bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–02–15
sixty-six papers selected by
Gavin McStay, Liverpool John Moores University
  1. PROTAC-Mediated Degradation of Class I HDACs by JPS016 Alleviates Septic Cardiomyopathy via Mitophagy-Driven Exopher Formation and Mitochondrial Quality Control.
  2. Overloaded mitochondrial stress drives reproductive damage in GC-1 mouse spermatogonia cells exposed to nickel nanoparticle.
  3. Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.
  4. Esculin Alleviated NLRP3 Inflammasome Activation by Inducing PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury.
  5. Albiflorin alleviates osteoporosis through suppression of osteoclast mitophagy via the Rap1a/ERK signaling pathway.
  6. p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
  7. Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control.
  8. Review Article: Dynamin-Related Protein 1 in Cancer Progression: Mechanisms and Implications.
  9. Xuming tongmai decoction modulates astrocyte polarization and mitophagy via the PINK1/Parkin pathway in a rat model of acute ischemic stroke.
  10. Effect of Mitophagy on the Tension-Driven Osteogenic Differentiation of Periodontal Ligament Stem Cells During Ageing.
  11. Bridging tradition and modernity: mitochondrial dynamics as a Traditional Chinese Medicine therapeutic target in cardiovascular disease.
  12. DRP1 in Reproduction and Reproductive Aging.
  13. MOTS-c attenuates cardiac dysfunction following high altitude exposure by promoting mitophagy.
  14. Role of mitophagy in breast cancer: mitophagy-apoptosis balance and reactive oxygen species play determining role.
  15. The Disrupted Mitochondrial Quality Control Network: A Unifying Mechanism and Therapeutic Target for Chemotherapy-Induced Multi-Organ Toxicity.
  16. Biomimetic Selenium-Encrusted Prussian Blue Nanozyme for Myocardial Infarction by Coordinated Enhancement of Mitophagy and Reactive Oxygen Species Scavenging.
  17. Isoflurane aggravates pre-existing proteotoxicity in adult nematodes by suppressing mitochondrial fitness.
  18. Distinct roles of PINK1 autophosphorylation in neonatal hypoxia with or without convulsions.
  19. Mitochondrial fusion safeguards stomatal defence in plants.
  20. The role of mitochondrial autophagy activated NLRP3 inflammasome in postpartum depression-like behaviors induced by stress during pregnancy.
  21. Haikun Shenxi Capsule Alleviates Alzheimer's Disease by Targeting Mitophagy to Clear Turbidity Toxin.
  22. Modified Banxia Xiexin Decoction promotes mitochondrial fission in colon cancer cells by inhibiting the CHD6-TMEM65 axis.
  23. Afzelin resists UVA damage through autophagy and synergizes with ganoderic acid A to skin photoaging.
  24. The UBC/SIRT5/DRP1 axis regulates mitochondrial dynamics to alleviate Staphylococcus aureus-induced oxidative stress and senescence in bovine mammary epithelial cells.
  25. Endoplasmic Reticulum Stress Induced by Turbulence of Mitochondrial Fusion and Fission Was Involved in Isoproterenol-Induced H9c2 Cell Injury.
  26. Mitophagy dynamics during oxidative to reductive stress shift potentiates arsenite-induced malignant transformation potential in human keratinocytes.
  27. Ddx17 Mitigates Sepsis-Induced Cardiomyopathy by Regulating Mitochondrial Dynamics in Cardiomyocytes.
  28. IN-UTERO PROTEIN DEFICIENCY LEADS TO IMPAIRED HEPATIC LIPID METABOLISM IN ADULT MALE RATS.
  29. Adipose-derived mesenchymal stem cell exosomes enhance diabetic wound healing via the amelioration of fibroblast senescence through the SMARCAL1-Drp1 signaling pathway.
  30. XIST Improves Mitophagy and Exerts Perioperative Myocardial Protection Through miR-212-3p/CALCOCO2/OPTN.
  31. Integrative Machine Learning and Experimental Validation Identify FIS1 as a Candidate Biomarker Linked to Mitochondrial Dynamics in Pulmonary Hypertension.
  32. Regulation of mitochondrial biogenesis and energy metabolism in the heart.
  33. Zonal Hepatocellular Responses to Acute Ethanol Consumption: Impacts on Mitochondrial Function and Liver Metabolism.
  34. HFPO-TA induces cardiac developmental damage in zebrafish by disrupting mitochondrial dynamics through FABP3.
  35. Mitochondria-related genes or proteins affect the progression of hepatocellular carcinoma: roles, mechanisms and potential treatments.
  36. Lactiplantibacillus plantarum GUANKE ameliorates influenza a virus-induced inflammation and lung barrier dysfunction through enhancing mitophagy and improving oxidative phosphorylation.
  37. Isopimaric Acid Derived from Torreya nucifera Blocks Autophagy and Mitophagy to Sensitize Colon Cancer Cells to Nutrient Starvation.
  38. FXR overexpression restores NLRP3-mediated mitophagy and improves mitochondrial dysfunction in alcoholic liver disease.
  39. Lycopene mitigates T-2 toxin-induced hepatic ferroptosis by targeting the Nrf2/mitophagy axis in mice.
  40. Correction: Xu et al. Notch1 Protects Against Ischemic-Reperfusion Injury by Suppressing PTEN-Pink1-Mediated Mitochondrial Dysfunction and Mitophagy. Cells 2023, 12, 137.
  41. SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury.
  42. Machine learning and bioinformatics-based identification of mitophagy-related diagnostic biomarkers in bronchiolitis obliterans.
  43. Polylactic acid microplastic exposure induced male reproductive toxicity and decreased testosterone levels by accelerating Leydig cell senescence.
  44. Mitochondrial presequences are more than just address labels.
  45. Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling.
  46. Cepharanthine Triggers Ferroptosis in Gastric Cancer by PINK1/FUNDC1-Mediated Mitophagy-Dependent GPX4 Degradation.
  47. CD38 degrades MAVS through mitophagy to inhibit type I interferon secretion in nasopharyngeal carcinoma cells and impairs CD8+T cell-mediated anti-tumor immunity.
  48. Dose-Dependent Biphasic Effect of Palmitic Acid on Oligodendrocyte Function: Impacts on Viability, Differentiation, and Myelination.
  49. Dual targeting of oncogenic microtubules and mitochondria in PDAC.
  50. Elovl6 inhibits colorectal cancer progression through stearic acid-mediated mitochondrial fusion and metabolic reprogramming.
  51. Piperine improves ischemic brain injury by promoting the regulation of the AMPK/PGC-1α pathway by Apelin 13.
  52. Proximity labeling unveils potential roles of the Miro2-CISD1 network in mitochondrial dynamics and neuronal differentiation.
  53. TREM1 as a master regulator of mitophagy-pyroptosis crosstalk in myocardial infarction: A dual-target strategy for precision therapy.
  54. Subcellular proteomic analyses reveal REEP5 knockdown in the mouse heart disrupts mitochondrial networks.
  55. Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.
  56. Super-Refractory Status Epilepticus (SRSE) in a Patient With Compound Heterozygous OPA1 Variants: Case Report and Literature Review.
  57. Ginsenoside Rg5 targets the KAT8-CISD2 axis to maintain mitochondrial homeostasis and antagonize senescence.
  58. Autophagy in kidney physiology: from cellular quality control to organ metabolism.
  59. MFN2-CD36 Interaction Regulates Mitochondrial Lipid Digestion in Cancer-Associated Fibroblasts and Promotes Esophageal Squamous Cell Carcinoma Progression.
  60. Integrative transcriptomic and machine learning analysis identifies PYCARD and IFI30 as immune-lysosomal biomarkers of ANCA-associated glomerulonephritis.
  61. USP18 improves mitochondrial homeostasis by stabilizing PKM2 and promoting M2 polarization in macrophages to relieve acute lung injury.
  62. β - sitosterol promotes the SUMOylation of DRP1 in alveolar macrophages and alleviates sepsis-associated acute lung injury.
  63. Molecular mechanisms of mitochondrial AAA+ proteases.
  64. Comparative Analysis of Melatonin and Sildenafil in a Rat Model of Pulmonary Arterial Hypertension: Insights into Oxidative Stress, Inflammation, and Mitochondrial Biogenesis.
  65. Mitochondrial-Localized FABP4 Inhibits Ferroptosis-Dependent Mycobacterium tuberculosis Dissemination by Maintaining Mitochondrial Homeostasis.
  66. Dysregulated iron homeostasis Drives mitochondrial Injury and ferroptosis susceptibility in MELAS fibroblasts.
  1. Int J Biochem Cell Biol. 2026 Feb 11. pii: S1357-2725(26)00014-2. [Epub ahead of print] 106910
    PROTAC-Mediated Degradation of Class I HDACs by JPS016 Alleviates Septic Cardiomyopathy via Mitophagy-Driven Exopher Formation and Mitochondrial Quality Control.
    Zhaokai Li, Weijian Zhang, Guoqiang Zhang.
      Septic cardiomyopathy (SCM) is a severe complication of sepsis with limited targeted treatment options, largely due to mitochondrial dysfunction in cardiomyocytes. Exophers, extracellular vesicles responsible for removing damaged mitochondria, represent a newly recognized mechanism of mitochondrial quality control, yet their upstream regulation remains unclear. This study tested the hypothesis that targeted degradation of Class I histone deacetylases (HDACs) using a PROTAC compound, JPS016, could alleviate SCM by promoting mitophagy-dependent exopher formation. An in vitro SCM model was established in HL-1 cardiomyocytes treated with lipopolysaccharide (LPS), and the effects of JPS016 on mitochondrial homeostasis, HDAC degradation, histone modifications, mitophagy, and exopher production were assessed using molecular and imaging techniques. JPS016 treatment significantly enhanced cell viability, reduced mitochondrial damage, and increased both histone acetylation and lactylation. Mechanistically, JPS016 activated the PINK1/Parkin mitophagy pathway and markedly increased the formation of exophers. Pharmacological inhibition experiments demonstrated that mitophagy, rather than general autophagy, was essential for exopher biogenesis and the protective effect of JPS016. These findings identify HDAC degradation as a novel upstream regulator of exopher-mediated mitochondrial clearance and support the therapeutic potential of PROTAC-based interventions in SCM.
    Keywords:  HDAC; PROTAC; exopher; mitochondrial quality control; mitophagy; septic cardiomyopathy
    DOI:  https://doi.org/10.1016/j.biocel.2026.106910
  2. Cell Biol Toxicol. 2026 Feb 11.
    Overloaded mitochondrial stress drives reproductive damage in GC-1 mouse spermatogonia cells exposed to nickel nanoparticle.
    Lu Kong, Geyu Liang, Yán Wāng.
      Nickel nanoparticles (Ni NPs) are widely used in industrial and commercial sectors, raising concerns about their potential occupational and environmental toxicity. Male infertility has increased significantly in recent decades, with environmental exposures playing a recognized role. Ni NPs have been identified as toxic agents that induce testicular damage and sperm abnormalities, yet their underlying molecular mechanisms are unknown. In this study, mouse spermatogonia GC-1 cells were used as an in vitro model to explore the role of mitochondrial autophagy (mitophagy) in the induced apoptosis of Ni NPs. Ni NPs significantly reduced cell viability, increased intracellular ROS levels, disrupted mitochondrial membrane potential, and triggered germ cell apoptosis. PINK1 and Parkin, key mitophagy-related proteins, exhibited significant upregulation. Cyclosporin A was used to inhibit mitophagy, attenuating mitochondrial damage and reducing apoptosis. In addition, PINK1 knockdown achieved by lentiviral transfection confirmed its critical role in mediating Ni NPs-induced mitophagy and subsequent cell death. These findings demonstrate that overactivation of the PINK1/Parkin pathway promotes apoptosis to Ni NPs exposure by mitophagy. Our study provides new mechanistic insights into the role of mitophagy in reproductive damage caused by nanomaterials.
    Keywords:  Apoptosis; Autophagy; Metal nanoparticle; Mitochondrial dysfunction; Reproductive toxicology
    DOI:  https://doi.org/10.1007/s10565-026-10153-8
  3. Autophagy. 2026 Feb 12. 1-3
    Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.
    Hanna Hakansson, Jack H Howden, Josef T Kittler.
      Mitochondria regulate ATP production, calcium buffering, and apoptotic signaling, and clearing dysfunctional mitochondria by mitophagy is essential for cellular homeostasis. While PINK1-dependent mitophagy is well-characterized in neurons, its function in glial cells such as astrocytes is less understood. Our study demonstrates that PINK1-mitophagy in astrocytes occurs faster and with less spatial restriction compared to neurons. This pathway was specifically regulated in astrocytes by the glycolytic enzyme, HK2 (hexokinase 2), which forms a glucose-dependent complex with PINK1 following mitochondrial damage. Inflammation also induces HK2-PINK1 mitophagy, and its activation in astrocytes protects against cytokine-induced neuronal death. Our findings characterize a novel HK2-PINK1 pathway in astrocytes that bridges mitophagy, metabolism, and immune signaling.Abbreviation: HK2: hexokinase 2; PD: Parkinson disease; PINK1: PTEN induced kinase 1; S65: serine 65.
    Keywords:  Astrocyte; HK1; PINK1; mitochondria; mitophagy; neurodegeneration; parkin
    DOI:  https://doi.org/10.1080/15548627.2026.2623987
  4. Mol Neurobiol. 2026 Feb 12. 63(1): 432
    Esculin Alleviated NLRP3 Inflammasome Activation by Inducing PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury.
    Jinyu Lin, Bowen You, Xin Yang, Xue Li, Wenjuan Sun, Zhongyu Xu, Yi Zhang, Xuhui Tong, Shuying Dong.
      Cerebral ischemia/reperfusion injury (CIRI) refers to the secondary brain injury that occurs when blood supply is restored to ischemic cerebral tissue, and represents one of the primary causes of adult disability and mortality. Current evidence indicates that aesculin exhibits antioxidative and anti-inflammatory activities; however, its therapeutic effects on CIRI remain to be elucidated. The objective of this study was to investigate the potential role of Esculin (ESCU) in protecting against CIRI and to elucidate its underlying mechanisms. Adult male mice were used to establish the middle cerebral artery occlusion/reperfusion (MCAO/R) model. The mice were administered varying doses of ESCU or a reference positive control drug. To evaluate the neuroprotective effects of ESCU, neurological deficit scores were assessed, and cerebral blood flow was measured. 2,3,5-triphenyltetrazolium chloride staining, H&E staining, and Nissl staining were used to determine neuronal damage. NLRP3-related markers and mitophagy-related markers were determined to investigate the mechanism of action of ESCU. ESCU afforded robust neuroprotection in mice, ameliorating functional deficits, reducing infarct size, and preserving neuronal structure. It potently alleviated oxidative stress and restored mitochondrial function (reduced ROS, improved cristae morphology, and increased mitochondrial membrane potential). Mechanistically, ESCU activated mitophagy (upregulating LC3Ⅱ, PINK1, and Parkin; downregulating p62) and inhibited the NLRP3 inflammasome (downregulating NLRP3, GSDMD-N, cleaved caspase-1, IL-1β, and IL-18). Notably, the mitophagy inhibitor Mdivi-1 abolished ESCU's inhibition of the NLRP3 pathway, establishing a causal relationship. Thus, ESCU mitigates cerebral ischemia-reperfusion injury by coordinately enhancing mitophagy and suppressing NLRP3 inflammasome activation. Our study demonstrates that ESCU attenuates CIRI mechanistically by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. These findings not only elucidate a novel pathway underlying ESCU's neuroprotection but also position it as a promising therapeutic candidate for CIRI, warranting further investigation into its precise targets and clinical potential.
    Keywords:  Cerebral ischemia-reperfusion injury; Esculin; Mitophagy; NLRP3 inflammasome; PINK1/Parkin
    DOI:  https://doi.org/10.1007/s12035-026-05722-1
  5. Phytomedicine. 2026 Jan 28. pii: S0944-7113(26)00132-7. [Epub ahead of print]153 157893
    Albiflorin alleviates osteoporosis through suppression of osteoclast mitophagy via the Rap1a/ERK signaling pathway.
    Cheng Tang, Jingxian Yu, Dong Sheng, Yong Gu, Donglong Xia, Kuibing Lan, Yajun Li, Yunshang Yang, Chengcheng Feng, Yu Gong, Long Xiao, Zhirong Wang.
       OBJECTIVES: Dysregulated mitophagy coupled with osteoclast activation orchestrates the development and progression of osteoporosis.Although albiflorin (ALB) exhibits bone-protective effects through anti-inflammatory and antioxidant activities, its precise mechanism-particularly regarding mitochondrial regulation-remains unknown. This study therefore investigates ALB as a novel osteoclast inhibitor by examining its molecular mechanism in regulating mitophagy via the Rap1a/ERK signaling pathway.
    MATERIALS AND METHODS: ALB was evaluated using murine models of postmenopausal osteoporosis. Key methodologies included RNA sequencing (RNA-seq) for gene expression pathway analysis, transmission electron microscopy (TEM) for visualization of mitochondrial and autophagic structures, MitoTracker/LysoTracker co-staining for assessment of mitophagy, and Western blotting for protein signaling validation. The impact of ALB on osteoclast differentiation and the prevention of bone loss was evaluated in both laboratory and live animal studies..
