagy from antiviral to proviral pathways.
    Keywords:  ATG4A; ATG8 family; GABARAP; LC3B; mitophagy; virophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2608972
  46. Cell Death Discov. 2025 Dec 20.
    Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.
    Ping Zhang, Peng Huang, Qiongye Dong, Juan Luo, Guanghui Cui, Xin Guo, Minghua Li, Xia Long, Hongyu Zhang, Wei V Zheng, Peng Cui.
      Parkinson's disease (PD) is a challenging neurodegenerative disorder. Recently, therapy of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has emerged as a significant advancement in regenerative medicine. Melatonin (MT), acting as a mitochondrial targeting hormone, exhibits neuroprotective properties in neurodegenerative diseases and modulates stem cell differentiation through mitochondrial dynamics. However, the precise mechanism by which MT influences dopaminergic (DA) neuronal differentiation in hiPSCs through regulating mitochondrial dynamics remains unclear. In this study, we developed and optimized a technical protocol for the in vitro functional neuronal differentiation of hiPSCs. Our findings demonstrate that MT enhances the differentiation potential of hiPSCs toward neuroectoderm and significantly improves the efficiency of NSCs differentiation into DA neurons by more than three times within hiPSCs. Using the specific MT receptor inhibitor, Luzindole, we confirmed its inhibitory effect on MT-mediated promotion of neural differentiation. Mechanistically, we propose that MT enhances functional DA neuron differentiation from hiPSCs by activating mitochondrial dynamics-mediated WNT/β-catenin signaling pathways. Additionally, we elucidated the critical role of mitofusin2 (MFN2) in enhancing the directed differentiation of DA neurons from hiPSCs. In vivo studies validated the efficacy of MT-treated hiPSC-derived DA progenitor cells in regenerating tyrosine hydroxylase (TH)-positive DA neurons and improving motor function in a MPTP-induced mouse model of Parkinson's disease. In conclusion, this study highlights the potential clinical relevance of MT-enhanced differentiation of hiPSCs into DA neurons, offering promising implications for the treatment of PD.Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41420-025-02906-x
  47. Cells. 2025 Dec 05. pii: 1932. [Epub ahead of print]14(24):
    Placental-Derived Mesenchymal Stem Cells Triggers Lipid Metabolism in a Rat Model Thioacetamide-Induced Ovarian Disease via Increased CPT1A Expression for Mitochondrial Dynamics.
    Hyeri Park, Jun Hyeong You, Jin Seok, Dae Hyun Lee, Hankyu Lee, Gi Jin Kim.
      Lipid accumulation disrupts mitochondrial dynamics, leading to dysfunctional energy metabolism and increased oxidative stress. However, the relationship between mitochondrial dynamics and ovarian function in therapeutic contexts is still not fully elucidated. Therefore, the objective of this study was to demonstrate whether increased carnitine palmitoyltransferase 1A (CPT1A) expression induced by placenta-derived mesenchymal stem cells (PD-MSCs) improves ovarian function in ovaries of a lipid toxicity-induced rat model by regulating lipid metabolism and mitochondrial dynamics. A rat model of injury was induced through intraperitoneal administration of thioacetamide (TAA) for 12 weeks. During the 8th week of induction, PD-MSCs (2 × 106 cells) were transplanted via the tail vein. Initially, we examined the engraftment of PD-MSCs. The inflammatory response (e.g., IL-6, TNFα) and apoptosis (e.g., LDH levels, TUNEL assay) were significantly increased in the non-transplanted (NTx) group compared to the normal group; however, they were significantly decreased in the transplanted (Tx) group compared to the NTx group (* p < 0.05). Additionally, oxidative stress was attenuated through the regulation of mitochondrial dynamics, including the expression of DRP1, ATP5B, and PGC1α, in the Tx group compared to the NTx group (* p < 0.05). In the NTx group, abnormally accumulated lipid droplets were observed due to dysfunctional mitochondria, whereas in the Tx group, the accumulation of lipid droplets and the expression of CPT1A were significantly comparable to those in the normal group (* p < 0.05). The levels of the steroidogenesis markers (e.g., CYP11A1 and HSD3β1) were decreased in the NTx group compared to the normal group and increased in the Tx group compared to the NTx group (* p < 0.05). The levels of sex hormone and follicular development were protected in the Tx group compared to the NTx group. Furthermore, cocultivation of PD-MSCs with etomoxir (CPT1A inhibitor)-treated primary theca cells increased the expression of steroidogenesis. In conclusion, PD-MSCs improve ovarian function in TAA-induced injury by reducing lipid accumulation and oxidative stress through the regulation of lipid metabolism and mitochondrial dynamics. The upregulation of CPT1A and related mitochondrial proteins contributes to enhanced steroidogenesis and restoration of ovarian homeostasis. These findings offer new insights into the application of stem cell therapies for reproductive medicine.
    Keywords:  lipid metabolism; mitochondria dynamics; ovarian dysfunction; placenta-derived mesenchymal stem cell; steroidogenesis
    DOI:  https://doi.org/10.3390/cells14241932
  48. bioRxiv. 2025 Dec 16. pii: 2025.12.13.693635. [Epub ahead of print]
    The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
    Bryanna Shao, Bartosz Kula, Han Le, Prasanna Venkhatesh, Prasanna Katti, Andrea G Marshall, Siddharth Chittaranjan, Suraj Thapilyal, Namdar Hari Kalpana, C Nivedya, Adam Roszczyk, Harrison Mobley, Mason Killion, Emelina St John, Pamela Martin, Benjamin Rodrigiuez, Markis' Hamilton, LaCara Bell, Sunjay M Wyckoff, Laurent A Moran, Mark Philips, David Hubert, Briar Tomeau, Jeremiah M Afolabi, Annet Kirabo, Ismary Blanco, Samantha Reasonover, Lauren E Drake, Ethan S Lippmann, Chantell Evans, Monica M Santisteban, Taneisha G Cheairs, Sepiso Mesenga, Celestine Wanjalla, Jennifer Gaddy, Ronald McMillan, Calixto P Hernandez Perez, Htet Htet Paing, Jenny C Schafer, Bret Mobley, Julia Berry, Amber Crabtree, Oleg Kovtun, Shawn Goodwin, Edgar Garza Lopez, Chandravanu Dash, Dao-Fu Dai, Tyne W Miller-Fleming, Antentor Hinton, Nathan A Smith.
      Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.
    DOI:  https://doi.org/10.64898/2025.12.13.693635
  49. Int J Surg. 2025 Dec 22.
    New insight into the risk stratification and treatment priority of breast cancer: TMT scoring system.
    Zhe Qi, Yuechao Yang, Zhisu Wang, Sen Li, Deheng Li, Lei Chen, Mingtao Feng, Changshuai Zhou, Xin Chen, Bin Hao, Xiaojun Wu, Yang Gao, Liangdong Li, Yiqun Cao.
       BACKGROUND: Breast cancer continues to pose a significant global health burden, accounting for a substantial proportion of cancer-related mortality in women worldwide. Despite advancements in therapeutic strategies, overall survival rates remain suboptimal, underscoring the critical need for innovative prognostic tools to improve patient outcomes.
    METHODS: In this study, we introduced a novel tumor mitochondria transfer (TMT) scoring system based on 17 core genes to assess mitochondrial dynamics and their potential impact on the tumor microenvironment (TME). Utilizing comprehensive datasets from TCGA-BRCA and GEO databases, we investigated the association between TMT scores and immune-metabolic features at both multi-cell and single-cell resolutions. Single-cell RNA sequencing (scRNA-seq) profiles were used to delineate the biological consequences of mitochondrial transfer. Additionally, co-culture experiments were conducted to validate our findings.
    RESULTS: Our analysis revealed that elevated TMT scores are strongly associated with adverse clinical outcomes in patients with breast cancer. Tumors with high TMT scores exhibited pronounced hypoxia, immune suppression, and metabolic reprogramming. Specifically, these tumors demonstrated impaired T-cell functionality and enhanced mitochondrial transfer to tumor cells, suggesting a pivotal role for mitochondrial dynamics in promoting immune evasion and metabolic adaptations that drive tumor progression.
    CONCLUSIONS: The TMT score may represent a novel prognostic biomarker in breast cancer, highlighting the intricate relationship between mitochondrial transfer and tumor pathophysiology. Our findings suggested that targeting mitochondrial dynamics could be a potential therapeutic avenue for exploration, which might enhance breast cancer management strategies. Further exploration of the mitochondrial mechanisms in cancer biology may pave the way for more precise and effective therapeutic interventions.
    Keywords:  T cell; breast cancer; immunosuppression; metabolism reprogramming; mitochondria
    DOI:  https://doi.org/10.1097/JS9.0000000000004615
  50. Environ Pollut. 2025 Dec 19. pii: S0269-7491(25)01936-0. [Epub ahead of print] 127562
    Trifloxystrobin induces oxidative stress-dependent activation of the OMA1-DELE1-HRI integrated stress response leading to apoptosis in human neuroblastoma cells.
    Hanen Chaabani, Imen Ayed, Karima Rjiba, Salwa Abid, Joel Eyer, Damien Arnoult.
      Trifloxystrobin (TFX), a potent inhibitor of complex III in the mitochondrial respiratory chain, is a widely used strobilurin fungicide whose neurotoxic mechanisms remain poorly defined. This study investigated the molecular pathways underlying TFX-induced toxicity in human SH-SY5Y neuronal-like neuroblastoma cells, with particular emphasis on oxidative stress, mitochondrial dysfunction, and activation of the Integrated Stress Response (ISR). TFX exposure (24 h) exhibited an IC50 of approximately 100 μM, induced G0/G1 cell cycle arrest, and triggered mitochondria-mediated apoptosis, as evidenced by loss of mitochondrial membrane potential (ΔΨm), Bax activation, cytochrome c release, DNA fragmentation, phosphatidylserine exposure, and caspase-3 activation. These effects were accompanied by increased mitochondrial superoxide levels and decreased ATP production, indicating profound mitochondrial impairment. Pretreatment with N-acetylcysteine (NAC) markedly restored cell viability, reduced ROS accumulation, prevented ΔΨm dissipation, and diminished apoptotic damage. Mechanistically, TFX activated the ISR through the OMA1-DELE1-HRI mitochondrial stress signaling axis, as confirmed by loss-of-function experiments targeting these proteins. Importantly, both NAC and the ISR inhibitor ISRIB (Integrated Stress Response InhiBitor) significantly attenuated ISR activation and the resulting apoptosis, demonstrating that oxidative stress serves as an upstream trigger for ISR engagement and cell death. Collectively, these findings reveal that TFX induces oxidative stress-dependent activation of the OMA1-DELE1-HRI ISR pathway, linking mitochondrial dysfunction to apoptosis in human neuroblastoma cells. To our knowledge, this is the first report identifying ISR activation as a mechanistic component of strobilurin fungicide-induced neurotoxicity.
    Keywords:  ISR; SH-SY5Y cells; Trifloxystrobin; apoptosis; oxidative stress
    DOI:  https://doi.org/10.1016/j.envpol.2025.127562
  51. BME Front. 2025 ;6 0204
    Prussian Blue Nanoparticles Promoting Diabetic Bone Regeneration via Mitochondrial Recovery.
    Anqi Gu, An Lao, Weiqi Li, Ziyang Liu, Chuang Zhou, Jianqiang Cai, Qiang Chen, Kaili Lin, Lijuan Song, Xiangbing Wu, Jiaqiang Liu.