    RESULTS: ALB significantly inhibited osteoclastogenesis and osteoclast differentiation, thereby effectively reducing osteoporosis in murine models. RNA-seq analysis revealed that ALB modulated mitophagy by regulating the expression of Rap1a and components of the ERK signaling pathway. Validation through TEM demonstrated suppressed mitochondrial autophagy, while MitoTracker/LysoTracker co-staining confirmed a reduction in mitophagy. Furthermore, Western blot analysis showed that ALB inhibited osteoclast activation via the Rap1a/ERK signaling axis.
    CONCLUSION: ALB mitigates postmenopausal osteoporosis by suppressing osteoclast activation through Rap1a/ERK-dependent inhibition of mitophagy. These findings identify ALB as a promising therapeutic strategy for osteoporosis, addressing the need for safer long-term treatment options.
    Keywords:  Chinese medicine; Mitophagy; Osteoclast; Osteoporosis
    DOI:  https://doi.org/10.1016/j.phymed.2026.157893
  6. Aging Cell. 2026 Feb;25(2): e70402
    p62/SQSTM1 Condensation Modulates Mitochondrial Clustering to Participate in Mitochondrial Quality Control.
    Shan Sun, Jiaqi Xin, Yingping Zhang, Bojun Yang, Dan Su, Rui Ni, Qilian Ma, Ningning Li, Guoqiang Ma, Qiang Peng, Siqian Chen, Jochen H M Prehn, Kin Yip Tam, Hongfeng Wang, Zheng Ying.
      Mitochondrial quality control is tightly associated with aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD-associated protein p62 drives "mitochondrial clustering" (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin-mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form "grape-like" clusters during PINK1/Parkin-mediated mitophagy, which is tightly associated with aging-related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a "brake" to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD-related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the "brake" machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology.
    DOI:  https://doi.org/10.1111/acel.70402
  7. bioRxiv. 2026 Jan 28. pii: 2026.01.26.701793. [Epub ahead of print]
    Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control.
    T Carroll, D Pfendler, H Alhaj Arhayem, R Thoma, A Müller-Eigner, A Straut, G V W Johnson, K Nehrke.
      Tau protein accumulates myriad post-translational modifications as Alzheimer's disease (AD) progresses, and early-disease tau modifications such as phosphorylation at threonine 231 (T231) likely play a key role in AD pathogenesis. Here, a series of "tunable tau" strains was developed in C. elegans to test the relative impact of tau pseudo-phosphorylation of T231 (T231E) compared to protein expression level as a driver of phenotypic penetrance and severity. Multiple copies of a cassette coding for pan-neuronal wildtype tau or T231E were inserted at a genomic safe harbor loci to create a repertoire of strains expressing tau from low to high levels. In stereotypical behavioral assays of locomotory activity, T231E selectively impacted phenotypic severity compared to wild-type human tau controls, which further tracked with age and tau expression level. However, deficits in associative memory were non-selective between tau and T231E. Moreover, genetic, pharmacologic, and molecular approaches indicated that mitophagy modulation could suppress T231E phenotypes. Additionally, a robust mitochondrial unfolded protein response (UPRmt) occurred in T231E, and loss of atfs-1 , a transcription factor central to the UPRmt suppressed T231E toxicity. These results demonstrate that phenotypic severity is invariably associated with tau dosage, while early-AD relevant modifications can be causative drivers of selective deficits. Consistent with recent findings, enhancing mitophagy or suppressing potentially maladaptive consequences of persistent UPRmt induction can be beneficial. This provides a solid foundation for further interrogation into mitochondrial quality control disruption as a potential root cause for AD pathogenesis.
    Highlights: Matched sets of pan-neuronal, multi-copy tau strains enhance experimental controlPhosphomimetic tau elicits selective behavioral and neuronal dysfunctionPhosphomimetic tau triggers a unique mitochondrial unfolded responseTau depletion and mitochondrial interventions rescue observed deficits.
    Visual Abstract:
    DOI:  https://doi.org/10.64898/2026.01.26.701793
  8. Crit Rev Oncog. 2025 ;30(4): 71-83
    Review Article: Dynamin-Related Protein 1 in Cancer Progression: Mechanisms and Implications.
    Mankun Wei, Ying Liu, Jianxiang Liu, Shourong Wu.
      Dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission, plays a pivotal role in cancer progression by modulating diverse oncogenic processes. This review highlights the multifaceted contributions of DRP1 to tumorigenesis, emphasizing its involvement in metabolic reprogramming, metastasis, drug resistance, cancer stem cell (CSC) maintenance, and cell death regulation. DRP1 drives metabolic shifts, such as enhanced glycolysis and fatty acid oxidation, to fuel tumor growth and survival. It promotes metastasis by facilitating epithelial-mesenchymal transition (EMT), mitochondrial dynamics, and oxidative stress regulation. DRP1 also mediates chemoresistance through mitochondrial fission-dependent mechanisms and modulates CSC stemness via asymmetric division and metabolic plasticity. Furthermore, DRP1 influences apoptosis and ferroptosis, making it a potential therapeutic target. Pharmacological inhibition of DRP1 has shown promise in sensitizing tumors to therapy and suppressing CSC populations. This review underscores DRP1 as a critical nexus in cancer biology, with broad implications for developing targeted anticancer strategies.
    DOI:  https://doi.org/10.1615/CritRevOncog.2025061752
  9. Brain Res. 2026 Feb 10. pii: S0006-8993(26)00061-2. [Epub ahead of print] 150203
    Xuming tongmai decoction modulates astrocyte polarization and mitophagy via the PINK1/Parkin pathway in a rat model of acute ischemic stroke.
    Li Ran, Xiaofang Lan, Zixiu Zeng, Xinyuan Yu, Rui Yang, Jun Tang.
       BACKGROUND: Acute ischemic stroke (AIS) is a leading global cause of disability and mortality, with limited therapeutic options beyond reperfusion strategies. Evidence suggests that mitophagy and astrocyte polarization play critical roles in neuronal survival and inflammatory regulation after stroke. Xuming tongmai (XMTM) decoction has shown clinical potential in improving AIS outcomes, but the underlying mechanisms remain unclear. This study aimed to investigate the molecular mechanisms of XMTM in the middle cerebral artery occlusion (MCAO) model rats, with a specific focus on its role in regulating astrocyte polarization and mitophagy.
    METHODS: In vivo, the MCAO model rats were established and administered 12.90 g/kg and 25.80 g/kg XMTM decoction, with 20 mg/kg aspirin serving as the positive control. In vitro, an oxygen-glucose deprivation/reperfusion (OGD/R) model was induced in astrocytes. Serum containing XMTM (XMTM serum) was prepared from rats administered XMTM decoction. The optimal working concentration of XMTM serum was determined using the CCK-8 assay before cell treatment. OGD/R-induced astrocytes were treated with negative serum, XMTM serum, Mdivi-1 (a mitophagy inhibitor), si-NC, si-PINK1, or their combination. The therapeutic effects of XMTM on MCAO rats were evaluated through pathological analysis, cerebral infarct volume measurement, and neurological deficit scoring. Astrocyte polarization was assessed using A1-type markers (C3, iNOS) and A2-type markers (Arg1, S100A10), while XMTM serum components were characterized by LC-MS/MS. Mitophagy activity was determined by measuring the mitochondrial membrane potential (MMP) and quantifying the expression levels of PINK1, Parkin, LC3II/I, p62, and reactive oxygen species (ROS) RESULTS: 25.80 g/kg XMTM decoction significantly reduced cerebral infarct volume, ameliorated neurological deficits, and improved pathological outcomes in AIS rats. LC-MS/MS results revealed that the main components of XMTM in the blood were alkaloids, anthraquinones, flavonoids, and phenolic acids. Both in vivo and vitro experiments demonstrated that XMTM upregulated Arg1 and S100A10 expression but downregulated C3 and iNOS, activated the PINK1/Parkin signaling pathway, and induced mitophagy in astrocytes. However, these beneficial effects of XMTM serum were abolished by si-PINK1 and mdivi-1.
    CONCLUSION: XMTM decoction exerts its neuroprotective effects in AIS rats by targeting the PINK1/Parkin-mediated mitophagy pathway, which subsequently promotes the polarization of astrocytes toward the neuroprotective A2 phenotype.
    Keywords:  Acute ischemic stroke; Astrocyte polarization; Mitophagy; Xumingtongmai decoction; the PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.brainres.2026.150203
  10. Int Dent J. 2026 Feb 07. pii: S0020-6539(26)00004-3. [Epub ahead of print]76(2): 109408
    Effect of Mitophagy on the Tension-Driven Osteogenic Differentiation of Periodontal Ligament Stem Cells During Ageing.
    Chuhan Peng, Yidan Zhang, Linna Bai, Xinyu Zhang, Bowen Xu, Kai Yang.
       OBJECTIVES: Age-related differences in orthodontic tooth movement (OTM) and mechanical force-induced osteogenesis have been reported. Mitophagy plays a crucial role in bone metabolism and various age-related diseases, and BCL2-interacting protein 3 (BNIP3) is a mitophagy-related receptor. This study aimed to elucidate the role of mitophagy associated with BNIP3 on age-related changes in the orthodontic tension-driven osteogenic differentiation of periodontal ligament stem cells.
    MATERIALS AND METHODS: Periodontal ligament stem cells (PDLSCs) from adolescent (6-week-old) and adult (8-month-old) rats were cultured and stretched using a Flexcell system. The effects of mitophagy associated with BNIP3 were assessed via real-time quantitative PCR and western blot analyses. Moreover, a rat model of OTM across different ages was established for in vivo analyses. The function of mitophagy in age-related osteogenic differentiation induced by orthodontic force on the tension side was evaluated via microcomputed tomography and immunohistochemistry analyses.
    RESULTS: Under tension, the expression of the mitophagy factor BNIP3, the autophagy factor microtubule-associated protein light chain 3 (LC3), and the osteogenic factors Runt-related transcription factor 2 (RUNX2) and Osterix (OSX) significantly increased in rPDLSCs over time. The expression of these factors was also upregulated in the rat OTM model under orthodontic force. Compared with the adolescent group, the adult group exhibited lower levels of mitophagy and osteogenic differentiation after tension both in vivo and in vitro. Enhanced mitophagy induced by carbonyl cyanide m-chlorophenyl hydrazone upregulated the expression of the aforementioned factors in an adult rat OTM model.
    CONCLUSIONS: Mitophagy is associated with osteogenic activity induced by tension force in PDLSCs and may play a substantial role in regulating age-related changes in the OTM process.
    Keywords:  Age-related changes; BNIP3; Mitophagy; Orthodontic tension force; Periodontal ligament stem cells
    DOI:  https://doi.org/10.1016/j.identj.2026.109408
  11. Chin Med. 2026 Feb 09. 21(1): 65
    Bridging tradition and modernity: mitochondrial dynamics as a Traditional Chinese Medicine therapeutic target in cardiovascular disease.
    Chengyu Du, You Yu, Meng Li, Jin Zhou, You Wang, Xuefeng Guo, Huan Zhang, Zheng Li, Yelei Han, Min Pang, Rui Yu.
       BACKGROUND: A pathological link exists between mitochondrial fission/fusion imbalance and cardiovascular disease (CVD). Traditional Chinese Medicine (TCM), based on concepts such as "Qi stagnation and blood stasis" and "Yin-Yang imbalance," helps balance mitochondrial function through the combined effects of multiple components, providing a comprehensive treatment approach for CVD.
    AIMS OF THE STUDY: To methodically clarify the molecular processes by which TCM formulations, extracts, and bioactive compounds target mitochondrial dynamics to intervene in CVD over the past five years, highlighting their ethnopharmacological significance in "multi-component and multi-target" synergistic actions.
    METHODS: This study searched PubMed, Web of Science, Wanfang, and VIP databases (2019-2024), using the Boolean search formula: ("cardiovascular disease" OR "CVD") AND ("mitochondrial dynamics" OR "mitochondrial fission" OR "mitochondrial fusion") AND ("Traditional Chinese Medicine" OR "TCM") AND ("active compounds" OR "bioactive components"). After deduplication with EndNote, 183 articles were systematically screened and included, comprising in vitro experiments using cardiomyocyte models, in vivo studies based on animal models of CVD, and mechanistic investigations utilizing ex vivo tissues or cellular experiments (all human clinical trials were excluded).
    RESULTS: Formulations such as Buyang Huanwu Decoction (BYHWD) and Qishen Yiqi Dropping Pills (QSYQ) improved heart conditions by reducing dynamin-related protein 1 (Drp1) overactivity and increasing mitofusin 2 (Mfn2) and optic atrophy 1 (OPA1) levels. Bioactive compounds, such as salidroside(Sal), prevented Drp1 from causing mitochondria to split apart by activating the AMP-activated protein kinase(AMPK)/Sirtuin 1(SIRT1) pathway, while astragaloside IV facilitated better mitochondrial fusion to enhance energy utilization.
    CONCLUSION: TCM manages mitochondria dynamics through multi-target mechanisms, connecting "overall treatment" with "specific targeting" for heart disease therapy. Further ethnopharmacological translation requires standardized screening of bioactive components and the development of innovative drug delivery systems. The study suggests a "Traditional Chinese Medicine-Mitochondrial Dynamics Intervention Model (TCM-MDIM)," which combines organelle-level mitochondrial regulation with the principle of balancing blood and qi to offer novel approaches to the targeted therapy of cardiovascular disorders.
    Keywords:  Cardiovascular disease; Mitochondrial dynamics; Multi-target therapy; TCM and mitochondrial dynamics; Traditional Chinese medicine
    DOI:  https://doi.org/10.1186/s13020-025-01225-8
  12. Biol Reprod. 2026 Feb 09. pii: ioag035. [Epub ahead of print]
    DRP1 in Reproduction and Reproductive Aging.
    Cheng-Rung Huang, Yin-Hua Cheng, Yung-Chiao Chang, Pei-Ling Weng, Kuo-Chung Lan.
      Dynamin-related protein 1 (DRP1) is a central regulator of mitochondrial fission and plays a critical role in maintaining mitochondrial function, distribution, and turnover in reproductive cells. Mitochondrial integrity is essential for oocyte quality, folliculogenesis, fertilization, embryonic development, and ultimately, female reproductive longevity. In this review, we synthesize evidence from mammalian and invertebrate models to illustrate the essential roles of DRP1 in reproductive physiology and aging. Genetic deletion or pharmacologic inhibition of DRP1 results in mitochondrial clustering, energy failure, increased reactive oxygen species (ROS) production, meiotic arrest, and embryo fragmentation. Furthermore, DRP1 dysfunction has been increasingly implicated in age-associated reproductive decline due to impaired mitophagy and defective organelle crosstalk. Model systems such as mice, pigs, and C. elegans have demonstrated that DRP1 activity is modulated by metabolic and epigenetic pathways, including NAD+/sirtuin signaling and GTP metabolism. Therapeutic interventions aimed at restoring DRP1 function-including nicotinamide mononucleotide (NMN), coenzyme Q10 (CoQ10), and dietary modulation-have shown promising effects in delaying reproductive aging and improving oocyte or embryo competence in animal models. Despite the current absence of human interventional efficacy data, DRP1 is a plausible and testable target in reproductive biology, with preclinical findings indicating potential relevance to infertility treatment and reproductive aging. This review highlights DRP1 as a key target in reproductive biology, emphasizing its translational potential for treating infertility and mitigating age-related oocyte deterioration.
    Keywords:  Aging; DRP1; Fertility; Mitochondria; Oocyte; Reproduction
    DOI:  https://doi.org/10.1093/biolre/ioag035
  13. Free Radic Biol Med. 2026 Feb 05. pii: S0891-5849(26)00084-5. [Epub ahead of print]247 157-172
    MOTS-c attenuates cardiac dysfunction following high altitude exposure by promoting mitophagy.
    Zihang Feng, Yuan Xing, Jing Lou, Han Li, Ziang Zhang, Min Li, Qing Zhu, Yang Cui, Jia Li, Feng Gao, Wei Yi, Yang Sun, Xing Zhang.
      Prolonged exposure to high altitude (HA) results in a range of systemic changes, some of which, specifically for the heart, particularly cardiac changes, remain difficult to reverse after returning to low altitude. Cardiac de-acclimatization after HA exposure and its underlying mechanisms remain unclear. In this study, mice were subjected to a decompression chamber to simulate a 6000-m altitude exposure for 10 days, followed by the other 10-day de-acclimatization period at a lower altitude of 400 m. The cardiac dysfunction induced by HA exposure persisted throughout the de-acclimatization, accompanied with sustained mitochondrial dysfunction and the short peptide mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) deficiency. Exogenous supplementation of MOTS-c during de-acclimatization effectively alleviated the cardiac dysfunction post HA exposure. Mechanistically, MOTS-c activated the PTEN-induced putative kinase 1 (Pink1)/Parkin pathway, promoting mitophagy and improving mitochondrial quality. Silencing Pink1 abolished the protective effects of MOTS-c during de-acclimatization. Additionally, reduced circulating MOTS-c levels were observed in patients with high altitude heart disease and acute coronary syndrome. These results suggest that HA exposure leaves a memory of cardiac dysfunction upon return to lower altitude. This is attributed to a sustained deficiency in MOTS-c. MOTS-c maintains mitochondrial quality through promoting mitophagy, highlighting its therapeutic potential for treating HA-induced cardiac dysfunction during de-acclimatization.
    Keywords:  Cardioprotection; De-acclimatization; High altitude exposure; MOTS-C; Mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.064
  14. Front Physiol. 2025 ;16 1716765
    Role of mitophagy in breast cancer: mitophagy-apoptosis balance and reactive oxygen species play determining role.
    Lung Yiu, Yan Wah Chong, Shuyi Yan, Suk Ying Tsang.
      This review aims to present a current overview of the role of mitophagy in breast cancer progression, especially from the point of view of when the cancer is in the untreated state or under chemotherapeutic treatment. We aim to explain the apparently contradictory results as reported in numerous studies on the differential role of mitophagy in breast cancer. We propose that different levels of reactive oxygen species (ROS), and the balance between mitophagy and apoptosis under different conditions are the major reasons to explain for the "discrepancy". If the cancer cells are untreated, a medium level of ROS promotes cancer progression. Mitophagy inhibition, which leave the dysfunctional mitochondria to generate more ROS, would therefore increase cancer progression. On the other hand, if the cancer cells are undergoing chemotherapeutic treatment, the excessively high level of ROS generated would stimulate both mitophagy and apoptosis, where mitophagy would inhibit apoptosis. In this case, inhibiting mitophagy would potentiate apoptosis and therefore enhance treatment effectiveness. The molecular mechanisms underlying the regulation between mitophagy and apoptosis are also discussed in this review. In summary, the review shall provide important insights for the role of mitophagy in breast cancer. It is proposed that the identification of the molecules involved in balancing mitophagy and apoptosis, and combined therapeutic strategies are the key areas for future exploration.
    Keywords:  BNIP3; PINK1; apoptosis reversal; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphys.2025.1716765
  15. Biology (Basel). 2026 Jan 26. pii: 230. [Epub ahead of print]15(3):
    The Disrupted Mitochondrial Quality Control Network: A Unifying Mechanism and Therapeutic Target for Chemotherapy-Induced Multi-Organ Toxicity.
    Yaling Li, Ningning Ding, Xiufan Liu, Qi Si, Yong Wang, Changtian Li, Yongqi Liu.
      Chemotherapy remains a cornerstone of systemic cancer treatment, yet dose-limiting toxicities-cardiotoxicity, neurotoxicity, and nephrotoxicity-affect 40-80% of patients, interrupt 20-30% of treatment cycles, and double long-term mortality. We propose that these seemingly distinct organ toxicities converge on a single mechanism: selective disruption of the MQC network. MQC comprises five interdependent modules-biogenesis, dynamics, mitophagy, proteostasis, and the recently characterized migrasome-mediated mitocytosis-collectively maintaining ATP supply, redox balance, and Ca2+ homeostasis in high-demand tissues. Chemotherapeutics such as anthracyclines, platinum agents, and taxanes simultaneously repress PGC-1α-driven biogenesis, hyperactivate Drp1-mediated fission, impair autophagosome-lysosome fusion, and inhibit mitocytosis, triggering mitochondrial collapse, ROS overflow, and cell death. This first-in-field review delineates organ-specific MQC pathways and catalogs druggable interventions-including small molecules, natural products, and nano-delivery systems-that restore MQC checkpoints. We present an integrated "MQC disruption-multi-organ toxicity-targeted intervention" framework, identifying Drp1 hyperactivation, late-stage mitophagy arrest, and mitocytosis inhibition as core therapeutic nodes. Targeting these pathways offers a promising strategy to decouple anticancer efficacy from off-target toxicity, potentially enabling optimized dosing, reducing treatment discontinuation, and improving long-term prognosis. Most MQC-targeted agents, however, remain in preclinical or early-phase trials.
    Keywords:  active compounds; chemotherapy toxicity; mitochondrial quality control system; multi-target therapy; organ protection
    DOI:  https://doi.org/10.3390/biology15030230
  16. ACS Nano. 2026 Feb 10.
    Biomimetic Selenium-Encrusted Prussian Blue Nanozyme for Myocardial Infarction by Coordinated Enhancement of Mitophagy and Reactive Oxygen Species Scavenging.
    Hao Ling, Annan Liu, Yu Zhang, Quan Lin, Chunli Song.
      The vicious cycle between reactive oxygen species (ROS) burst and impaired mitochondria represents a core pathological driver in myocardial infarction (MI). Synergistically promoting ROS scavenging and enhancing mitophagy to achieve dual restoration of redox homeostasis and energy metabolism are crucial for the effective treatment of MI. To address this, we developed a biomimetic sesame cube-shaped selenium-doped Prussian blue nanozyme (SP) featuring Se0/Fe2+/Fe3+ active sites. By leveraging the superoxide dismutase (SOD)-like activity of the nanozyme, superoxide anions (·O2-) are converted into hydrogen peroxide (H2O2). Simultaneously, the material's catalase (CAT)-mimetic activity further decomposes the resulting H2O2 into oxygen (O2) while cooperatively activating PINK1/Parkin-mediated mitophagy via selenium-enhanced electron transport. The nanozyme was subsequently integrated into a hydrogel to form the SP@Gel through dynamic Schiff base cross-linking between aldehyde-modified hyaluronic acid and amine-functionalized nanozyme. Upon injection into the infarcted myocardium, this hydrogel enables the sustained release of nanozymes. The SP@Gel exhibits excellent capabilities in promoting ROS scavenging and mitigating oxidative damage, thereby improving myocardial redox homeostasis. Furthermore, the SP@Gel enhances cardiac mitophagic flux and regulates this process via the PTEN-induced putative kinase 1 (PINK1)/Parkin/microtubule-associated protein 1 light chain 3 beta (LC3B) pathway, facilitating the restoration of mitochondrial structure and energy metabolism. These findings were further validated by metabolomics analyses. SP@Gel injection mediated remodeling of the MI microenvironment, resulting in significantly reduced infarct size, suppressed fibrosis, enhanced angiogenesis, and substantially improved cardiac function. This integrated nanozyme-hydrogel system represents a promising therapeutic strategy for MI, achieving synergistic treatment through the dual regulation of oxidative stress and mitochondrial quality control.
    Keywords:  biomimetic; enhancement of mitophagy; myocardial infarction; prussian blue; reactive oxygen species scavenging; selenium
    DOI:  https://doi.org/10.1021/acsnano.5c17071
  17. Sci Rep. 2026 Feb 10.
    Isoflurane aggravates pre-existing proteotoxicity in adult nematodes by suppressing mitochondrial fitness.
    Tayir Elami, Huadong Zhu, Reut Bruck-Haimson, Vijigisha Srivastava, Adam Zaretsky, Irit Cohen, Einav Gross, Ehud Cohen.
      Post operative delirium (POD) is an acute complication, characterized by fluctuating attention and confusion, which may develop and persist into cognitive decline. POD is most commonly observed in elderly patients, particularly those with preexisting cognitive impairments. Isoflurane, a widely used volatile anesthetic, is associated with POD. However. how exposure to isoflurane affects the integrity of the proteome is largely obscure. Utilizing the nematode C. elegans, we found that isoflurane leads to a long-lasting decline in protein homeostasis (proteostasis) of adult animals that express neurodegeneration-causing, abnormally long poly-glutamine stretches. Isoflurane-induced proteostasis impairments are dependent on the aging-regulating transcription factors DAF-16/FOXO and SKN-1/NRF, and can be alleviated by the knockdown of certain components of the mitophagy mechanism. Accordingly, induction of mitochondrial biogenesis protects worms that are challenged by protein aggregation from isoflurane-induced proteotoxicity. Our observations provide novel insights into the mechanism that links isoflurane, proteotoxicity and POD, and highlight the potential of mitophagy modulators as alleviators of POD.
    Keywords:   C. elegans ; Aging; Isoflurane; Mitochondria; Proteostasis; Volatile anesthetics
    DOI:  https://doi.org/10.1038/s41598-026-38591-8
  18. Int Immunopharmacol. 2026 Feb 09. pii: S1567-5769(26)00187-6. [Epub ahead of print]174 116343
    Distinct roles of PINK1 autophosphorylation in neonatal hypoxia with or without convulsions.
    Yujie Zhai, Xiaoqian Wang, Hua Zhou, Yunrong Zhang, Qiaoyun Wang, Wenxiao Cao, Mengshuang Liu, Anqing Gao, Hongliu Sun.
      This study explored the distinct roles of PINK1 in neonatal hypoxia with and without convulsions. Various models of hypoxia with different severities have been established using neonatal C57BL/6 J mice. In addition, short hairpin RNA (shRNA) interventions targeting translocase of the outer mitochondrial membrane 7 or mitochondrial ATPase associated with diverse cellular activities, such as protease 1 homolog, inhibitor, and promoter of PINK1 autophosphorylation, were administered to modulate PINK1 activity levels. After exposure to severe hypoxia (15 min) that induced convulsions, phosphorylated PINK1 levels increased, accompanied by enhanced mitophagy, increased mitochondrial reactive oxygen species, neuronal damage and elevated epileptic susceptibility. Moreover, inhibition of PINK1 phosphorylation alleviates oxidative stress injury and reduces epileptic susceptibility, whereas enhancement of PINK1 phosphorylation aggravates oxidative stress damage. PINK1-induced mitophagy and oxidative stress injury were also elevated following mild hypoxia (130 s), without convulsions. However, unlike the 15-min hypoxic condition, either increasing or suppressing PINK1 phosphorylation via shRNA intervention exacerbated hypoxia-induced injury. These findings suggest that excessive phosphorylated PINK1 levels following severe hypoxia with convulsions, promote neuronal injury and increase epileptic susceptibility. In contrast, moderate PINK1 phosphorylation, induced by mild hypoxia without convulsions, exerts neuroprotective effects. Overall, this study elucidates the dual roles of PINK1 autophosphorylation in neonatal hypoxia with and without convulsions, and provides a theoretical basis for the therapeutic modulation of PINK1 activity in neonatal hypoxia.
    Keywords:  Epileptic susceptibility; Mitophagy; Neonatal hypoxia; Neuronal injury; Oxidative stress; PINK1
    DOI:  https://doi.org/10.1016/j.intimp.2026.116343
  19. Nat Plants. 2026 Feb 10.
    Mitochondrial fusion safeguards stomatal defence in plants.
      
    DOI:  https://doi.org/10.1038/s41477-026-02233-8
  20. Prog Neuropsychopharmacol Biol Psychiatry. 2026 Feb 11. pii: S0278-5846(26)00037-0. [Epub ahead of print] 111641
    The role of mitochondrial autophagy activated NLRP3 inflammasome in postpartum depression-like behaviors induced by stress during pregnancy.
    Jiaqi Li, Ye Li, Yanxia Zhang, Hongyu Li, Can Liu, Yunyun Du, Mengjun Chang, Suzhen Guan.
      Postpartum depression is a severe mental disorder affecting approximately 10% to 20% of women after childbirth, yet the physiological mechanism behind this is poorly understood. The NLRP3 inflammasome is pivotal in neuroinflammatory and neural disorders. It undergoes a dual modulation by mitochondrial autophagy during its activation phase, and its role in the occurrence and development of postpartum depression is worth exploring. A model of chronic stress during pregnancy in rats was established by subjecting the animals to chronic unpredictable mild stress (CUMS) starting from the third day of mating to evaluate the direct effect of pregnant stress on PPD and explore the mechanism. After rat model was established, the emotional function was observed by Open-field test (OFT), Sucrose preference test (SPT), Tail suspension test (TST), Forced swimming test (FST), mitophagy and NLRP3 inflammasome activation determined by ELISA and Western Blotting. The results showed that rats exposed to chronic stress during pregnancy exhibited postpartum depression-like behaviors such as anxiety, anhedonia, and despair. Significant neuronal damage from chronic stress was observed in the hippocampal CA1 region and the pyramidal cell layer of the prefrontal cortex, with disrupted mitochondrial structures. Accumulations of autophagosomes were found in the hippocampal CA1 region, and there was a decrease in mitochondrial membrane potential. The expression of NLRP3 inflammasome-related proteins and the expression of its downstream inflammatory cytokines IL-1β and IL-18 were both increased. Overall, our results highlighted that postpartum depression of chronic stress was closely associated with various stress factors experienced during pregnancy. During the onset and progression of PPD, stress led to impaired mitochondrial autophagy, and the incomplete clearance of damaged mitochondria activated the NLRP3 inflammasome, triggering an inflammatory response.
    Keywords:  Mitochondrial autophagy; NLRP3; Neuroinflammation; Postpartum depression; Stress during pregnancy
    DOI:  https://doi.org/10.1016/j.pnpbp.2026.111641
  21. J Ethnopharmacol. 2026 Feb 11. pii: S0378-8741(26)00218-7. [Epub ahead of print] 121367
    Haikun Shenxi Capsule Alleviates Alzheimer's Disease by Targeting Mitophagy to Clear Turbidity Toxin.
    Shan He, Xian-Jun Fu, Yan-Hua Sun, Ping Zhou, Song Zhang, Zhen-Guo Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: "Turbidity toxin damages brain" has been identified as a critical etiopathogenetic mechanism in Alzheimer's disease (AD). Haikun Shenxi Capsule (HKSX), a traditional Chinese medicine (TCM) formula with efficacy in dissolving turbidity and eliminating toxicant, is clinically used for chronic renal failure (CRF).
    AIM OF THE STUDY: Based on the TCM theory of "treating different diseases with the same therapy", this study aimed to investigated the neuroprotective effects and molecular mechanisms of HKSX on AD.
    MATERIALS AND METHODS: SAMP8 mice and N2aApp695 cells were used as AD models, behavioral, pathological assessments, as well as metabolomics, transmission electron microscopy (TEM), immunofluorescence (IF), immunohistochemistry (IHC) and western blot analyses, were conducted to validate HKSX's therapeutic effects and underlying mechanisms on AD.
    RESULTS: Behavioral testing results showed that HKSX significantly improved learning and memory impairments of SAMP8 mice in novel object recognition (NOR) test and Morris Water Maze (MWM) test, along with reduced levels of Aβ and p-Tau at Thr231 in hippocampus. In metabolomics profiling, HKSX was demonstrated to modulate 73 metabolites and key metabolic pathways, including unsaturated fatty acid biosynthesis, tricarboxylic acid (TCA) cycle, and D-glutamine/D-glutamate metabolism, which are closely related with mitochondria. TEM showed that HKSX improved mitochondrial swelling and cristae rupture in SAMP8 mice, accompanied by increased autolysosomes. HKSX also enhanced mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels, reduced reactive oxygen species (ROS) content, suggesting that it significantly improved mitochondrial structure and function. IHC showed that HKSX administration significantly increased PINK1-positive staining. IF double-labeling results indicated that HKSX promoted the co-localization of Parkin-Tom20, LC-3-LAMP, and mitochondria-lysosomes, providing direct evidence of mitophagy activation. However, inhibition of mitophagy with Mdivi-1 abrogated HKSX-induced activation of PINK1-Parkin signaling, blocked clearance of turbidity toxins, such as Aβ, p-Tau and ROS, and suppressed autophagosome formation in N2a/APP695 cells, confirming that HKSX-mediated neuroprotection is mitophagy-dependent.
    CONCLUSIONS: This study established that HKSX alleviated AD-like pathological features and cognitive deficits by activating PINK1-mediated mitophagy pathway. These results suggest that mitophagy may be involved in the cellular process of "eliminating turbidity toxins and detoxification," which provide a novel therapeutic angle for exploring TCM remedies that resolve turbidity in the treatment of AD.
    Keywords:  Alzheimer' disease; Haikun Shenxi capsule; PINK1; mitophagy; turbidity toxin damages brain
    DOI:  https://doi.org/10.1016/j.jep.2026.121367
  22. J Ethnopharmacol. 2026 Feb 07. pii: S0378-8741(26)00174-1. [Epub ahead of print]362 121323
    Modified Banxia Xiexin Decoction promotes mitochondrial fission in colon cancer cells by inhibiting the CHD6-TMEM65 axis.
    Zihong Wu, Chong Xiao, Xueke Li, Fengming You, Li Su.
       ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine Banxia Xiexin Decoction (BXD) and its modified version (mBXD) are traditional polyherbal formulations used to treat gastrointestinal diseases. Increasing evidence indicates that mBXD exhibits distinct anti-cancer properties; however, the mechanisms through which it modulates mitochondrial dynamics to inhibit colon cancer remain unclear.
    AIMS OF THE STUDY: To investigate the mechanisms by which mBXD suppresses colon cancer by regulating mitochondrial fusion-fission dynamics.
    MATERIALS AND METHODS: The chemical composition of mBXD was analyzed using UPLC-MS/MS. A subcutaneous CT26 colon cancer model was established and treated with mBXD. mBXD drug-containing serum was prepared and applied to HCT116 and CT26 cells. Tumor volume, small-animal live imaging, and histopathological features were evaluated. The effects of mBXD on mitochondria were examined through mitochondrial ultrastructure analysis, JC-1 detection, and assessment of ATP concentration and ROS levels. WB and qPCR were performed to determine the expression of molecules associated with the CHD6-TMEM65 axis and mitochondrial dynamics.