      Objective: This work aims to develop Prussian blue (PB) nanoparticles that mitigate bone marrow mesenchymal stem cell (BMSC) senescence and alleviate bone loss in type 2 diabetes (T2D). Impact Statement: PB nanozymes are established as a targeted therapeutic strategy for maintaining bone quality in T2D-addressing an unmet clinical need through innovative nanomaterial design. Introduction: Diabetes is associated with a higher risk of fractures through distinct mechanisms. Elevated blood sugar levels and excessive nutrition in T2D trigger reactive oxygen species (ROS) overproduction that impairs mitochondrial function, induces BMSC senescence, and compromises osteogenic potential. Engineered as artificial enzyme counterparts, nanozymes effectively eliminate ROS while circumventing the inherent constraints of natural antioxidant enzymes. Methods: PB nanoparticles were synthesized and fully characterized. BMSCs treated with high glucose plus palmitate-bovine serum albumin served as the diabetic cell model. The nanoparticles were evaluated for their capacity to scavenge ROS, modulate mitochondrial function, counteract cellular senescence, and restore osteogenic potential. Finally, their ability to attenuate bone loss was verified in a T2D mouse model. Results: We demonstrated that PB nanoparticles efficiently scavenge ROS, rebalance mitochondrial dynamics by up-regulating fusion proteins and down-regulating fission proteins, and restore membrane potential. These actions suppress BMSC senescence and revive osteogenic capacity, culminating in substantial attenuation of T2D-associated bone loss in vivo. Conclusion: These findings introduce a promising and innovative approach for managing bone quality in patients with T2D.
    DOI:  https://doi.org/10.34133/bmef.0204
  52. Exp Eye Res. 2025 Dec 18. pii: S0014-4835(25)00584-6. [Epub ahead of print]264 110811
    DCLRE1 downregulated by SYVN1-mediated ubiquitination and degradation, weakening mitochondrial homeostasis protection in ARC formation.
    Tianyu Cheng, Pengfei Li, Jiancen Tang, Hongping Cui, Jierui Jia, Lu Wang, Qian Li.
      DNA oxidative damage of lens epithelium cells (LECs) has been proved to be significantly related to age-related cataract (ARC). DCLRE1A, as a member of the DNA interstrand cross-links pathway, can repair damaged DNA. However, DCLRE1A has not been addressed in maintaining mitochondrial healthy. Our findings demonstrated that DCLRE1A alleviated mtDNA oxidative damage and mitochondrial dysfunction. Besides, the E3 ubiquitin ligase SYVN1 interacts with DCLRE1A and promotes its ubiquitination and degradation. Furthermore, SYVN1 knockdown exacerbated H2O2-induced lens opacity in both ex-vitro rat lenses and ARC mouse. Together, these results underscore the pivotal role of DCLRE1A ubiquitination in modulating mitochondrial homeostasis, offering novel insights into ARC pathogenesis. The E3 ubiquitin ligase SYVN1, related to DNA damage repair, offers a promising avenue for treating cataracts with antioxidative.
    Keywords:  Age-related cataract; DCLRE1A; Mitochondrial homeostasis; SYVN1
    DOI:  https://doi.org/10.1016/j.exer.2025.110811
  53. Front Physiol. 2025 ;16 1705821
    Current perspectives and trends on the role of mitochondria in renal ischemia-reperfusion injury from 2005 to 2024: a bibliometric analysis and literature review.
    Rui Yan, Yalong Zhang, Zewen Li, Kunpeng Li, Jiangwei Man, Li Yang.
       Background: Renal ischemia-reperfusion injury (RIRI) represents a leading cause of acute kidney injury (AKI). Mitochondria, serving as the central organelles for cellular energy metabolism and signal transduction, play a pivotal role in the pathogenesis of RIRI.
    Methods: Utilizing the three major academic databases-Web of Science Core Collection (WoSCC), PubMed, and Scopus, this study conducted a comprehensive bibliometric analysis and visualization to explore research trends and key thematic areas related to mitochondrial involvement in renal ischemia-reperfusion injury from 2005 to 2024.
    Results: Bibliometric analysis reveals a sustained increase in research output concerning mitochondrial roles in RIRI over the past two decades. China and the United States have emerged as the most active contributors in this field. The U.S. Department of Veterans Affairs leads in terms of total publications, while Dong Zheng from the Second Xiangya Hospital of Central South University has contributed the highest number of publications by an individual author. Kidney International and the Journal of the American Society of Nephrology are the most frequently cited journals. This study systematically identified key research themes, including the mechanisms of mitochondrial dysfunction in RIRI, mitochondrial quality control mechanisms, and potential therapeutic strategies targeting mitochondria.
    Conclusion: Through bibliometric analysis, this study elucidates the knowledge structure and developmental trends in mitochondrial research related to RIRI. Over the past 20 years, mitochondrial dysfunction, mitochondrial quality control, and mitochondria-targeted therapeutic approaches have consistently constituted major research hotspots in this domain.
    Keywords:  bibliometrics; mitochondrial quality control; mitochondrialmetabolic reprogramming; renal ischemia-reperfusion injury; targeted therapy
    DOI:  https://doi.org/10.3389/fphys.2025.1705821
  54. J Ethnopharmacol. 2025 Dec 19. pii: S0378-8741(25)01746-5. [Epub ahead of print]359 121053
    Atractylodes macrocephala Koidz. water extract alleviates exercise-induced fatigue by activating mitochondrial biogenesis via the PGC-1α/NRF1/TFAM axis.
    Guowei Ying, Jingjing Yu, Lin Jiao, Jie Liang, Zhangyun Wu, Binhui Pan, Su Gao, Suhong Chen, Guiyuan Lv.
       ETHNOPHARMACOLOGICAL RELEVANCE: In Traditional Chinese Medicine (TCM), Atractylodes macrocephala Koidz. (Baizhu) is a fundamental herb for fortifying the spleen and replenishing qi, specifically used to treat syndromes characterized by weakness, and poor appetite due to spleen qi deficiency. Despite its long-standing use, the scientific basis for its anti-fatigue effect remains unclear.
    AIM OF THE STUDY: This study aimed to systematically evaluate the anti-peripheral fatigue activity of AMWE and elucidate its underlying mechanisms, thereby providing a scientific basis for its development as a functional food ingredient.
    MATERIALS AND METHODS: A mouse model of peripheral fatigue was established over 33 days using forced swimming combined with intermittent fasting. During this period, mice were administered AMWE at doses of 0.75-3.0 g/kg body weight. The chemical composition of AMWE was characterized, and its effects on exercise performance, metabolic markers, muscle histology, and mitochondrial function were assessed.
    RESULTS: AMWE primarily contained 23.84 % polysaccharides (composed of 62.20 % glucose), 2.44 % Atractylenolide II, and 7.22 % Atractylenolide III. Treatment with AMWE improved physical condition, enhanced grip strength and exercise endurance, and increased liver and muscle glycogen storage. It also reduced anaerobic metabolites such as lactic acid (LA), lactate dehydrogenase (LDH), and blood urea nitrogen (BUN). AMWE ameliorated damage to the gastrocnemius and soleus muscles and elevated blood amino acid levels. Importantly, AMWE up-regulated the mRNA and protein expression of the PGC-1α/NRF1/TFAM axis, improved mitochondrial function, increased substrate levels of pyruvate (PA) and acetyl-CoA (A-CoA) in the TCA cycle, enhanced the activity of key enzymes pyruvate dehydrogenase (PDH) and citrate synthase (CS), and promoted ATP synthesis.
    CONCLUSION: AMWE exhibits significant anti-fatigue activity, which is achieved by promoting mitochondrial biogenesis and enhancing mitochondrial function via activation of the PGC-1α/NRF1/TFAM axis. The underlying mechanism is associated with the activation of the AMPK/SIRT1/PGC-1α signaling axis and the subsequent upregulation of downstream NRF1/TFAM, leading to improved TCA cycle flux and ATP production.
    Keywords:  Anti-fatigue; Atractylodes macrocephala Koidz.; Mitochondrial biogenesis; Peripheral fatigue
    DOI:  https://doi.org/10.1016/j.jep.2025.121053
  55. Nat Prod Res. 2025 Dec 24. 1-8
    Fiscalin B exerts an anticancer effect through mitochondria-modulated apoptosis and cell cycle arrest in human hepatocellular carcinoma.
    Siqi Wang, Yi Huang, Songtao Wang, Hao Gong, Qingqin He, Dingmeng Zhang, Zhenfeng Fang, Le Zhou, Kuan Lin, Yongxiang Song.
      Liver cancer remains the leading cause of cancer-related deaths; however, current therapeutic drugs are largely ineffective. This study aimed to investigate the anticancer activity of fiscalin B, a compound extracted from marine fungi, against HepG2 cells and further explore the underlying mechanisms. Our findings revealed that fiscalin B treatment produced overloaded reactive oxygen species (ROS) and induced apoptosis in HepG2 cells, further disrupt the mitochondrial membrane potential, inducing mitochondrial dysfunction. Fluorescence microscopy revealed alterations in the distribution of TOM20 and activation of lysosomes in fiscalin B-treated HepG2 cells. The disruption of mitochondria following fiscalin B treatment marked an improved mitophagy. Moreover, fiscalin B induced G0/G1 cell cycle arrest in HepG2 cells by increasing the phosphorylation of p70S6K and S6, thus affecting the expression of key cell cycle regulators. Overall, fiscalin B exerts an anticancer effect by inducing mitochondria-modulated autophagic cell death and cell cycle arrest in hepatocellular carcinoma (HCC) cells.
    Keywords:  Apoptosis; Fiscalin B; cell cycle arrest; hepatocellular carcinoma; mitophagy
    DOI:  https://doi.org/10.1080/14786419.2025.2605553
  56. Microbiol Spectr. 2025 Dec 22. e0138525
    PI3K/Akt/mTOR signaling pathway mediates energy metabolic reprogramming and regulates mitochondrial homeostasis in host cells exposed to Toxoplasma gondii.
    Kangzhi Xu, Shifan Zhu, Jing Ma, Mingyue Zu, Jin Yang, Fan Xu, Linwei Dai, Dandan Liu, Yanhong Wang, Xinjun Zhang, Siyang Huang, Jinjun Xu, Zhiming Pan, Jianping Tao, Zhaofeng Hou.
      Toxoplasma gondii (T. gondii) relies on host cells for energy and nutrition. Our previous studies showed that T. gondii regulates host cell apoptosis via the mitochondrial pathway, highlighting the essential role of mitochondria in its parasitism. In this study, T. gondii infection was found to significantly affect mitochondrial morphology and dynamic homeostasis in porcine kidney-15 (PK-15) cells, characterized by aggregated, swollen, fragmented, and oval-shaped mitochondria with disappearing cristae, accompanied by increased fusion and decreased fission. Additionally, the energy metabolic reprogramming of PK-15 cells exposed to T. gondii was affirmed from the perspectives of glucose consumption; changes in NAD+/NADH, lactate, pyruvate, and ATP production; and expressions of proteins related to glycolysis and oxidative phosphorylation (OXPHOS). T. gondii-induced mitochondrial damage impaired the OXPHOS process; however, the glycolysis level was significantly increased. Mechanistically, we demonstrated that activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway played a critical role in energy metabolic reprogramming and mitochondrial damage induced by T. gondii, and this effect could be attenuated by LY294002 (a PI3K inhibitor), which significantly reduced intracellular proliferation of T. gondii through inhibiting PI3K/Akt/mTOR signaling pathway. These findings highlight the PI3K/Akt/mTOR pathway as a key mediator of T. gondii-induced cellular metabolic reprogramming and mitochondrial dysfunction; however, its potential as a therapeutic target remains to be validated in vivo.IMPORTANCEToxoplasma gondii, a globally distributed obligate intracellular protozoan parasite, poses severe health risks to immunocompromised individuals and pregnant women, causing miscarriage and fetal abnormalities. Current therapies suffer from high toxicity and limited targets, with unclear mechanisms underlying host-parasite interactions. This study reveals a novel parasitic strategy: T. gondii hijacks host mitochondrial dynamics and energy metabolism. Infection disrupts mitochondrial morphology and suppresses oxidative phosphorylation while activating the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway to drive metabolic reprogramming, enhancing glycolysis to meet energy demands. Critically, inhibiting PI3K/Akt/mTOR with LY294002 reduces intracellular parasite proliferation, validating this pathway as a therapeutic target. Conventional antiparasitic drugs targeting the parasite directly face resistance challenges. By focusing on host metabolic regulation via PI3K/Akt/mTOR, this work advances understanding of parasitism and proposes host-directed therapies to disrupt parasite proliferation by modulating the metabolic microenvironment, highlighting its therapeutic potential against toxoplasmosis.