    RESULTS: The main components of mBXD were identified as flavonoids and alkaloids. These compounds significantly inhibited tumor growth, with higher concentrations of mBXD drug-containing serum reducing the survival, invasion, and migration of HCT116 and CT26 cells. Moreover, mBXD markedly promoted mitochondrial fission in cancer cells, reduced ATP levels, and induced ROS accumulation. It significantly upregulated DRP1 expression while inhibiting CHD6 and TMEM65, with no notable effect on OPA1.
    CONCLUSIONS: The chemical constituents of mBXD mainly comprise flavonoids and alkaloids. These components markedly inhibit the growth of subcutaneous tumors in CT26 colon cancer-bearing mice and suppress the viability, invasiveness, and migratory capacity of HCT116 and CT26 cells. The underlying mechanism may involve the promotion of mitochondrial fission in cancer cells through inhibition of the CHD6-TMEM65 axis, ultimately leading to apoptosis. Nonetheless, the present study has certain limitations. The precise mechanisms by which mBXD induces mitochondrial fission and inhibits the CHD6-TMEM65 axis warrant further investigation in future research.
    Keywords:  CHD6-TMEM65 axis; Colon cancer; Mitochondrial fusion—fission dynamics; Modified Banxia Xiexin Decoction
    DOI:  https://doi.org/10.1016/j.jep.2026.121323
  23. Phytomedicine. 2026 Jan 22. pii: S0944-7113(26)00019-X. [Epub ahead of print]153 157782
    Afzelin resists UVA damage through autophagy and synergizes with ganoderic acid A to skin photoaging.
    Jia-Hua Zou, Mei-Ling Tai, Bao-Ying Li, Jian-Jun Liu, Zhi-Meng Zhang, Han Wang, Dong-Li Zhang, Zhuang Zhou, Shan-Shan Feng, Man-Mei Li, Zhong Liu.
       BACKGROUND: Chronic UVA exposure accelerates photoaging by inducing oxidative stress and mitochondrial dysfunction. Autophagy maintains dermal homeostasis, but its decline promotes aging. Afzelin, a flavonoid with antioxidant activity, has not been fully studied for its autophagy-related photoprotective effects.
    PURPOSE: To determine whether afzelin protects against UVA-induced photoaging through autophagy and mitophagy activation, and to assess its synergy with ganoderic acid A (GAA), a triterpenoid possessing established anti-aging activity.
    METHODS: UVA-irradiated and D-galactose-induced senescence models of human dermal fibroblasts were examined by Western blotting, immunofluorescence, and flow cytometry. A 20-day UVA mouse model evaluated topical efficacy. Synergy was calculated using the Bliss model.
    RESULTS: Afzelin restored UVA-impaired cell viability and reduced β-galactosidase, p53, and p21 while recovering Lamin B1. It lowered ROS levels and restored mitochondrial membrane potential (2.8-fold) via AMPK-AKT/mTOR-ULK1 and PINK1-Parkin activation. Combined with GAA (50 mM), afzelin showed strong synergy (Bliss = 67.6 ± 5.1). In vivo, co-treatment reduced epidermal thickness (∼37.3 %), restored collagen I and elastin, and suppressed p53/p21 expression.
    CONCLUSION: Afzelin alleviates UVA-induced photodamage by activating autophagy and mitophagy. Together with the anti-aging triterpenoid GAA, it exerts synergistic anti-photoaging effects, supporting its potential as a natural autophagy-targeting agent for skin rejuvenation.
    Keywords:  Afzelin; Autophagy; Ganoderic acid A; Mitophagy; Photoaging; UVA
    DOI:  https://doi.org/10.1016/j.phymed.2026.157782
  24. PLoS Pathog. 2026 Feb 12. 22(2): e1013975
    The UBC/SIRT5/DRP1 axis regulates mitochondrial dynamics to alleviate Staphylococcus aureus-induced oxidative stress and senescence in bovine mammary epithelial cells.
    Huijie Hu, Naiyuan Jiang, Juxiong Liu, Junlong Bi, Xuanting Liu, Bin Xu, Yu Cao, Wenjin Guo, Shoupeng Fu.
      Staphylococcus aureus (S. aureus)-driven senescence of bovine mammary epithelial cells is a key determinant of mammary gland health, yet its molecular basis remains poorly defined. Sirtuin 5 (SIRT5), a mitochondria-localized desuccinylase, may play an important regulatory role in this process. This study aimed to elucidate the mechanisms by which S. aureus drives cellular senescence and to define the contribution of the SIRT5-mitochondrial axis to delaying senescence. We found pronounced oxidative stress and cellular senescence in mammary tissues from cows with S. aureus mastitis, accompanied by marked downregulation of SIRT5. In an S. aureus-infected epithelial cell model, infection induced mitochondrial stress characterized by excessive mitochondrial fragmentation, loss of membrane potential, and increased mitochondrial superoxide, along with oxidative damage and cellular senescence. Mechanistically, S. aureus toxins and the toxin-induced inflammatory response cooperatively drove mitochondrial stress, which in turn increased intracellular bacterial burden and exacerbated cell death. During infection, SIRT5 protein abundance was significantly reduced. Mass spectrometry and co-immunoprecipitation analyses indicated that infection upregulated the ubiquitin-conjugating enzyme ubiquitin C (UBC), enhanced its interaction with SIRT5, and promoted ubiquitin-mediated degradation of SIRT5. Loss of SIRT5 increased succinylation of dynamin-related protein 1 (DRP1), inhibited its ubiquitin-mediated degradation, and led to its excessive accumulation on the outer mitochondrial membrane, thereby promoting excessive mitochondrial fission. Functionally, SIRT5 overexpression markedly alleviated mitochondrial stress, oxidative damage, and senescence phenotypes. When mitochondrial fission was forcibly enhanced, the cytoprotective effect of SIRT5 was substantially weakened, confirming that SIRT5 acts through a pathway dependent on mitochondrial integrity. Collectively, S. aureus infection releases toxins and induces inflammatory injury, during which UBC-mediated SIRT5 degradation activates DRP1-dependent mitochondrial hyper-fragmentation, aggravating mitochondrial stress, oxidative stress, and mammary epithelial cell senescence. These findings identify SIRT5 as a critical regulator of redox and mitochondrial homeostasis in mammary epithelial cells and a potential therapeutic target for mitigating oxidative damage associated with bovine mastitis.
    DOI:  https://doi.org/10.1371/journal.ppat.1013975
  25. Int J Mol Sci. 2026 Jan 30. pii: 1390. [Epub ahead of print]27(3):
    Endoplasmic Reticulum Stress Induced by Turbulence of Mitochondrial Fusion and Fission Was Involved in Isoproterenol-Induced H9c2 Cell Injury.
    Shengnan Zhang, Liqin Chen, Fuquan Jia, Shuguang Zhang, Huimin Zhang, Weibo Shi, Bin Cong.
      Alterations in mitochondrial fusion and fission dynamics are critical determinants of cellular fate. However, how stress-induced mitochondrial fusion and fission affect the physiological and pathological processes in cardiomyocytes remains poorly understood. Based on an established in vitro model of stress-induced cardiomyocyte injury using isoproterenol-treated H9c2 cells, this study aimed to investigate whether the dysregulation of mitochondrial dynamics-specifically, an imbalance between fusion and fission-activates the IRE1α-ASK1-JNK endoplasmic reticulum stress signaling pathway, thereby contributing to cardiomyocyte damage. Under this experimental paradigm, cell viability was evaluated using the CCK-8 assay. Concurrently, immunofluorescence staining was employed to assess reactive oxygen species accumulation, the expression of key mitochondrial fusion/fission proteins, and components of the ER stress pathway (IRE1α, ASK1, and JNK). Results demonstrated that isoproterenol treatment elevated intracellular ROS levels and induced significant changes in both mitochondrial dynamics-related proteins and the IRE1α-ASK1-JNK signaling axis. In contrast, administration of the mitochondrial fission inhibitor Mdivi-1 attenuated ROS accumulation, restored the expression of the affected proteins toward normal levels, and alleviated cardiomyocyte injury. Collectively, these findings indicate that the disruption of mitochondrial fusion/fission dynamics triggers endoplasmic reticulum stress via the IRE1α-ASK1-JNK cascade, which participates in the pathological progression of cardiomyocyte injury.
    Keywords:  ISO; cardiomyocyte injury; endoplasmic reticulum stress; mitochondria fission; mitochondria fusion
    DOI:  https://doi.org/10.3390/ijms27031390
  26. J Hazard Mater. 2026 Feb 06. pii: S0304-3894(26)00293-1. [Epub ahead of print]504 141315
    Mitophagy dynamics during oxidative to reductive stress shift potentiates arsenite-induced malignant transformation potential in human keratinocytes.
    Qianlei Yang, Xingrun Li, Qi Kong, Yuqi Yang, Haixuan Xia, Rui Yan, Xiaoyun Zhang, Hui Lu, Ting Zhang, Chen Zhao, Bohan Xu, Koichi Kato, Xiaoyan Zhong, Yan An.
      Oxidative stress hypothesis of carcinogenicity from arsenic exposure is well-researched, reductive stress is increasingly emerging, and particularly, how cells undergo malignant transformation during the redox stress switch remains unclear. Herein, long-term (0-35 passages), low-dose (1.0 μM) sodium arsenite (NaAsO2) exposure induces redox stress transition from oxidative to reductive stress in immortalized human keratinocytes (HaCaT) cells, driving malignant transformation via nuclear factor erythroid-2 related factor 2 (NRF2)-mediated PTEN-induced putative kinase 1 (PINK1)-PARK2 encoded E3 ubiquitin ligase (Parkin)-dependent mitophagy dynamics. Initially, NaAsO2 elevates reactive oxygen species (ROS) to induce oxidative stress, but prolonged exposure reduces ROS while increasing reducing equivalents to form reductive stress at the cellular and mitochondrial levels. Sustained NRF2 activation post-ROS stimulation initiates mitophagy with a progressive enhancement from 42.8 % to 96 % through the PINK1-Parkin pathway, which is confirmed by inhibition with 10.0 μM cyclosporin A (CsA) or NRF2 siRNA, and activation with 10.0 μM carbonyl cyanide 3-chlorophenylhydrazone (CCCP). This study highlights NRF2 modulates the redox homeostasis in a spatiotemporal dynamic manner and mitophagy dynamics works as a core mechanism underlying arsenite-induced cell malignant transformation, offering potential developing preventive and therapeutic strategies targeting mitophagy.
    Keywords:  Arsenite exposure; Malignant transformation; Mitophagy dynamics; Redox shift; Spatiotemporal modulation
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141315
  27. Clin Exp Pharmacol Physiol. 2026 Feb;53(2): e70105
    Ddx17 Mitigates Sepsis-Induced Cardiomyopathy by Regulating Mitochondrial Dynamics in Cardiomyocytes.
    Ya-Ting Jiang, Li-Ran Su, Fang-Jing Ni, Luo-Ye Lu, Yu-Qiang Gong, Jun Luo, Chen-Xi Shen, Yang Cao.
      Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, in which mitochondrial dysfunction contributes to poor outcomes. DEAD-box helicase 17 (Ddx17), a member of the DEAD-box RNA helicase family, is known to regulate mitochondrial function, but its role in SICM remains unclear. In this study, mice with cardiomyocyte-specific Ddx17 knockdown (Ddx17-cKD) and overexpression (Ddx17-OE) were generated, and sepsis models were established using cecal ligation and puncture. Mechanistic findings were further validated in vitro using immunoprecipitation and dual-luciferase assays. Ddx17 expression was markedly reduced in the cardiac tissues of septic mice and in lipopolysaccharide-treated cardiomyocytes. Knockdown of Ddx17 increased mitochondrial reactive oxygen species accumulation, enhanced cell death and decreased superoxide dismutase activity. In contrast, Ddx17 overexpression attenuated mitochondrial apoptosis and oxidative stress, restored adenosine triphosphate production and mitochondrial membrane potential and improved cardiac function in septic mice. Mechanistically, Ddx17 interacted with signal transducer and activator of transcription 3 (STAT3) to suppress transcription of the mitochondrial fission protein dynamin-related protein 1 while maintaining the level of the fusion protein mitofusin 1, thereby preserving mitochondrial integrity and cardiomyocyte homeostasis. These findings demonstrate that Ddx17 protects against sepsis-induced cardiomyopathy by regulating mitochondrial dynamics, reducing oxidative stress and preventing apoptosis, thereby highlighting Ddx17 as a potential therapeutic target for septic cardiac dysfunction.
    Keywords:  Ddx17; STAT3; mitochondrial dynamics; oxidative stress; sepsis‐induced cardiomyopathy
    DOI:  https://doi.org/10.1111/1440-1681.70105
  28. J Nutr. 2026 Feb 11. pii: S0022-3166(26)00054-4. [Epub ahead of print] 101405
    IN-UTERO PROTEIN DEFICIENCY LEADS TO IMPAIRED HEPATIC LIPID METABOLISM IN ADULT MALE RATS.
    Vipin A Vidyadharan, Chandrasekhar Yallampalli, Chellakkan S Blesson.
       BACKGROUND: In-utero exposure to a low-protein (LP) diet is a well-established model of developmental programming linked to increased risk of chronic metabolic diseases, including lean Type 2 Diabetes (T2D).
    OBJECTIVE: In this study, we investigated the long-term effects of maternal LP diet on hepatic lipid metabolism and mitochondrial dynamics in adult lean T2D male rat offspring.
    METHODS: Pregnant Wistar rats were fed either a control (20% protein) or isocaloric low-protein (6% protein) diet during gestation, and male offspring were examined in adulthood. Hepatic lipid accumulation, mitochondrial function, and related signaling pathways were analyzed using integrated histological, metabolomic, and molecular methods. Student's t-test and two-way ANOVA were used for statistical analyses.
    RESULTS: In LP-programmed livers, Oil Red O staining and TEM revealed increased lipid accumulation, with a 55% increase in lipid droplet area compared with controls. Further, relative levels of carnitine and acylcarnitines were elevated (carnitine 66%, deoxycarnitine 33%, glutarylcarnitine 37%, malonylcarnitine 44%, methylglutarylcarnitine 83%; p ≤ 0.05), consistent with disrupted fatty-acid handling. Transcriptionally, β-oxidation genes (Acadm, Acads, Cact) were ∼2-fold downregulated, and the lipogenic gene Acaca was ∼1.5-fold upregulated (p ≤ 0.05), indicating a shift toward lipid synthesis and reduced mitochondrial fatty-acid oxidation. TCA-cycle intermediates were lower (p ≤ 0.05) in LP, with citrate (∼2.5-fold), succinate (∼1.5-fold), and malate (∼1.2-fold), suggesting impaired oxidative metabolism. Mitochondrial remodeling was evident with increased OPA1 (115%) and decreased FIS1 (35%), alongside reduced mitophagy regulators LC3B (45%) and BNIP3L (41%) (all, p ≤ 0.05), suggesting compromised mitochondrial quality control. mtDNA copy number was unchanged, but multiple PKC isoforms were increased (p ≤ 0.05), consistent with altered intracellular insulin signaling.
    CONCLUSION: Our findings collectively demonstrate that in-utero protein restriction induces persistent impairments in hepatic mitochondrial function and lipid metabolism, contributing to the developmental origins of insulin resistance and metabolic dysfunction.
    Keywords:  Developmental Origins of Health and Disease; Lipid Accumulation; Metabolically Dysfunctional-Associated Steatotic Liver Disease; Mitochondrial dysfunction; Mitophagy; β-oxidation
    DOI:  https://doi.org/10.1016/j.tjnut.2026.101405
  29. Biochim Biophys Acta Mol Basis Dis. 2026 Feb 06. pii: S0925-4439(26)00035-9. [Epub ahead of print]1872(4): 168187
    Adipose-derived mesenchymal stem cell exosomes enhance diabetic wound healing via the amelioration of fibroblast senescence through the SMARCAL1-Drp1 signaling pathway.
    Hang Wu, Xuan Jiang, Jieyun Cai, Changhong Li, Xihang Yuan, Yifeng Huang, Yang Xiong, Xiangdong Qi, Chiyang Li.
      Delayed healing of diabetic wounds (DW) represents a significant complication among diabetic patients, for which current therapeutic approaches remain suboptimal. Accumulating evidence indicates that fibroblast senescence plays a critical role in the impaired healing of diabetic wounds. Abnormal mitochondrial morphology has long been associated with cellular senescence and age-related pathologies, suggesting that mitochondrial dynamics are compromised during senescence. In this study, we explored the potential mechanisms through which adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) facilitate diabetic wound repair. We initially confirmed the presence of a substantial number of senescent fibroblasts in diabetic wound tissues. Subsequent investigations demonstrated that exosomes derived from adipose-derived stem cells can effectively alleviate fibroblast senescence. In-depth mechanistic analyses revealed that these exosomes suppress the expression of SMARCAL1, a chromatin remodeling protein, thereby enhancing the transcription of mitochondrial dynamin-related protein 1 (Drp1), and ultimately restoring mitochondrial dynamics and alleviating senescence in human dermal fibroblasts (HDFs). In vivo experiments further demonstrated that exosome administration significantly reduced HDFs senescence and accelerated wound healing in a diabetic mouse model. Collectively, our findings suggest that ADSC-Exos promote diabetic wound healing by mitigating HDFs senescence via the SMARCAL1-Drp1-mitochondrial dynamics pathway. This study elucidated the molecular mechanisms underlying exosome-mediated fibroblast senescence rescue and proposed a novel therapeutic strategy for diabetes-related wound management through targeted clearance of senescent cells.