    Keywords:  LY294002; PI3K/Akt/mTOR; Toxoplasma gondii; energy metabolic reprogramming; mitochondrial dynamics
    DOI:  https://doi.org/10.1128/spectrum.01385-25
  57. Free Radic Biol Med. 2025 Dec 20. pii: S0891-5849(25)01448-0. [Epub ahead of print]
    TRAF6 mediates vascular remodeling via endoplasmic reticulum stress-mitophagy in hypoxic pulmonary hypertension.
    Xuezhao Wang, Yuanzhou He, Ke Li, Zhifeng Xue, Xiaochen Li, Min Xie, Xiansheng Liu.
       BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is a cardiopulmonary disease marked by pulmonary vascular remodeling and elevated resistance in the pulmonary arteries. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator in the pathophysiology of multiple diseases, yet its functional involvement in HPH remains poorly understood.
    METHODS: We first examined TRAF6 expression and localization in lung tissues from HPH patients and experimental mouse models using Western blotting and immunofluorescence. Adeno-associated virus 9 (AAV9) with the SM22α promoter was used to achieve spatially restricted silencing of TRAF6 in vascular smooth muscle cells in vivo. Subsequently, hypoxic human pulmonary arterial smooth muscle cells (HPASMCs) were subjected in vitro to EdU proliferation assays, Transwell migration assays, Annexin V-FITC/PI apoptosis detection, electron microscopy, immunofluorescence, flow cytometry, qPCR, and Western blotting to evaluate TRAF6's effects on phenotypic modulation and mitophagy.
    RESULTS: TRAF6 was significantly overexpressed in both human HPH tissues and experimental HPH mouse models. Inhibition of TRAF6 attenuated hypoxia-induced phenotypic switching of HPASMCs in vitro, while in vivo TRAF6 silencing ameliorated pulmonary vascular remodeling and right ventricular hypertrophy. Mechanistically, TRAF6 knockdown suppressed mitochondrial dysfunction and excessive mitophagy in HPASMCs under hypoxia. Notably, hypoxia upregulated TRAF6 expression in the endoplasmic reticulum (ER), where it selectively activated the IRE1/XBP1 signaling axis during ER stress. Crucially, inhibition of the IRE1α/XBP1s pathway partially reversed TRAF6-mediated regulation of mitophagy, proliferation, migration, and apoptosis resistance in HPASMCs.
    CONCLUSIONS: Our findings demonstrate that TRAF6 exacerbates endoplasmic reticulum stress and dysregulates mitophagy, thereby driving pathological HPASMC proliferation and migration during HPH progression. TRAF6 inhibition presents a potential therapeutic intervention against the pathological vascular remodeling in HPH.
    Keywords:  Endoplasmic reticulum stress; Mitophagy; Pulmonary hypertension; Pulmonary vascular remodeling; TNF receptor associated factor 6
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.032
  58. Mol Neurodegener. 2025 Dec 22.
    Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.
    Di Hu, Xiaoyan Sun, Xin Qi.
       BACKGROUND: Mitochondrial dysfunction and α-Synuclein (αSyn) aggregation are defining features of Parkinson's disease (PD), yet the mechanistic link between them remains poorly understood. Although our previous findings suggest that the interaction between αSyn and ClpP (a mitochondrial matrix protease) contributes to PD progression, the pathogenic and therapeutic relevance of this interaction remains elusive.
    METHODS: We employed biochemical and cell biological approaches to investigate how αSyn and ClpP are mutually regulated. Additionally, we determined the pathogenic impact of αSyn-ClpP interaction by using decoy peptide CS2 in αSyn-PFF inoculated primary neurons, PD patient iPSC-derived dopaminergic neurons, and a transgenic mouse model of PD carrying αSyn-A53T mutation.
    RESULTS: We identified mitochondrial protease ClpP as a key regulator of αSyn pathology. We show that αSyn interacts with ClpP through its non-amyloid-β component (NAC) domain, leading to impaired ClpP activity and mitochondrial proteotoxic stress. ClpP, in turn, negatively regulates αSyn aggregation and propagation by stabilizing its native tetrameric form. To interrupt this pathogenic interaction, we developed a decoy peptide, CS2, which binds the NAC domain of αSyn and restores ClpP function. CS2 treatment reduced mitochondrial oxidative stress and αSyn neurotoxicity in neuronal cultures, primary cortical neurons inoculated with αSyn preformed fibrils, and dopaminergic neurons derived from PD patient iPSCs. In mThy1-hSNCA transgenic mice, subcutaneous administration of CS2 restored ClpP levels, decreased αSyn pathology and neuroinflammation, and improved both cognitive and motor function.
    CONCLUSION: These findings highlight the αSyn-ClpP interaction as a druggable target and support CS2 as a potential disease-modifying therapy for PD and related synucleinopathies.
    Keywords:  ClpP; Decoy peptide inhibitor; Mitochondrial dysfunction; Mitochondrial proteostasis; Parkinson’s disease; Protein–protein interaction; αSyn aggregation
    DOI:  https://doi.org/10.1186/s13024-025-00918-w
  59. Biochemistry (Mosc). 2025 Dec;90(12): 1919-1928
    Mechanisms of Intracellular Selection of Mitochondrial DNA.
    Georgii Muravyov, Dmitry A Knorre.
      Eukaryotic cells contain multiple mitochondrial DNA (mtDNA) molecules. Heteroplasmy is coexistence in the same cell of different mtDNA variants competing for cellular resources required for their replication. Here, we review documented cases of emergence and spread of selfish mtDNA (i.e., mtDNA that has a selective advantage in a cell but decreases cell fitness) in eukaryotic species, from humans to baker's yeast. The review discusses hypothetical mechanisms enabling preferential proliferation of certain mtDNA variants in heteroplasmy. We propose that selfish mtDNAs have significantly influenced the evolution of eukaryotes and may be responsible for the emergence of uniparental inheritance and constraints on the mtDNA copy number in germline cells.
    Keywords:  heteroplasmy; intracellular selection; mitochondrial DNA; mitophagy; mtDNA quality control; selfish gene
    DOI:  https://doi.org/10.1134/S0006297925603296
  60. Adv Sci (Weinh). 2025 Dec 22. e09822
    A Cold Stress-Activated Endocrine Sentinel Chemical Hormone Promotes Insect Survival via Mitochondrial Adaptations Through the Adipokinetic Hormone Receptor.
    Jiao Zhou, Junxian Chen, Hongxia Zhang, Lu Guo, Kevin Mai, Elijah Abraham, Dilip V Prajapati, Yue Chang, Jing Ning, Xinchen Wang, Defeng Li, Dan-Dan Zhang, Jianghua Sun, Rebecca A Butcher, Lilin Zhao.
      Seasonal temperature fluctuations present a major survival challenge for insects, requiring physiological adaptation that confers resilience to cold stress. However, the hormone mechanisms governing mitochondrial adaptation to overcome cold stress remain poorly understood. Here, we identify that the endogenous ascaroside C9 (asc-C9) acts as a chemical signal that markedly improves survival following acute cold exposure by coupling lipolysis to mitochondrial adaptation. We show that diapause larvae maintain compact mitochondrial cristae and display 2.7-fold higher post-chill survival compare to non-diapause larvae, whose mitochondria undergo swelling and fragmentation. Cold stress triggers diapause-specific accumulation of asc-C9 (ascr#10) in the subcutaneous fat body. Exogenous asc-C9 recruits the adipokinetic hormone receptor (AKHR) to activate the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-uncoupling protein 4 (UCP4) axis, thereby stimulating mitochondrial biogenesis, enhance uncoupled respiration, lowering the adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio, and synchronously accelerate lipid mobilization and increasing cold resilience. This asc-C9-AKHR-mitochondria module is functionally conserved in Drosophila melanogaster and Caenorhabditis elegans, indicating that ascaroside-mediated metabolic reprogramming is an ancient stress-adaptation strategy. Our findings reveal a sentinel hormone-driven lipid-to-mitochondria circuit that enables insects to survive extreme cold through targeted mitochondrial flexibility.
    Keywords:  adipokinetic hormone receptor; ascarosides hormone; diapause; mitochondrial biogenesis; mitochondrial uncoupling; survival
    DOI:  https://doi.org/10.1002/advs.202509822
  61. Chem Biomed Imaging. 2025 Dec 22. 3(12): 888-898
    Mitochondrial Unfolded Protein Responsive Imaging and Surgical Navigation in Ovarian Cancer.
    Quan Wang, Chen Xiong, Xiaoyu Xing, Renzhi Wu, Jingxin Wang, Meng Wu, Fei Li, Shixuan Wang, Xiaoding Lou, Fan Xia, Jun Dai.
      Unfolded proteins, as critical biomarkers in cancer, hold significant potential for tumor-specific imaging. However, the content of unfolded proteins within distinct subcellular organelles varies markedly and reflects divergent physiological implications. Currently, few fluorescent probes enable precise quantification and imaging of mitochondrial unfolded proteins. Herein, we report a fluorescent probe, MAP, for accurate imaging of mitochondrial unfolded proteins. MAP incorporates a triphenylphosphonium group that specifically targets mitochondria, with cellular uptake efficiency proportional to mitochondrial membrane potential. Within mitochondria, the maleimide moiety of MAP covalently reacts with thiol groups on unfolded proteins, restricting molecular rotation and suppressing intramolecular charge transfer (ICT), thereby triggering a significant fluorescence enhancement. Owing to the hyperpolarized mitochondrial membrane potential and abundant mitochondrial unfolded proteins in SKOV3 cells, MAP with superior biocompatibility achieves tumor-specific imaging with a high signal-to-noise ratio (9.5), enabling precise intraoperative navigation for ovarian cancer resection. This molecular design strategy provides a foundational framework for developing organelle-specific unfolded protein probes and advancing image-guided surgical applications.
    Keywords:  fluorescence imaging; maleimide−thiol chemistry; mitochondrial membrane potential; mitochondrial unfolded protein; ovarian cancer; surgical navigation
    DOI:  https://doi.org/10.1021/cbmi.5c00075
  62. J Headache Pain. 2025 Dec 22.
    Schwann cell Lrp1 deletion drives trigeminal neuron sensitization and orofacial pain by modulating mitochondrial function and TRPV1/TRPA1 activity.
    Zhiting Gong, Morgan Zhang, Naijiang Liu, Kesava Asam, Stefano Martellucci, Bradley Aouizerat, Wendy Campana, Yi Ye.
       BACKGROUND: Orofacial pain, affecting 10-15% of adults, is a prevalent form of chronic pain that remains a major clinical challenge. The Schwann cell involvement in this pathophysiology is not fully understood. Low-density lipoprotein receptor-related protein 1 (LRP1) in Schwann cells has an unclear role in orofacial pain mechanisms.
    FINDINGS: We demonstrate that Schwann cell-specific conditional knockout of Lrp1 (scLrp1-/-) in mice leads to pronounced mechanical and thermal hypersensitivity in the orofacial region. RNA-seq of trigeminal ganglia (TG) from scLrp1-/- mice revealed broad changes in mitochondrial and metabolic pathways, reactive oxygen species (ROS) signaling, calcium homeostasis, and neurodegeneration-related processes. Altered mitochondrial function and ROS production in the TG were further confirmed with Seahorse metabolic flux analysis and biochemical assays. Additionally, mechano- and thermos-sensitive ion channels TRPV1 and TRPA1 are overexpressed and sensitized in the TG isolated from scLrp1-/- mice. Schwann cells isolated from scLrp1-/- mice displayed defective oxLDL uptake and excessive H₂O₂ release. Conditioned medium from LRP1 ablated Schwann cells induced orofacial hypersensitivity in vivo and robustly activated TG neurons in vitro in a TRPV1/TRPA1 dependent manner.
    CONCLUSIONS: Our results demonstrate that Schwann cell LRP1 safeguards mitochondrial function and supports neuron-glia metabolic coupling in the trigeminal system. The finding that LRP1 deficiency in Schwann cells drives orofacial pain in the absence of external insults highlights Schwann cells as active drivers, rather than passive amplifiers of chronic pain and identifies LRP1 as a promising target for orofacial pain management.