    Keywords:  Adipose-derived mesenchymal stem cell-derived exosomes; Cellular senescence; Chromatin remodeling; Diabetic wounds; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168187
  30. APMIS. 2026 Feb;134(2): e70157
    XIST Improves Mitophagy and Exerts Perioperative Myocardial Protection Through miR-212-3p/CALCOCO2/OPTN.
    Lili Zhou, Hang Qi, Liping Zhu, Dongcai Feng.
      Acute coronary syndrome (ACS) is a high-risk disease among cardiovascular diseases. This study is to screen for lncRNA ceRNA regulatory network in acute coronary syndrome associated with percutaneous coronary intervention (PCI) and to validate the XIST/miR-212-3p/CALCOCO2/OPTN axes. lncRNA, miRNA, and mRNA expression microarray data were retrieved and downloaded from the GEO database. Dysregulated lncRNAs and miRNAs were collected using the GEO database. Target genes were predicted and subjected to KEGG pathway analysis. The serum levels of lncRNA XIST, miR-212-3p, CALCOCO2, and OPTN were detected by RT-qPCR. The H9C2 hypoxia-reoxygenation (H/R) injury model was established. The cell viability was detected. The related indicators of mitophagy were detected by flow cytometry and Western blot. Six PCI-related lncRNAs were identified in ACS, linked to 44 PCI-associated miRNAs and 159 PCI-associated mRNAs. KEGG pathway analysis suggested the mitophagy pathway, which involved XIST/miR-212-3p/CALCOCO2/OPTN axes. The levels of XIST, CALCOCO2, and OPTN were increased while the level of miR-212-3p was decreased in PCI patients. Taken together, our results suggest that lncRNA-miRNA-mRNA networks associated with PCI in ACS were presented. In the H/R cell model, XIST promoted mitophagy through miR-212-3p/CALCOCO2/OPTN. XIST can promote mitophagy through the miR-212-3p/CALCOCO2/OPTN axis, thereby alleviating myocardial cell injury.
    Keywords:  CeRNA network; acute coronary syndrome; lncRNA; mitophagy; percutaneous coronary intervention
    DOI:  https://doi.org/10.1111/apm.70157
  31. Cells. 2026 Feb 05. pii: 301. [Epub ahead of print]15(3):
    Integrative Machine Learning and Experimental Validation Identify FIS1 as a Candidate Biomarker Linked to Mitochondrial Dynamics in Pulmonary Hypertension.
    Yu Zhang, Qing Dai, Lijun Gong, Runxiu Zheng, Wei Huang, Feiying Wang, Rong Yuan, Lan Song, Aiguo Dai.
      Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling and a paucity of effective therapeutic interventions. Although dysregulated mitochondrial dynamics are implicated in this remodeling process, the key regulatory molecules and downstream mechanisms remain incompletely defined. This study aimed to systematically characterize molecular alterations associated with mitochondrial dynamics in PH and to explore the functional relevance and potential mechanisms of prioritized candidate genes. We integrated transcriptomic datasets from PH models with MitoCarta annotations to identify mitochondria-related differentially expressed genes. Candidate genes were prioritized using WGCNA and three machine-learning algorithms (LASSO, SVM-RFE, and random forest). These candidates were then experimentally evaluated in a hypoxia-induced PH mouse model and hypoxia-stimulated mouse pulmonary artery smooth muscle cells (mPASMCs) using qRT-PCR, Western blotting, immunohistochemistry, and transmission electron microscopy. Functional assays and assessments of mitochondrial injury were performed to investigate pathogenic relevance. Our analysis identified four key genes, with FIS1 showing high ROC/AUC-based discriminatory performance in both the training dataset and the independent replication dataset. Hypoxia was associated with increased FIS1 expression, mitochondrial fragmentation, loss of mitochondrial membrane potential, and ROS accumulation. We further observed that FIS1 knockdown suppressed mPASMC proliferation and migration, alleviated mitochondrial injury, and attenuated ferroptosis-associated alterations, accompanied by reduced lipid peroxidation, decreased Fe2+ accumulation, and partial normalization of ferroptosis-related marker proteins. Taken together, these findings suggest that FIS1 may contribute to PH pathogenesis through mitochondrial fission and ferroptosis-associated stress, potentially promoting aberrant PASMC phenotypes and pulmonary vascular remodeling. This work provides a mechanistic rationale and molecular leads that may inform molecular stratification and mechanistically informed therapeutic exploration targeting mitochondrial pathways in PH.
    Keywords:  FIS1; ferroptosis; machine learning; mitochondrial dynamics; pulmonary hypertension
    DOI:  https://doi.org/10.3390/cells15030301
  32. Chin Med J (Engl). 2026 Feb 13.
    Regulation of mitochondrial biogenesis and energy metabolism in the heart.
    Peilu She, Fei Mo, Ping Zhu, Tao P Zhong.
       ABSTRACT: Mitochondrial homeostasis is regulated by processes such as biogenesis, dynamics, and mitophagy, and is essential for maintaining cardiac function while preserving structural integrity, energy supply, and redox balance. Given their high reliance on mitochondrial adenosine triphosphate generation, cardiomyocytes are particularly vulnerable to mitochondrial dysfunction. In the cardiovascular system, mitochondria respond to various pathophysiological conditions, such as ischemia-reperfusion injury, hypertension, diabetic cardiomyopathy, and heart failure. Mitochondrial impairment drives cardiovascular disease progression through deficient energy production, elevated oxidative stress, activation of inflammatory responses, and programmed cell death. Growing evidence highlights the critical roles of epigenetic and transcriptional networks in the coordinated regulation of mitochondrial biogenesis and metabolism. Targeting these processes is a promising therapeutic strategy to improve mitochondrial health in cardiovascular diseases. This review systematically summarizes recent advances, outlines the key regulatory mechanisms of mitochondrial biogenesis and metabolism, and explores their pathophysiological roles and therapeutic potential.
    Keywords:  Epigenetics; Heart; Homeostasis; Mitochondria; Transcription
    DOI:  https://doi.org/10.1097/CM9.0000000000004011
  33. Toxicol Sci. 2026 Feb 11. pii: kfag013. [Epub ahead of print]
    Zonal Hepatocellular Responses to Acute Ethanol Consumption: Impacts on Mitochondrial Function and Liver Metabolism.
    Matthew T Savoca, Kenji Takemoto, Jiangting Hu, Li Li, Zhi Zhong, John J Lemasters.
       BACKGROUND: Hepatocellular mitochondrial depolarization (mtDepo) after ethanol (EtOH) increases respiration to stimulate EtOH detoxification. mtDepo also triggers mitophagy, which may contribute to alcohol-associated liver disease. This study characterized sublobular respiration and distribution of mtDepo and mitophagy after acute EtOH.
    METHODS: C57BL/6J and GFP-LC3 transgenic mice were gavaged with 6 g/kg EtOH or vehicle and administered MitoTracker Red (MTR). Hepatocytes were zonally sorted by MTR fluorescence for assessment of oxygen consumption rates (OCRs). Cytochrome P4502E1 (CYP2E1) immunolabeling identified central halves of liver lobules.
    RESULTS: After vehicle, MTR localized to mitochondria throughout lobules, indicating polarization, with higher OCRs in periportal (PP) hepatocytes compared to pericentral (PC). After EtOH, MTR fluorescence became diffuse in CYP2E1-positive central halves of lobules, signifying mtDepo, whereas portal halves remained polarized. GFP-LC3 puncta marking mitophagy also increased predominantly in central halves. Surface hepatocytes accessible by multiphoton microscopy were CYP2E1-positive and developed mtDepo and GFP-LC3 puncta after EtOH. After hepatocyte isolation, mtDepo reversed shown by rhodamine 123 uptake. At 6 h post-EtOH, OCRs approximately doubled in both PP and PC hepatocytes, returning to baseline by 24 h, but PC displayed greater proportional increases.
    CONCLUSIONS: Acute EtOH induces mtDepo and mitophagy predominantly in central halves of lobules, including within <50-μm of the liver surface. Although mtDepo reverses after isolation, elevated respiratory capacity persists. Due to central half mtDepo, PP and PC hepatocytes contribute about equally to the respiratory burst after EtOH.
    Keywords:  Alcohol-associated liver disease; ethanol; liver zonation; mitochondrial depolarization; mitophagy; oxygen consumption rate
    DOI:  https://doi.org/10.1093/toxsci/kfag013
  34. Environ Res. 2026 Feb 11. pii: S0013-9351(26)00346-4. [Epub ahead of print] 124018
    HFPO-TA induces cardiac developmental damage in zebrafish by disrupting mitochondrial dynamics through FABP3.
    Xing Liu, Mingzhu Xia, Xinyi Wu, Ruobing Chen, Yuting Peng, Yi Fan, Junjie Han, Yichun Zhao.
      Hexafluoropropylene oxide trimer acid (HFPO-TA), a widely used substitute for perfluorooctanoic acid (PFOA), has raised concerns about potential cardiotoxicity. The study investigated mechanisms underlying HFPO-TA-induced cardiac developmental toxicity. Network toxicology and molecular docking identified the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid-binding protein-3 (FABP3) as key targets. In zebrafish embryos, HFPO-TA exposure caused pronounced cardiac developmental toxicity, indicated by pericardial edema, increased heart rate, and downregulated cardiac development genes (gata4, nkx2.5, sox9b, vmhc). Mechanistic analyses showed that HFPO-TA upregulated FABP3 while suppressing PPARγ and its coactivator PGC-1α. These changes disrupted mitochondrial dynamics by inhibiting fusion-related factors (Mfn1, Mfn2, Opa1) and enhancing fission-related factors (Drp1, Fis1), which further promoted apoptosis. Notably, CRISPRi-mediated FABP3 knockdown alleviated cardiac malformations, improved cardiac developmental gene expression, restored PPAR pathway activity, rebalanced mitochondrial dynamics, and reduced apoptosis. Collectively, HFPO-TA induces cardiac developmental toxicity via FABP3 activation, suppression of the PPARγ/PGC-1α axis, mitochondrial dynamics imbalance, and apoptosis. FABP3 represents a pivotal regulator in HFPO-TA-induced cardiac developmental toxicity and provides toxicological evidence supporting potential intervention targets for congenital heart disease.
    Keywords:  FABP3; HFPO-TA; Heart development; Mitochondrial dynamics; Network toxicology; PPAR
    DOI:  https://doi.org/10.1016/j.envres.2026.124018
  35. Am J Cancer Res. 2026 ;16(1): 1-14
    Mitochondria-related genes or proteins affect the progression of hepatocellular carcinoma: roles, mechanisms and potential treatments.
    Nan Wu, Wenli Sai.
      Mitochondria-related genes or proteins can affect various functional indicators of mitochondria, encompassing ATP synthesis, the generation of reactive oxygen species, and the intricate process of mitochondrial autophagy. Numerous researches have unveiled a profound association between mitochondrial dysfunction and the onset, progression, and prognosis of hepatocellular carcinoma. In recent years, a large number of studies have conducted experiments on mitochondria-related genes or proteins to explore their roles and mechanisms in causing mitochondrial functional changes and thereby influencing the progression of hepatocellular carcinoma. Over the past five years, a plethora of studies have been meticulously conducted on mitochondria - related genes and proteins. The aim is to precisely define their functions and the underlying molecular mechanisms in triggering mitochondrial functional aberrations, thereby affecting the progression of HCC. This review is dedicated to comprehensively recapitulating the pertinent progress made in the past half - decade. Additionally, it will delve into how these factors can present feasible and prospective therapeutic modalities for the management of HCC.
    Keywords:  Mitochondria; hepatocellular carcinoma; mitophagy; reactive oxygen species; reactive oxygen species mitophagy
    DOI:  https://doi.org/10.62347/QKAE4855
  36. Cell Mol Life Sci. 2026 Feb 10.
    Lactiplantibacillus plantarum GUANKE ameliorates influenza a virus-induced inflammation and lung barrier dysfunction through enhancing mitophagy and improving oxidative phosphorylation.
    Simin Lu, Kun Yue, Siqin He, Jielan Mi, Tao Yang, Yuewen Yang, Hanyu Ma, Zhihong Ren, Lili Ren, Jianguo Xu.
      Pulmonary inflammatory response represents a predominant complication arising from influenza virus infections. This investigation elucidates the protective efficacy of Lactiplantibacillus plantarum GUANKE (GUANKE) supplementation against influenza A virus (IAV)-induced pulmonary damage in C57BL/6 murine models, with particular emphasis on its mechanistic underpinnings. The results showed that the use of GUANKE (5 × 109 CFU/day) or exogenous linoleic acid (a metabolite of GUANKE) supplementation (40 mg/kg) significantly attenuated inflammatory cytokine secretion while counteracting virus-mediated downregulation of pulmonary barrier proteins. Mechanistic profiling revealed that GUANKE and GUANKE-derived linoleic acid modulates mitochondrial quality control through enhanced Parkin-dependent mitophagy coupled with restored mitochondrial oxidative phosphorylation (OXPHOS) capacity, thereby providing protection in IAV-infected mice.
    Keywords:   Lactiplantibacillus plantarum GUANKE; Linoleic acid; Mitochondrial; Mitophagy; OXPHOS
    DOI:  https://doi.org/10.1007/s00018-026-06081-9
  37. Cell Stress Chaperones. 2026 Feb 10. pii: S1355-8145(26)00007-6. [Epub ahead of print] 100151
    Isopimaric Acid Derived from Torreya nucifera Blocks Autophagy and Mitophagy to Sensitize Colon Cancer Cells to Nutrient Starvation.
    Rambukkana Maggonage Thiruni Dananjana Perera, Su-Lim Kim, Ji-Hyang Kim, Kyeoung Cheol Kim, Dong-Sun Lee.
      Autophagy and mitophagy are essential survival mechanisms that enable cancer cells to adapt to metabolic stress, particularly during nutrient deprivation. Therefore, targeting these pathways presents a promising therapeutic strategy. Thus, this study aimed to investigate the potential of isopimaric acid (IPA), a diterpenoid compound derived from Torreya nucifera, to disrupt autophagy-related processes in colon cancer cells. Notably, IPA treatment promoted the accumulation of autophagosomes, as indicated by increased LC3-II and p62 protein levels, suggesting an inhibition of autophagic flux rather than an enhancement of initiation. Further analysis revealed that IPA impaired lysosomal function and blocked autophagosome degradation. IPA also suppressed mitophagy by downregulating key regulators, including PINK1 and Parkin, resulting in mitochondrial dysfunction and the accumulation of reactive oxygen species (ROS). Particularly, IPA was non-toxic under nutrient-rich conditions but induced significant cell death under serum starvation conditions. To our knowledge, these findings are the first to show that IPA selectively induces apoptotic cell death in nutrient-deprived colon cancer cells by disrupting both late-stage autophagy and PINK1/Parkin-mediated mitophagy. Furthermore, this research establishes the development of innovative therapeutic strategies that specifically target metabolic stress and combination therapy.
    Keywords:  Lysosomal dysfunction; autophagy inhibition; colon cancer; isopimaric acid; mitophagy; starvation therapy
    DOI:  https://doi.org/10.1016/j.cstres.2026.100151
  38. Free Radic Biol Med. 2026 Feb 07. pii: S0891-5849(26)00108-5. [Epub ahead of print]247 173-186
    FXR overexpression restores NLRP3-mediated mitophagy and improves mitochondrial dysfunction in alcoholic liver disease.
    Jiaqi Chen, Wenyu Wang, Xia Li, Rui Wang, Yating Xiao, Changyuan Wang, Chong Wang, Renchao Dong, Lina Hao, Qiang Meng.
      Alcoholic liver disease (ALD) is a common chronic liver disease worldwide, directly caused by excessive and prolonged alcohol consumption. To date, there are no acknowledged therapeutic approaches for treating ALD. The reason is that ALD pathogenesis is multifactorial and only partially understood. Mitochondrial dysfunction-related mitophagy and inflammation are essential factors that play critical roles in the pathogenesis and progression of ALD. The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays a well-established role in liver protection, but whether and how it counteracts ALD by regulating mitophagy remains unknown. This study aimed to demonstrate the protective effect of FXR overexpression against ethanol-induced liver injury by suppressing NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting mitophagy recovery. The mouse ALD models were established using the DeCarli liquid diet with 5% ethanol (v/v). We established FXR-overexpressing mice by intravenous injection of FXR-mediating lentivirus (LV-FXR). The results revealed that FXR expression was significantly downregulated in liver tissues of ALD patients compared to normal subjects using the Gene Expression Omnibus (GEO) database. FXR overexpression reduced the liver-to-body weight ratio and improved biochemical markers in mice. Overexpression of FXR in mice significantly alleviated ethanol-induced hepatitis, improved mitophagy, and inhibited NLRP3 inflammasome activation and the secretion of IL-18 and IL-1β. In vitro, we transfected AML-12 cells with either pcDNA-FXR or FXR siRNA plasmids before ethanol exposure. Overexpression of FXR markedly attenuated ethanol-induced mitochondrial damage and NLRP3 inflammasome activation. Conversely, FXR knockdown exacerbated both outcomes. In conclusion, FXR overexpression protects against ethanol-induced liver injury through a novel mechanism by suppressing mitochondrial damage, oxidative stress, and NLRP3 inflammasome activation.
    Keywords:  Alcoholic liver disease; Farnesoid X receptor (FXR); Mitophagy; NLRP3 inflammasome; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.012
  39. NPJ Sci Food. 2026 Feb 07.
    Lycopene mitigates T-2 toxin-induced hepatic ferroptosis by targeting the Nrf2/mitophagy axis in mice.
    Xu Yang, Wenxi Song, Zhi Lu, Yunhe Chen, Youshuang Wang, Tingyu Huang, Yu Liu, Yiming Wang, Shuai Chen, Yanfei Li, Xuebing Wang, Cong Zhang.
      T-2 toxin is a typical mycotoxin that seriously threatens human and animal health. Liver is the major target organ of T-2 toxin. To elucidate the precise hepatotoxicity mechanism and discover a natural antagonist of T-2 toxin. T-2 toxin (0, 0.5, 1, 2 mg/kg BW)-induced liver injury model, Ferrostatin-1 (1 mg/kg·BW) interference model, Parkin-/- mice model, Nrf2-activating model (tBHQ, 20 mg/kg·BW) and lycopene (5 mg/kg·BW) treatment model were constructed. Proteomics revealed that ferroptosis is a critical hepatotoxicity mechanism of T-2 toxin. Blocking ferroptosis alleviated the liver damage and mitophagy under T-2 toxin threat. However, these processes were exacerbated in Parkin-/- mice. In vivo mouse model confirmed that Nrf2 activation increased PINK-Parkin mediated mitophagy and alleviated T-2 toxin-induced ferroptosis, suggesting that Nrf2/mitophagy axis was involved in T-2 toxin-induced hepatic ferroptosis. Further analysis revealed that lycopene promoted Nrf2 nuclear translocation and PINK-Parkin mediated mitophagy to mitigate T-2 toxin-induced hepatic ferroptosis.
    DOI:  https://doi.org/10.1038/s41538-026-00736-4
  40. Cells. 2026 Jan 30. pii: 262. [Epub ahead of print]15(3):
    Correction: Xu et al. Notch1 Protects Against Ischemic-Reperfusion Injury by Suppressing PTEN-Pink1-Mediated Mitochondrial Dysfunction and Mitophagy. Cells 2023, 12, 137.
    Qirong Xu, Sheng Liu, Qiang Gong, Rongrong Zhu, Jichun Liu, Qicai Wu, Xueliang Zhou.
      In the original publication [...].
    DOI:  https://doi.org/10.3390/cells15030262
  41. Autophagy. 2026 Feb 08.
    SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury.
    Fei Gao, Zhiwang Li, Tian Peng, Bo Lin, Xiang Wang, Xingui Dai, Chenmu Ai, Guicheng Li, Feng Yang, Xianzhong Lin, Yun Zhang, Tao Li.
      Previous studies have shown that SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1) provides protective effects against lipopolysaccharide (LPS)-induced acute lung injury (ALI), however the underlying mechanism remains unclear. A recent study highlighted SIGMAR1's protective role against ferroptosis but did not fully elucidate the mechanism involved. Endothelial ferroptosis, which significantly affects microvascular permeability, has garnered increasing attention in research. In this context, we aimed to investigate how SIGMAR1 mitigates endothelial ferroptosis in ALI induced by LPS. PRE-084 (SIGMAR1 activator) inhibited endothelial ferroptosis and microvascular hyperpermeability in ALI induced by LPS; however, this effect was blocked by mitophagy inhibition. Knockout of sigmar1 worsened microvascular hyperpermeability and endothelial ferroptosis, but these effects were mitigated by activating SIRT3 (sirtuin 3). Conversely, inhibiting SIRT3 blocked the upregulation of SIGMAR1-mediated mitophagy and limited endothelial ferroptosis in ALI induced by LPS. In addition, LPS exposure led to the acetylation of lysine 498 in ATP5F1A/ATP5A1 (ATP synthase F1 subunit alpha). Importantly, downregulating ATP5F1A acetylation prevented the SIRT3 inhibition from blocking the effects of SIGMAR1 in facilitating mitophagy and preventing ferroptosis. Interestingly, downregulating ATP5F1A acetylation or activation of SIRT3 did not alter the effects of PRE-084 on ALI when mitophagy was inhibited, suggesting that SIGMAR1's ALI protective effects involve ATP5F1A- or SIRT3-dependent mitophagy. In conclusion, our findings indicate that SIGMAR1 alleviates endothelial ferroptosis and microvascular hyperpermeability in LPS-induced ALI through SIRT3-mediated mitophagy. Furthermore, the deacetylation of ATP5F1A at lysine 498 by SIRT3 is essential for SIGMAR1-mediated PRKN/parkindependent mitophagy.
    Keywords:  ATP synthase F1 subunit alpha; Acetylation; SIGMAR1; acute lung injury; ferroptosis; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2629294
  42. Medicine (Baltimore). 2026 Feb 13. 105(7): e47672
    Machine learning and bioinformatics-based identification of mitophagy-related diagnostic biomarkers in bronchiolitis obliterans.
    Ying Wang, Wenbin Peng.
      This study aimed to explore the molecular mechanisms associated with mitophagy in BO and identified mitophagy-associated BO diagnostic genes. Using Gene Expression Omnibus database data, differentially expressed genes in BO patients vs controls were analyzed via Gene Ontology enrichment. Algorithms like Boruta, least absolute shrinkage and selection operator, and Random Forest screened BO-specific genes. Mitophagy genes were sourced from PathCards and correlated with BO-specific genes via single-sample gene set enrichment analysis (ssGSEA). Receiver operating characteristic curves evaluated the diagnostic performance of these genes. Two hundred and six differentially expressed genes were identified, in which immune-related pathways such as the B-cell receptor signaling pathway and lymphocyte differentiation were significantly enriched. Machine learning screening yielded 30 BO signature genes, among which KLRC3 and CD36 were significantly correlated with ssGSEA enrichment score of the mitophagy gene sets. Receiver operating characteristic analysis confirmed their diagnostic value with AUCs of 0.648 and 0.640, respectively. This finding indicated that KLRC3 and CD36 are not only significantly correlated with ssGSEA enrichment score of the mitophagy gene sets but also have diagnostic value for BO.
    Keywords:  bronchiolitis obliterans (BO); diagnose; machine learning; mitophagy
    DOI:  https://doi.org/10.1097/MD.0000000000047672
  43. Environ Pollut. 2026 Feb 07. pii: S0269-7491(26)00148-X. [Epub ahead of print]395 127778
    Polylactic acid microplastic exposure induced male reproductive toxicity and decreased testosterone levels by accelerating Leydig cell senescence.
    Zhencheng Fan, Xinglong Wang, Yunqi Wu, Shuhao Li, Liang Kong, Shoujun Li, Tan Ma, Chun Pan.
      Polylactic acid microplastics (PLA-MPs), despite being marketed as biodegradable and eco-friendly alternatives to conventional plastics, have raised growing concerns regarding their potential adverse effects on human health. The reproductive toxicity of PLA-MPs exposure in male mammals has been confirmed in previous studies, but its specific effects on testosterone biosynthesis remain unclear. Male mice were treated with PLA-MPs at doses of low, medium, and high (0.01, 0.1, and 1 mg/d, respectively) for a duration of 28 days in this study. Our results demonstrated that PLA-MPs were enriched in mouse testes and led to a dose-dependent decrease in the serum testosterone concentration. We also observed the accumulation of senescent Leydig cells in the testis, along with inhibited autophagy and mitophagy. Moreover, we identified the critical involvement of autophagy and mitophagy in PLA-MPs-induced Leydig cell senescence. Re-establishment of autophagy and mitophagy effectively reserved the senescence of Leydig cell. Overall, our study revealed that PLA-MPs inhibit autophagy and mitophagy, thereby promoting Leydig cell senescence and subsequently reducing testosterone synthesis and secretion. These results advance our understanding of the pathogenic mechanisms underlying PLA-MPs-induced reproductive toxicity in male mammals.
    Keywords:  Autophagy; Mitophagy; Polylactic acid microplastics; Senescence; Testosterone
    DOI:  https://doi.org/10.1016/j.envpol.2026.127778
  44. Protein Sci. 2026 Mar;35(3): e70491
    Mitochondrial presequences are more than just address labels.
    Erik Marcel Heller, Svenja Lenhard, Doron Rapaport, Johannes Herrmann.
      Most mitochondrial proteins are synthesized in the cytosol as precursor proteins with N-terminal presequences. These presequences serve as targeting signals that facilitate the binding to mitochondrial surface receptors and translocation across the mitochondrial membranes. However, recent studies showed that presequences can be more than address tags. They can contain degradation signals recognized by components of the ubiquitin-proteasome system, and therefore, serve as timers that determine the lifespan of newly synthesized precursor proteins. Moreover, presequences can interact with components of the cytosolic chaperone system to prevent or delay precursor folding. Finally, presequences of some dually localized proteins contain targeting information not only for mitochondria but also for other cellular destinations such as the nuclear lumen or chloroplasts in plant cells. Thus, presequences contain multifaceted information to endow mitochondrial precursor proteins with specific properties that are critical for the early steps of mitochondrial protein biogenesis.
    Keywords:  Presequence; chaperones; mitochondria; proteasome; protein import; ubiquitin ligases
    DOI:  https://doi.org/10.1002/pro.70491
  45. Free Radic Biol Med. 2026 Feb 09. pii: S0891-5849(26)00107-3. [Epub ahead of print]
    Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling.
    Feng Jin, Zengtao Song, Yu Deng, Hongkai Yang, Yajiang Yuan, Zhanpeng Guo, Haosen Zhao, Xifan Mei.
      Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and chronic neuroinflammation. Cytosolic release of mitochondrial DNA (mtDNA) acts as a potent damage-associated molecular pattern (DAMP) that activates the cGAS-STING pathway and amplifies inflammation. However, the precise mechanisms by which mtDNA-driven innate immune signaling contributes to SCI pathology and how this pathway can be therapeutically modulated remain incompletely understood. In this study, we identify zinc as a dual-function regulator that preserves mitochondrial integrity and attenuates mtDNA-triggered innate immune activation after SCI. In both in vivo and in vitro models, zinc enhanced PINK1-Parkin dependent mitophagy, promoted the removal of damaged mitochondria, and stabilized mitochondrial membranes through the regulation of BAX, BAK, and VDAC1. These actions collectively reduced mtDNA leakage, thereby suppressing cGAS-STING signaling. Zinc further promoted anti-inflammatory microglial polarization and improved locomotor recovery in SCI mice. These findings uncover a previously unrecognized role of mtDNA-cGAS-STING signaling in SCI and identify zinc as a potential therapeutic candidate that restores mitochondrial-immune homeostasis to achieve neuroprotection.
    Keywords:  cGAS-STING pathway; mitophagy; mtDNA; neuroinflammation; spinal cord injury; zinc
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.010
  46. Am J Chin Med. 2026 ;54(1): 329-348
    Cepharanthine Triggers Ferroptosis in Gastric Cancer by PINK1/FUNDC1-Mediated Mitophagy-Dependent GPX4 Degradation.
    Fubo Jing, Bing Yan, Chunlan Liu, Wenshuai Zhu, Muhua Luan, Zhaotian Feng, Yuanxin Xing, Xiaoli Ma, Liang Zhang, Yunshan Wang, Yanfei Jia.
      Cepharanthine (CEP), a natural compound derived from the plant Stephania cephalantha Hayata, demonstrates pharmacological properties including anti-inflammatory, immuno-regulatory, antiviral, antitumor and antiparasitic effects. Due to its insidious progression and drug resistance, gastric cancer (GC) continues to have a high incidence and mortality rate worldwide. While the great potential of ferroptosis in cancer therapy is well-established, and CEP has shown potential antitumor activity, the role of ferroptosis in CEP's impact on GC remains unknown. Our aim in this study is to uncover what role ferroptosis has in the impact of CEP on GC. To investigate this, cell viability was measured by CCK-8 assay, and the effect of CEP on GC cell ferroptosis was assessed by Fe2[Formula: see text], DCFH-DA, and TEM. Integrated transcriptomic analyses revealed the critical pathways involved in CEP-induced ferroptosis, and JC-1, MitoSOX Red, Mito-Tracker, and immunofluorescence staining were used to evaluate mitophagy. The interaction between CEP and PINK1 was further confirmed by molecular docking, CETSA, and DARTS, and a xenograft tumor was used both to evaluate the effect of CEP on GC and to verify its mechanism through immunohistochemistry and western blotting. It was found that CEP could induce ferroptosis in GC cells by inducing an increase in reactive oxygen species, malondialdehyde, and intracellular Fe[Formula: see text] levels, and that it had little effect on normal gastric epithelial cells. Mechanistically, CEP binds directly to RUNX2, PINK1, and FUNDC1 to thereby activate PINK1-mediated mitophagy, prompt FUNDC1 to recruit GPX4 into mitochondria, and ultimately lead to the autophagic degradation of GPX4 and ferroptosis. A subcutaneous tumor model in nude mice confirmed the ferroptosis-associated antitumor efficacy of CEP in vivo. This study highlights that the natural compound CEP exerts its antitumor effects by activating mitophagy-dependent ferroptosis through a multi-target effect. CEP thus shows great promise as a potential drug candidate for GC treatment.
    Keywords:  Cepharanthine; FUNDC1; Ferroptosis; Gastric Cancer; Mitophagy; PINK1
    DOI:  https://doi.org/10.1142/S0192415X26500126
  47. Nat Commun. 2026 Feb 09.
    CD38 degrades MAVS through mitophagy to inhibit type I interferon secretion in nasopharyngeal carcinoma cells and impairs CD8+T cell-mediated anti-tumor immunity.
    Lin Liang, Wentao Li, Siyi Liu, Qian He, Feng Zeng, Jiaying Cao, Yan Lei, Yanling Li, Yanhong Zhou.
      Activating the type I interferon response in tumor cells and enhancing T cell-mediated anti-tumor immunity have broad clinical applications in tumor immunotherapy. However, the detailed mechanisms underlying the antitumor immune response and type I interferon response in nasopharyngeal carcinoma (NPC) remain unclear and require further elucidation. In this study, we identify CD38 in NPC cells as a key mediator impairing T cell antitumor immunity. Mechanistically, CD38 induces mitochondrial autophagy through PHB2, enhances the interaction between PHB2 and MAVS, leading to the degradation of MAVS protein, and inhibits the type I interferon response and CD8+T cell-mediated anti-tumor immunity. Importantly, CD38 promotes tumor progression and reduces the proportion of CD8+T cells and IFNγ+CD8+T cells in vivo via MAVS. In conclusion, these findings reveal previously unrecognized roles and mechanisms of CD38 in regulating anti-tumor T cell immunity, suggesting that inhibition of CD38 could initiate tumor-targeted immune responses, enhance anti-tumor immunity in patients, and provide new therapeutic strategies for NPC.
    DOI:  https://doi.org/10.1038/s41467-026-69339-7
  48. J Cell Physiol. 2026 Feb;241(2): e70145
    Dose-Dependent Biphasic Effect of Palmitic Acid on Oligodendrocyte Function: Impacts on Viability, Differentiation, and Myelination.
    Anna Palmiero, Luca Pipicelli, Giuliana La Rosa, Concetta Sozio, Carolina Punziano, Maddalena Raia, Raffaella Faraonio, Giovanna Vitolo, Mariarosaria Cammarota, Francesca Boscia, Ciro Menale, Mariarosaria Santillo, Simona Damiano.
      Palmitic acid (PA), the most abundant saturated fatty acid (SFA) in humans, plays a key role in energy metabolism, membrane synthesis, and signaling. Oligodendrocyte precursor cells (OPCs), which generate mature oligodendrocytes (OLs) forming the myelin sheath, are responsive to metabolic and redox signals. Despite increasing interest in lipid metabolism and mitochondrial dynamics as regulators of OPC fate, the effects of PA remain unclear. This study investigates the biphasic, dose-dependent effects of PA on OPCs using the oligodendrocyte precursor MO3.13 cell line and employs rat organotypic slice cultures to evaluate the effects of non-toxic PA doses under pathological conditions and on axonal (re)-myelination. In MO3.13 cells, high-dose PA (100 µM) induces mitochondrial fragmentation and caspase-7 activation, accompanied by reduced mitofusin-2 (MFN2) and phosphorylated dynamin-related protein 1 at Ser616 (p-DRP1), indicating altered fusion-fission balance and impaired reactive oxygen species (ROS) generation. In contrast, low-dose PA (25 µM) triggers a protective response involving nuclear factor erythroid 2-related factor 2 (Nrf2) activation and upregulation of antioxidant and lipid-regulatory genes (glutamate-cysteine ligase modifier subunit [GCLM], NAD(P)H dehydrogenase [quinone] 1 [NQO1], peroxisome proliferator-activated receptor gamma [PPARγ], and cluster of differentiation 36 [CD36]) resulting in reduced intracellular ROS and enhanced lipid mobilization. PA 25 µM promotes OPC differentiation by inhibiting migration and cell cycle progression and increasing myelin basic protein (MBP) and proteolipid protein (PLP) expression. Notably, early exposure (1 day) favors mitochondrial fusion, whereas prolonged exposure (4 days) shows a physiological shift to fission. PA 25 µM prevents neurodegeneration in hippocampal organotypic slice cultures exposed to a neuroinflammatory insult. In cerebellar organotypic slice cultures, PA 25 µM enhances axonal myelination and accelerates remyelination following lysolecithin-induced demyelination. These findings highlight the physiological relevance of low-dose PA in modulating OLs.