    Keywords:  Low-density lipoprotein receptor–related protein 1 (LRP1); Mitochondrial remodeling; Orofacial pain; Schwann cell; TRPA1; TRPV1
    DOI:  https://doi.org/10.1186/s10194-025-02250-6
  63. Alzheimers Dement. 2025 Dec;21 Suppl 1 e102430
    Basic Science and Pathogenesis.
    Hiranya Pintana, Patcharapong Pantiya, Chanisa Thonusin, Titikorn Chunchai, Suriphan Donchada, Busarin Arunsak, Guang Liang, Nipon Chattipakorn, Siriporn C Chattipakorn.
       BACKGROUND: Therapeutic approaches that aimed to improve brain mitochondrial function, could potentially mitigate age-related cognitive impairments. The myeloid differentiation factor-2 (MD2) inhibitor, L6H2, has been shown to alleviate brain mitochondrial dysfunction and cognitive deficits in obese rats. Mitochondrial division inhibitor-1 (MDV1) prevents excessive mitochondrial fission, promoting mitochondrial elongation, which has been reported to protect against neurotoxic damage. However, the effects of L6H2 and MDV1 on cognitive function and brain mitochondrial function in aged-female rats remain unclear. Thus, this study aims to investigate whether MD2-inhibitor (L6H2) or MDV1 attenuates cognitive impairment and brain mitochondrial dysfunction in aged-female rats.
    METHOD: Female Wistar rats (n = 15, aged 24 months) were randomly divided into three groups: 1) vehicle-treated as a control rats, 2) MD2 inhibitor-treated rats, and 3) MDV1-treated rats. Control rats received normal saline, MD2-treated rats received L6H2 (40 mg/kg/day, p.o.), and MDV1-treated rats were administered MDV1 (1.2 mg/kg/day, i.p.). After two-weeks of daily treatment, cognitive function was assessed using the Novel Object Location (NOL) test. Brain mitochondrial function was measured after euthanasia.
    RESULT: Only MD2-treated rats exhibited a significant reduction in brain mitochondrial reactive oxygen species (ROS) levels and an improvement in mitochondrial membrane potential, without affecting mitochondrial swelling, compared to the control group (Figure 1A-C). There were no significant differences in preference index between the objects during the familiarization phase, indicating no object bias across groups (Figure 1E). In the NOL test, none of the groups exhibited a significant preference for the new location, as the preference index in all groups was not different from the fixed control value of 50%. This indicates cognitive impairment in the aged-female rats, with neither treatment showing improvement. (Figure 1F).
    CONCLUSION: MD2-inhibitor (L6H2) reduced brain mitochondrial ROS production and improved mitochondrial membrane potential change in aged-female rats, but did not improve cognitive function or overall mitochondrial health. Additionally, MDV1 had no effect on mitochondrial function or cognitive outcomes. These results suggest that MD2-inhibitor may play a role in reducing brain mitochondrial oxidative stress, the doses and treatment duration used in this study were insufficient to significantly improve cognitive function in aged-female rats.
    DOI:  https://doi.org/10.1002/alz70855_102430
  64. Front Physiol. 2025 ;16 1658685
    Prohibitin 2 ameliorates cisplatin-induced acute kidney injury by modulating mitochondrial homeostasis.
    Qi Zhang, Xiaoyu Shi, Lu Yao, Ping Zhou, Wei Ding.
      Acute kidney injury (AKI), associated with a major health burden globally, is frequently caused by nephrotoxic agents, specifically cisplatin. Prohibitin (PHB) 2, a highly conserved mitochondrial protein localized at the inner mitochondrial membrane, is key to maintaining mitochondrial respiration, cristae morphogenesis, and regulating cell death. Despite being extensively assessed in chronic kidney disease models, the role of PHB2 in AKI, particularly cisplatin-induced AKI, warrants further exploration. Here, we investigated the protective effects of PHB2 in cisplatin-induced AKI in in vitro and in vivo models. The results demonstrated that cisplatin upregulated PHB2 expression both in vitro and in vivo. Mechanistically, PHB2 deficiency exacerbated cisplatin-induced cell apoptosis and mitochondrial dysfunction, indicated by increased caspase-3 activity and reactive oxygen species (ROS) production, as well as mitochondrial membrane potential loss, in vitro. Our Western blot analysis results further validated PHB2's involvement in autophagy processes within renal tubular cells. Nevertheless, PHB2 overexpression mitigated these detrimental effects, suggesting the protective role of PHB2 in cisplatin-induced AKI. In vivo, adeno-associated virus-mediated PHB2 overexpression reduced cisplatin-induced renal tubular injury and enhanced mitochondrial ultrastructure, supporting its potential therapeutic benefits. Taken together, our findings underscore the protective role of PHB2 in cisplatin-induced AKI, highlighting its potential as a therapeutic target for mitigating renal injury. Future studies elucidating the mechanisms underlying the protective effects of PHB2 and exploring its clinical implications in AKI management are warranted.
    Keywords:  acute kidney injury; cisplatin; mitochondrial dysfunction; prohibitin 2; renal protection
    DOI:  https://doi.org/10.3389/fphys.2025.1658685
  65. bioRxiv. 2025 Dec 12. pii: 2025.12.09.693285. [Epub ahead of print]
    Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.
    Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.
      Cells dynamically regulate chromatin in response to nutrient flux which promotes the transcriptional changes necessary for adaptation. The mechanistic target of rapamycin complex 1 (mTORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin stability feeds back to mTORC1 activation and stress adaption remains unknown. We previously identified histone H3 at lysine 37 (H3K37) as essential for the response to mTORC1 stress such that mutation of H3K37 to alanine (H3K37A) causes cell death upon mTORC1 inhibition. Herein, we show that H3K37-dependent chromatin stability prevents proteasome-mediated histone degradation, restricts mTORC1 signaling, and safeguards mitochondrial homeostasis during mTORC1 stress. Genetic interaction analyses reveal that H3K37A combined with mutants that destabilize chromatin, including loss of the Set2 H3K36 methyltransferase, Rpd3S histone deacetylase, or multiple histone deposition pathways, causes synthetic lethality when mTORC1 is inhibited. Transcriptome analysis indicates that H3K37A misregulates the mitochondrial transcriptome during mTORC1 stress, which increases mitochondrial reactive oxygen species (ROS) and triggers lethal mitochondrial retrograde signaling. Inactivation of retrograde signaling, or ROS neutralization, rescues viability of H3K37A and chromatin stability mutants during mTORC1 stress. These findings establish chromatin stability as a key safeguard that restrains mTORC1 activity and prevents toxic mitochondrial stress during metabolic adaptation.