    Keywords:  Nrf2; differentiation; mitochondrial dynamics; multiple sclerosis; myelination; oligodendrocyte; palmitic acid
    DOI:  https://doi.org/10.1002/jcp.70145
  49. Oncoscience. 2026 ;13 1-9
    Dual targeting of oncogenic microtubules and mitochondria in PDAC.
    Michael W Spinrad, Chun Cai, Lauren C Gattie, Rui Wang, Aman Bajwa, Wei Li, Evan S Glazer.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Microtubule inhibition is a promising therapeutic target as microtubule dynamics play a critical role in growth of metastases due to over expression of several β-tubulin subtypes compared to normal cells. Previous studies have shown that decreased expression of βIII- and βIVb-tubulin is associated with decreased PDAC cell growth. Bromodomain and Extra-Terminal domain (BET) proteins are transcription factors that regulate mitochondria proteins. In this study, we hypothesize that SB-216 and Veru-111 (related novel compounds) inhibit cell growth via suppression of oncogenic βIII- and βIVb-tubulin subtypes and mitochondria function via suppression of BRD4, the most active BET protein. PDAC cell growth was analyzed with the IncuCyte Live-Cell Analysis system. mRNA expression of βIII- and βIVb-tubulin was evaluated with quantitative real time PCR. Western blot analysis was performed for βIII, βIVb-tubulin, and BRD4 protein expression and expression of autophagy and mitophagy markers LC3B and p62/SQSTM1. Mitochondrial function/respiration was measured using a Seahorse XF-24 Flux Analyzer. Cell growth was greatly inhibited across all doses in multiple PDAC cell lines (p < .0001). mRNA expression of TUBB3 (βIII subtype) and TUBB4 (βIVb subtype) was significantly decreased (p < .05). BRD4 protein expression was reduced in with compensatory increase in mRNA expression. Treated PDCL had reduced mitochondrial respiration. Autophagy markers were increased in treated PDAC cells. Our data demonstrates that SB-216 effectively inhibits PDAC cell growth through inhibiting oncogenic microtubules and mitochondrial function. This novel approach simultaneously targets two hallmarks of cancer and patient demise.
    Keywords:  bromo- and extra-terminal domain; mitochondria; mitochondrial stress; mitophagy; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.18632/oncoscience.641
  50. Sci Adv. 2026 Feb 13. 12(7): eadz2892
    Elovl6 inhibits colorectal cancer progression through stearic acid-mediated mitochondrial fusion and metabolic reprogramming.
    Zhiqian Bi, Xiaoyao Chang, Shengyun Zhu, Shuilian Fu, Yuzhe Zhang, Tingting Wang, Feng Wang, Hongqin Zhuang, Zi-Chun Hua.
      Lipid metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the precise molecular mechanisms underlying lipid-mediated oncogenesis and the specific lipid metabolic enzymes involved remain largely elusive. Here, we identify elongation of very-long-chain fatty acid protein 6 (Elovl6) as a critical regulator in CRC progression. Clinical data reveal significant down-regulation of Elovl6 in colon cancer tissues, with low expression levels correlating with unfavorable patient prognosis. We demonstrate that Elovl6 exerts potent tumor-suppressive effects, significantly inhibiting cellular proliferation in vitro and attenuating tumor growth in vivo. Mechanistically, it maintains intestinal microbial homeostasis by preventing the expansion of opportunistic pathogens while simultaneously orchestrating metabolic reprogramming through modulation of phospholipid biosynthesis pathways. Notably, we find that stearic acid, a key Elovl6-derived metabolite, promotes mitochondrial fusion by stabilizing mitofusin 1 protein. These findings not only position Elovl6 as a promising therapeutic target but also suggest that dietary supplementation with stearic acid could represent a viable strategy for CRC prevention and treatment.
    DOI:  https://doi.org/10.1126/sciadv.adz2892
  51. Front Pharmacol. 2026 ;17 1746901
    Piperine improves ischemic brain injury by promoting the regulation of the AMPK/PGC-1α pathway by Apelin 13.
    Siyu Xi, Jiangbo Ma, Jing Yan, Yanzhong Li, Peng Zhang, Huiling Chen, Guangyu Yang, Xueyan Fu, Juan Liu, Yiwei Zhang.
       Background: Ischemic stroke (IS) persists as the second foremost cause of mortality and the primary cause of long-term disability globally, a burden largely attributable to a paucity of effective therapeutic strategies. Piperine (PIP) is a bioactive component of traditional Chinese medicine that has shown potential to reduce cell inflammation and pyroptosis. Recent studies indicate that mitochondrial biogenesis can improve ischemic stroke.
    Objective: In this study, we aimed to investigate the effect of PIP combined with Apelin 13 on mitochondrial biosynthesis in IS and determine its mechanism and whether PIP promotes Apelin 13.
    Methods: We used network pharmacology to screen chemical drugs for combination therapy for IS. Male Sprague-Dawley rats were utilized to induce a model of pMCAO, and primary cortical neuron cells were extracted to establish an oxygen-sugar deprivation-reperfusion model. To evaluate the changes in mitochondrial function of neuronal cells, we observed mitochondrial membrane potential via fluorescence microscopy, detected ROS levels by flow cytometry, and determined the ATP concentration by using a chemiluminescence multifunctional microplate reader. Western blot and qRT-PCR were used to detect the protein expression and mRNA content of Apelin 13 and the AMPK/PGC-1α pathway. In addition, the underlying mechanism of action of PIP promoting Apelin 13 in the regulation of the AMPK/PGC-1α pathway by using siRNA to reduce the content of Apelin 13 in primary cortical neurons was investigated.
    Results: The results of network pharmacology research indicated that Apelin 13 affects IS. PIP combined with Apelin 13 exerts neuroprotective effects against IS. The OGD/R group showed obvious mitochondrial functional damage, reduced mitochondrial membrane potential, increased reactive oxygen species level, and decreased ATP content compared with the Con group. Compared with the OGD/R group, the mitochondrial function detection and expression level of mitochondrial biogenesis-related factors in the PIP and Apelin 13 groups significantly improved, and the neuroprotective effect was more significant when the two were combined. Our in vitro and in vivo experiments revealed that, compared with the normal group, the mRNA and protein expression of Apelin 13 in the model group significantly decreased. Furthermore, the abundance of Apelin 13 in the PIP group substantially rose compared with that in the model group. When the expression of Apelin 13 was knocked down by si-Apelin 13, si-Apelin 13 effectively blocked the individual or even combined effects of PIP and Apelin 13.
    Conclusion: This study showed that PIP could promote Apelin 13 to activate mitochondrial biogenesis and decreased mitochondrial functional damage. The potential mechanism of activating mitochondrial biogenesis lies in the regulation of the AMPK/PGC-1α pathway. This study not only expands the understanding of the clinical application of PIP in the treatment of IS but also provides new insights into its internal mechanism.
    Keywords:  AMPK/PGC-1α pathway; Apelin 13; cerebral ischemia; mitochondrial biogenesis; piperine
    DOI:  https://doi.org/10.3389/fphar.2026.1746901
  52. Commun Biol. 2026 Feb 09. 9(1): 195
    Proximity labeling unveils potential roles of the Miro2-CISD1 network in mitochondrial dynamics and neuronal differentiation.
    Im Kyeung Kang, Sunwoo Lee, Tae Kwon Moon, A Reum Han, Dae Bong Yu, Minkyo Jung, Chulhwan Kwak, Jeong Kon Seo, Hyun-Woo Rhee, Seong Who Kim, Ha-Na Woo, Ji Young Mun, Heuiran Lee.
      Adult hippocampal neurogenesis, crucial for maintaining neural homeostasis, is integral to neurodegeneration. We previously identified Miro2 as a key regulator of mitochondrial dynamics and survival in hippocampal neural stem cells with potential relevance to Alzheimer's disease. Here, using TurboID-based proximity labeling, we explore Miro2's interaction networks and identify sixty-six unique interactors specific to hippocampal neural stem cells. Functional enrichment analysis reveals that these proteins are crucial for mitochondrial organization, transport, and neurodegeneration. CISD1 emerges as a significant interaction partner. Knockdown of Miro2 and CISD1 impairs mitochondrial trafficking in adult hippocampal stem cells, disrupted stem cell differentiation with increased cytotoxicity. Rescue experiments partially reverse cell death, and both Miro2 and CISD1 show increased expression and interaction during differentiation. These findings suggest the Miro2-CISD1 axis as a critical regulator of mitochondrial remodeling and neurogenesis, providing a framework for future studies on how mitochondrial dynamics contribute to neurodegenerative disease mechanisms.
    DOI:  https://doi.org/10.1038/s42003-025-08990-0
  53. Int Immunopharmacol. 2026 Feb 11. pii: S1567-5769(26)00197-9. [Epub ahead of print]174 116353
    TREM1 as a master regulator of mitophagy-pyroptosis crosstalk in myocardial infarction: A dual-target strategy for precision therapy.
    Xingwei Hu, Xiang He, Miaomiao Xiang, Yan Wang, Shuai Ma, Mengsha Li, Yi Ma.
      Myocardial infarction (MI), a global health crisis driven by dysregulated immune responses and genetic-environmental interplay, remains inadequately addressed by current therapies targeting programmed cell death (PCD). While apoptosis, mitophagy, and pyroptosis collectively orchestrate MI progression. Emerging evidence underscores the pivotal roles of mitophagy and pyroptosis in regulating NLRP3 inflammasome activation, however, the crosstalk between these processes remains a critical unresolved question in cardiovascular immunology. Here, we identify Triggering Receptor Expressed on Myeloid cells 1 (TREM1) as a central molecular nexus governing this axis. Leveraging integrative bioinformatics analysis of the GSE66360 dataset combined with functional validation in macrophage-specific and MI rodent models, we demonstrate that TREM1 overexpression suppresses PINK1/Parkin-mediated mitophagy while paradoxically exacerbating NLRP3-dependent pyroptosis. Moreover, TREM1 knockdown significantly improved post-MI cardiac function and attenuated fibrotic remodeling. These findings establish TREM1 as both a prognostic biomarker for MI and a pleiotropic therapeutic target capable of simultaneously dampening NLRP3 inflammasome hyperactivation and promoting cardiac functional recovery.
    Keywords:  Mitophagy; Myocardial infarction; Pyroptosis; TREM1
    DOI:  https://doi.org/10.1016/j.intimp.2026.116353
  54. Mol Cell Proteomics. 2026 Feb 09. pii: S1535-9476(26)00022-8. [Epub ahead of print] 101527
    Subcellular proteomic analyses reveal REEP5 knockdown in the mouse heart disrupts mitochondrial networks.
    Michelle Di Paola, Cristine J Reitz, Uros Kuzmanov, Kateleen Jia, Anthony O Gramolini.
      Receptor Expression-Enhancing Protein 5 (REEP5) is a cardiac-enriched, membrane-shaping protein localized to the sarco(endo)plasmic reticulum (SR/ER), where it supports membrane network architecture and cardiomyocyte function. While REEP5 has been implicated in calcium handling and contractility, its role in regulating inter-organelle communication and mitochondrial homeostasis remains less well-understood. In this study, we used recombinant adeno-associated virus serotype 9(rAAV9)-mediated shRNA knockdown of Reep5 in mouse hearts, combined with subcellular fractionation and data-independent acquisition mass spectrometry (DIA-MS), to define proteomic remodeling across microsomal (SR/ER), mitochondrial, and cytosolic compartments. Loss of REEP5 altered the composition of SR/ER membrane-shaping proteins, including upregulation of RTN4, ATL3, and CKAP4, suggesting a partial compensatory response. Microsomal, mitochondrial and cytosolic proteomes exhibited broad reorganization, with enrichment of proteins involved in redox adaptation and proteostasis, alongside depletion of mitochondrial import machinery and antioxidant enzymes. Imaging of isolated cardiomyocytes confirmed fragmented mitochondrial networks and increased reactive oxygen species (ROS), consistent with proteomic signatures of disrupted mitochondrial dynamics and oxidative stress. Gene ontology enrichment across all fractions highlighted widespread dysregulation in organelle-specific processes, including translation, protein localization, and metabolic remodeling. Notably, several altered pathways converged on mitochondria-associated membranes (MAMs), suggesting that REEP5 may support SR/ER-mitochondria tethering and functional crosstalk. These findings position REEP5 as a key regulator of organelle homeostasis in the heart and underscore how its loss disrupts mitochondrial integrity and inter-organelle communication across cellular compartments.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101527
  55. Blood Cancer Discov. 2026 Feb 10. OF1-OF13
    Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.
    Yutang Li, Xinting Hu, Xiangxiang Zhou.
      Mitochondria regulate critical cellular processes beyond energy production, including organelle quality control, programmed cell death, and intercellular and interorganellar communication. In hematologic malignancies, mitochondria undergo adaptations through mechanisms including genetic mutations, metabolic reprogramming, mitochondrial transfer, fusion, and mitophagy. These alterations create heterogeneity, contribute to therapeutic resistance, and can also reshape the tumor microenvironment to promote progression. Collectively, these findings suggest that mitochondria represent a promising frontier in next-generation therapeutics, with emerging strategies such as mitochondrial-targeted small molecules and mitochondrial transplantation holding significant therapeutic potential.
    SIGNIFICANCE: In this review, we summarize the functions of mitochondria beyond energy production and highlight the heterogeneity of mitochondrial functional adaptations in hematologic malignancies, as well as the vital role of mitochondrial alterations in reshaping the tumor microenvironment. Understanding these changes is critical to deciphering the pathophysiology of hematologic malignancies.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0338
  56. Ann Clin Transl Neurol. 2026 Feb 11.
    Super-Refractory Status Epilepticus (SRSE) in a Patient With Compound Heterozygous OPA1 Variants: Case Report and Literature Review.
    Pouria Mohammadi, Lara Basovic, Christopher Michael McGraw.
       OBJECTIVE: Super-Refractory Status Epilepticus (SRSE) is a rare, life-threatening neurological emergency with unclear etiology in many cases. Mitochondrial dysfunction, often due to disease-causing genetic variants, is increasingly recognized as a cause, with each gene producing distinct pathophysiological mechanisms.
    METHODS: We describe the detailed clinical, neurophysiological, neuroimaging, and molecular findings of a 19-year-old female with SRSE associated with compound heterozygous variants in OPA1, a key gene for mitochondrial inner membrane fusion and cristae maintenance. In addition, a literature review was performed, identifying 16 previously published cases reporting one or both of the variants observed in the present case.
    RESULTS: Despite a longstanding history of generalized hypotonia, celiac disease, optic atrophy, cerebellar ataxia, and progressive motor decline, the proband had no prior history of seizures. She developed super-refractory status epilepticus with occipital-predominant epileptiform activity and MRI showing transient diffusion restriction in the right parieto-occipital cortex and cerebellum. Genetic testing revealed a frameshift variant (p.Val903GlyfsTer3) and a missense variant (p.Ile382Met) in the GTPase domain, known to impair mitochondrial fusion. Unlike POLG or MELAS-associated seizures, typically driven by severe mtDNA depletion and respiratory chain failure, OPA1 dysfunction usually spares mtDNA copy number but disrupts mitochondrial dynamics. In severe biallelic loss-of-function, a "second-hit" stressor may trigger a diffuse energy crisis and catastrophic seizures.
    INTERPRETATION: This case of mitochondrial SRSE in a patient with no known infectious, autoimmune, or structural cause emphasizes the possible role of genetic background and mitochondrial disorders in the development of the disease. This case highlights a rare mitochondrial subtype of RSE, emphasizing the need to consider energy metabolism defects in unexplained refractory status epilepticus.
    Keywords:  OPA1; SRSE; mitochondrial disease; mitochondrial dynamics; super‐refractory status epilepticus
    DOI:  https://doi.org/10.1002/acn3.70287
  57. Phytomedicine. 2026 Feb 05. pii: S0944-7113(26)00162-5. [Epub ahead of print]153 157923
    Ginsenoside Rg5 targets the KAT8-CISD2 axis to maintain mitochondrial homeostasis and antagonize senescence.
    Jinmeng Chu, Qingzhi Zhao, Yizhen Wang, Chengyu Cai, Xueli Cui, Na Zhang, Tiantian Xu, Haoqing Dou, Fei Wang, Feiran Yu, Yong Cai, Jingji Jin.