    DOI:  https://doi.org/10.64898/2025.12.09.693285
  66. Phytomedicine. 2025 Dec 14. pii: S0944-7113(25)01348-0. [Epub ahead of print]150 157714
    Xin-Ji-Er-Kang alleviates chronic heart failure by suppressing mtDNA/cGAS-STING signaling through NR3C1-mediated MFN2 upregulation.
    Rumeng Zhang, Jiamin Wu, Dingyan Wang, Keke Li, Yifan Hou, Ying Yu, Chaolong Jin, Chunmiao Wang, Shan Gao.
       BACKGROUND: cGAS/STING signaling activation driven by mitochondrial DNA (mtDNA) release contributes to chronic heart failure (CHF) pathogenesis. Although the traditional Chinese medicine Xin-Ji-Er-Kang (XJEK) shows cardioprotective potential, its regulation of mtDNA dynamics remains unclear.
    PURPOSE: To elucidate how XJEK inhibits mtDNA/cGAS/STING-driven inflammation and improves CHF.
    METHODS: Murine myocardial ischemia-reperfusion (MIR) injury models and cardiomyocyte hypoxia/reoxygenation (H/R) models were used to evaluate the cardioprotective effects of XJEK in vivo and in vitro. High-throughput sequencing identified potential therapeutic targets of XJEK. Network pharmacology and bioinformatic analyses were then applied for target prediction and pathway enrichment. Integrated experimental approaches including RT-qPCR, immunofluorescence, immunoblotting, dual-luciferase reporter assays, and ChIP-qPCR were implemented to elucidate XJEK-mediated regulatory mechanisms governing cGAS/STING signaling in both models.
    RESULTS: XJEK treatment significantly ameliorated myocardial fibrosis and attenuated ventricular remodeling in mice with MIR-induced heart failure. High-throughput sequencing identified mitofusin 2 (MFN2) as a key regulator mediating XJEK's cardioprotective effects. XJEK rescued MIR- and H/R-induced downregulation of MFN2, thereby suppressing mtDNA release and the consequent excessive activation of the cGAS/STING signaling and downstream inflammatory responses. Furthermore, integrated network pharmacology and bioinformatic analyses revealed nuclear receptor subfamily 3 group C member 1 (NR3C1) as the transcription factor promoting MFN2 expression. Mechanistically, XJEK facilitated the nuclear translocation of NR3C1, enabling this process.
    CONCLUSION: XJEK attenuates CHF progression by facilitating NR3C1 nuclear translocation, enhancing its binding to the MFN2 promoter to upregulate transcription and expression, thereby suppressing mtDNA/cGAS/STING signaling activation and inflammatory responses.
    Keywords:  Chronic heart failure; Mitochondrial DNA; Mitofusin 2; Nuclear receptor subfamily 3 group C member 1; Xin-Ji-Er-Kang; cGAS/STING signaling
    DOI:  https://doi.org/10.1016/j.phymed.2025.157714
  67. Alzheimers Dement. 2025 Dec;21 Suppl 5 e103244
    Drug Development.
    Bhaskar Jyoti Dutta.
       BACKGROUND: Homocysteine (Hcy) is a sulfur-containing amino acid generated during protein catabolism, and elevated levels of Hcy, known as hyperhomocysteinemia (HHcy), have been implicated in various neurological disorders. Disruptions in Hcy metabolism, along with deficiencies in folate and vitamin B12, can lead to altered methylation and redox imbalances, which in turn affect calcium influx and contribute to the accumulation of amyloid and tau proteins-key factors in the development of cognitive impairment. Pterostilbene (PTE), a natural stilbene compound, has demonstrated potential in mitigating neurological deficits due to its antioxidant and anti-inflammatory properties. This background sets the stage for exploring pterostilbene's therapeutic potential in the context of HHcy-induced cognitive decline.
    METHOD: In this study, we developed a model of hyperhomocysteinemia (HHcy)-induced cognitive impairment (HHcy-Cog) by administering L-methionine, a precursor of homocysteine (Hcy). The experimental groups included: normal control rats, HHcy-Cog rats receiving 1.7g/kg of L-methionine orally, and HHcy-Cog rats treated with PTE at doses of 30 mg/kg or 60 mg/kg orally for 30 days. A battery of behavioral tests, including the Morris water maze and novel object recognition tests, were conducted to evaluate various aspects of memory and cognitive function in the treated animals. Following behavioral testing, the animals were sacrificed, and histopathological studies, immunohistochemistry (IHC), and Western blot analyses were performed on brain tissues to further investigate the molecular and cellular changes associated with cognitive impairment and the potential therapeutic effects of PTE.
    RESULT: PTE effectively reversed HHcy-induced cognitive impairment by significantly improving spatial and recognition memory, as evidenced by performance in behavioral tests. Additionally, PTE was found to enhance mitochondrial biogenesis through the SIRT1/PGC-1α/TFAM pathway, promoting mitochondrial health. It also improved synaptic plasticity, as shown by increased expression of synaptophysin and PSD-95, and supported adult neurogenesis, evidenced by upregulation of doublecortin expression in hippocampus.
    CONCLUSION: PTE effectively alleviates HHcy-induced cognitive impairment by enhancing memory function, mitochondrial biogenesis, synaptic plasticity, and adult neurogenesis. These results highlight PTE's potential as a therapeutic agent for combating cognitive decline in HHcy-related conditions.
    DOI:  https://doi.org/10.1002/alz70859_103244
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