       BACKGROUND: Mitochondria are central regulators of cellular energy metabolism and its dysfunction drives cellular senescence. CISD2, a mitochondrial outer membrane protein and longevity gene, declines with age, highlighting its role in cellular senescence; however, how its post-translational modifications (PTMs) regulate cellular senescence remains poorly understood.
    PURPOSE: This study aimed to elucidate the molecular mechanisms by which ginsenoside Rg5, as a regulator of histone acetyltransferase KAT8 activity, modulates CISD2 PTMs and thereby exerts anti-aging effects.
    METHODS: Using SILAC-based acetyl-proteomics, CISD2 was identified as a substrate of the KAT8/MSL acetyltransferase complex. The interaction between KAT8 and CISD2 was examined by Co-immunoprecipitation, GST pull-down, cycloheximide chase, and protein stability assays. KAT8-mediated acetylation of CISD2 was evaluated using in vitro lysine acetyltransferase assays, modification-specific antibodies, and site-directed mutagenesis. The functional impact of CISD2 acetylation on mitochondrial homeostasis was assessed by comparing CISD2 wild-type and K74 mutant cell lines using a series of assays, including ROS production, JC-1 staining, ATP measurement, SA-β-Gal staining, and analyses of mitochondrial morphology. The interaction between Rg5 and KAT8 was investigated using cellular thermal shift assays (CETSA), Rg5-PEGA pull-down, competitive binding assays, and UV-absorption spectroscopy. Evolutionary conservation was evaluated in C. elegans through genetic depletion of mys-2 (the KAT8 homolog) and cisd-1 (the CISD2 homolog). Mitochondrial function (JC-1, DCFH-DA, mtDNA content, and ATP levels) and cellular senescence (SA-β-Gal staining, EdU incorporation, and CCK-8 assays) were assessed in senescent cells and in C. elegans following CISD-1 and/or MYS-2 RNAi.
    RESULTS: We demonstrate for the first time that the KAT8/MSL complex acetylates CISD2 at K74, thereby preventing STUB1-mediated ubiquitination and degradation at K105. Importantly, acetylation of CISD2 at K74 preserves mitochondrial homeostasis and enhances cellular resistance to oxidative stress and aging. In C. elegans, simultaneous knockdown of MYS-2 and CISD-1 exacerbates mitochondrial dysfunction and shortens lifespan. Moreover, ginsenoside Rg5 directly binds to KAT8, promotes CISD2 acetylation at the K74 site, maintaining mitochondrial homeostasis, and alleviates aging-associated phenotypes in both cells and nematodes.
    CONCLUSION: This study reveals that KAT8-mediated acetylation of CISD2 at K74 preserves mitochondrial homeostasis by inhibiting ubiquitin-mediated degradation, representing a critical mechanism for counteracting cellular senescence. Ginsenoside Rg5 acts as a KAT8 agonist to target and activate this pathway, thereby providing a novel strategy for anti-aging intervention.
    Keywords:  Acetylation; CISD2; Cellular senescence; Ginsenoside Rg5; KAT8; Mitochondria
    DOI:  https://doi.org/10.1016/j.phymed.2026.157923
  58. Autophagy Rep. 2026 ;5(1): 2622228
    Autophagy in kidney physiology: from cellular quality control to organ metabolism.
    Takeshi Yamamoto, Satoshi Minami, Yoshitaka Isaka.
      Autophagy is a cellular process that maintains kidney physiology by recycling intracellular components to preserve homeostasis. In the kidney, autophagy supports energy metabolism and integrity across multiple cell types. Its regulation is tightly governed by nutrient availability, hormonal cues, and oxygen levels, primarily through signaling pathways such as mechanistic target of rapamycin kinase (mTOR), AMP-activated protein kinase (AMPK), and transcription factor EB (TFEB). Under physiological conditions, autophagy is dynamically regulated to meet metabolic demands. However, aging, obesity, and metabolic stress impair lysosomal function, leading to a pathological state termed autophagic stagnation, in which autophagosomes accumulate but degradative flux is compromised. Rather than being uniformly protective, this stagnation promotes cellular damage and contributes to kidney disease progression. Notably, autophagic stagnation in proximal tubular epithelial cells (PTECs) contributes to acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition and exacerbates lipotoxicity in obesity-related kidney disease. Recent studies highlight the importance of transcriptional regulators - including TFEB and MondoA - in maintaining autophagic activity and mitochondrial homeostasis. Therapeutic strategies aimed at restoring autophagic flux - pharmacologically or through lifestyle interventions such as caloric restriction - hold promise for preserving kidney function. Deeper understanding of cell type - specific autophagy regulation will be critical for developing targeted and context-specific therapies.
    Keywords:  Mitophagy; Rubicon; autophagic stagnation; fibroblast growth factor 21 (FGF21); lipophagy; lysophagy; proximal tubular epithelial cells (PTECs)
    DOI:  https://doi.org/10.1080/27694127.2026.2622228
  59. Cancer Lett. 2026 Feb 11. pii: S0304-3835(26)00072-8. [Epub ahead of print] 218309
    MFN2-CD36 Interaction Regulates Mitochondrial Lipid Digestion in Cancer-Associated Fibroblasts and Promotes Esophageal Squamous Cell Carcinoma Progression.
    Xiao Shi, Chen Zhang, Yuxia Long, Jian Chen, Lihua Ren, Ruihua Shi.
      Stromal cells in the tumor microenvironment actively drive tumor progression, with cancer-associated fibroblasts (CAFs) representing its most abundant and functionally critical component. CAFs hijack the mitochondrial fusion pathway in esophageal squamous cell carcinoma (ESCC), promoting tumor progression by optimizing lipid metabolism and preserving mitochondrial integrity against damage from metabolic waste. Further investigation is needed to understand how tumor tissues avoid damage from substances, such as reactive oxygen species, while accumulating and absorbing lipids. This study investigates the hypothesis that mitochondria achieve lipophilic localization on the inner side of the cell membrane through the fatty acid transferase CD36 and promote mitochondrial fusion by interacting with mitofusin-2 (MFN2), thereby integrating smaller-volume mitochondria into larger ones that better withstand external stress and maintain mitochondrial bioactivity. We evaluated the interaction between MFN2 and CD36 using molecular simulations and amino acid mutations and screened compounds such as rosmarinic acid (RA) that inhibits this protein interaction. RA hinders CAF survival by disrupting the protective mitochondrial mechanisms. Our findings show that the MFN2-CD36 interaction enhances CAF energy metabolism and preserves mitochondrial activity. Thus, this study established that CD36 mediates the localization of CAF mitochondria to the cytoplasm and promotes lipid metabolism. CD36 enhances mitochondrial fusion by interacting with MFN2, thereby enabling CAFs to tolerate harmful damage during metabolic processes. Understanding how CD36 and MFN2 interact in CAFs can provide valuable references for clinical diagnosis and treatment of ESCC.
    Keywords:  CD36; MFN2; cancer-associated fibroblasts; esophageal squamous cell carcinoma; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.canlet.2026.218309
  60. Ren Fail. 2026 Dec;48(1): 2624286
    Integrative transcriptomic and machine learning analysis identifies PYCARD and IFI30 as immune-lysosomal biomarkers of ANCA-associated glomerulonephritis.
    Liyuan Bei, Jing Liao, Zhenhua Yang, Shihua Li, Mu Huang, Ling Lei.
       OBJECTIVES: ANCA-associated glomerulonephritis (ANCA-GN) is an immune-mediated kidney disease leading to acute or chronic renal failure. This study investigates the role of mitophagy-related genes in ANCA-GN, as mitochondrial dysfunction is closely linked to the pathogenesis of various kidney diseases.
    METHODS: This study analyzed transcriptomic data from GEO datasets (GSE104948 and GSE108109) to investigate mitophagy-related mechanisms in ANCA-GN. Methods included batch correction, consensus clustering (identifying two subtypes), weighted gene co-expression network analysis (WGCNA), differential expression screening, and machine learning (LASSO, random forest, SVM-RFE). A diagnostic nomogram was constructed and validated, and immune cell infiltration was profiled.
    RESULTS: Analyses revealed distinct activation of immune pathways, including complement and phagosome signaling, alongside abnormal infiltration of CD8+ T cells in ANCA-GN. Subtype-specific analysis identified 131 differentially expressed genes (DEGs), while 143 DEGs distinguished ANCA-GN from controls.Intersection analysis and machine learning prioritized two hub genes, PYCARD and IFI30, which exhibited strong diagnostic accuracy (AUC >0.9) and correlated with CD8+ T-cell infiltration. A nomogram model validated their clinical utility (AUC >0.9). Functional enrichment highlighted phagocytosis and immune signaling pathways. Immune profiling revealed significant upregulation of 20 immune cell types in ANCA-GN.
    CONCLUSIONS: These findings suggest that mitophagy-immune crosstalk drives ANCA-GN progression, with PYCARD and IFI30 as potential diagnostic biomarkers. This study provides mechanistic insights into ANCA-GN pathogenesis and proposes novel targets for clinical intervention.
    Keywords:  ANCA-associated vasculitis; IFI30; PYCARD; glomerulonephritis; inflammasome; mitophagy
    DOI:  https://doi.org/10.1080/0886022X.2026.2624286
  61. Pathol Res Pract. 2026 Jan 29. pii: S0344-0338(26)00034-8. [Epub ahead of print]280 156383
    USP18 improves mitochondrial homeostasis by stabilizing PKM2 and promoting M2 polarization in macrophages to relieve acute lung injury.
    Wensha Nie, Siyi Wang, Yongze Liu, Jiawu Yang, Qinglang Dai, Yuan Liao, Feng Li.
       BACKGROUND: Acute lung injury (ALI) has high incidence and mortality rates among patients. Studies have shown that USP18 is widely involved in the immunomodulatory process and that macrophage polarization plays a key role in the progression of ALI. This study aimed to explore the potential molecular mechanism through which USP18 promotes M2 macrophage polarization and alleviates ALI.
    METHODS: RAW264.7 cell injury and ALI mouse animal models were established by LPS induction. Lung tissue injury was evaluated by HE staining. Protein expression was evaluated by Western blotting, immunofluorescence and ELISA. Mitochondrial function was evaluated using JC-1 staining and ROS and ATP assays.
    RESULTS: USP18 is highly expressed in the lung tissues of ALI model mice. Overexpression of USP18 significantly alleviated pathological injury to lung tissue in mice with LPS-induced ALI; reduced MPO activity, the number of inflammatory cells and the protein content in BALF; and decreased the levels of the M1 markers iNOS, CD80, and CD86 and the proinflammatory factors IL-1β, IL-6, and TNF-α. Moreover, the expression of the M2 markers Arg1, CD206, and CD163 and the anti-inflammatory factor IL-10 increased, thereby inhibiting the M1 polarization of macrophages induced by LPS. Furthermore, USP18 markedly increased mitochondrial ATP levels and transmembrane potential, reduced ROS levels, and alleviated mitochondrial dysfunction in macrophages. Further studies have shown that USP18 stabilizes the expression of PKM2 through deubiquitination, while knockdown of PKM2 weakens the ability of USP18 to improve mitochondrial function and inhibit LPS-induced M1 polarization in macrophages.
    CONCLUSION: USP18 stabilizes the expression of PKM2 via deubiquitination, thereby enhancing mitochondrial homeostasis and promoting M2 macrophage polarization to alleviate ALI.
    Keywords:  Acute lung injury; M2 macrophage polarization; Mitochondrial homeostasis; PKM2; USP18
    DOI:  https://doi.org/10.1016/j.prp.2026.156383
  62. Biochem Pharmacol. 2026 Feb 11. pii: S0006-2952(26)00131-0. [Epub ahead of print] 117800
    β - sitosterol promotes the SUMOylation of DRP1 in alveolar macrophages and alleviates sepsis-associated acute lung injury.
    Bailun Wang, Ziyi Zhou, Chang Sun, Angran Gu, Jiahan Wang, Hongqian Wang, Dong Wang, Yizheng Yang, Xinyue Li, Yuelan Wang, Changping Gu.
      Acute lung injury (ALI) represents the most frequent complication of sepsis; however, effective drug-based interventions are still unavailable. β-sitosterol (BS) has demonstrated anti-inflammatory effects and protective properties on alveolar epithelial barriers. This study investigated the mechanism by which BS targets alveolar macrophages to attenuate sepsis-associated acute lung injury (SALI) via in vivo and in vitro experiments. Sepsis was induced in mice through cecal ligation and puncture (CLP), and BS was administered orally. An in vitro model of lipopolysaccharide (LPS)-induced MH-S cell infection validated the proposed mechanism. Macrophage polarization and mitochondrial function were assessed using flow cytometry, electron microscopy, and Western blot analysis. Results showed that BS suppressed reactive oxygen species (ROS) production and M1 macrophage polarization in LPS-stimulated MH-S cells. Mechanistically, BS promoted lysosomal degradation of dynamin-related protein 1 (DRP1) via SUMO2/3-mediated SUMOylation, preserving mitochondrial integrity and function. Transfection of MH-S cells with DRP1 plasmid abolished the BS-mediated mitochondrial protection mechanism, reducing inhibition of oxidative stress and M1 polarization. In summary, BS inhibits M1 polarization of alveolar macrophages by promoting DRP1 SUMOylation, effectively alleviating SALI in mice. These findings support BS as a potential therapeutic agent for SALI, providing a theoretical basis for clinical application.
    Keywords:  DRP1; Macrophages; Oxidative stress; SUMOylation; Sepsis-associated acute lung injury; β − sitosterol
    DOI:  https://doi.org/10.1016/j.bcp.2026.117800
  63. J Biol Chem. 2026 Feb 06. pii: S0021-9258(26)00134-1. [Epub ahead of print] 111264
    Molecular mechanisms of mitochondrial AAA+ proteases.
    S Quinn W Currie, Monica M Goncalves, Aaron D Schimmer, Siavash Vahidi.
      Mitochondrial AAA+ proteases, LONP1, ClpXP, YME1L (i-AAA), and the m-AAA complex, maintain protein quality and shape organelle function. Growing interest in these enzymes stems from their association with neurodegeneration, cardiomyopathy, metabolic disease, and cancer. Recent structural and biophysical work clarifies how ATP-driven conformational cycles enable substrate recognition, unfolding, translocation, and proteolysis, and how assembly state, subunit composition, and regulatory inputs tune activity. These insights help interpret patient variants and guide experiments that connect mechanism to phenotype. Here we review shared mechanistic principles across the four proteases, contrast their architectures and regulatory features, and relate these properties to substrate selection and disease mechanisms, with emphasis on evidence from structural, biochemical, and cellular studies. We also survey strategies to modulate function. Small molecules, exemplified by Dordaviprone (ONC201) which activate human ClpP, provide proof of concept, and emerging modalities such as engineered macromolecules, may offer the selectivity and localization required to correct disease mechanisms or exploit disease dependencies. By integrating mechanism, disease links, and modulation strategies, this review provides a framework for translating basic insight on mitochondrial AAA+ proteases into new tools and, ultimately, therapies.
    Keywords:  ClpXP; LONP1; YME1L; i-AAA; m-AAA; mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.111264
  64. Mol Cell Endocrinol. 2026 Feb 10. pii: S0303-7207(26)00037-7. [Epub ahead of print] 112760
    Comparative Analysis of Melatonin and Sildenafil in a Rat Model of Pulmonary Arterial Hypertension: Insights into Oxidative Stress, Inflammation, and Mitochondrial Biogenesis.
    Silvio Tasca, Patrick Türck, Daniela Drosdowski, Cristina Campos Carraro, Adriane Belló-Klein, Alexandre Luz de Castro, Alex Sander da Rosa Araujo.
      Pulmonary artery hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to the augmented afterload of the right ventricle (RV), hypertrophy, and heart failure. Oxidative stress and inflammation in the RV may be involved in the physiopathology of PAH. Because of their antioxidant properties, melatonin and sildenafil could be possible therapeutic agents for the treatment of PAH. Therefore, the present study evaluated the protective effects of melatonin against oxidative stress, inflammation, and mitochondrial biogenesis in the RV of rats with PAH. Wistar rats were divided into four groups: control (CTR), monocrotaline (MCT), monocrotaline treated with sildenafil (MCT+SIL), and monocrotaline treated with melatonin (MCT+MEL). PAH was induced using a single dose of MCT (60 mg/kg, i.p.). Sildenafil citrate (50 mg/kg/day) and melatonin (10 mg/kg/day) were then administered by gavage, beginning on the first day of the experimental protocol. On the day 21, echocardiographic, morphometric, oxidative/nitrosative stress and Western blotting analyses were performed. Animals that received melatonin or sildenafil demonstrated an increased tricuspid annular plane systolic excursion (TAPSE) when compared with non-treated animals, indicating an improvement in RV contractility. Both melatonin and sildenafil treatment decreased lipid peroxidation (LPO) and reestablished sulfhydryl levels. Melatonin administration decreased the protein expression level of nuclear factor kappa beta (NF-κB), while sildenafil decreased xanthine oxidase expression. Both treatments increased peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1α) expression. Based on our findings, melatonin showed a protective effect similar to sildenafil in the RV of a rats model of PAH.
    Keywords:  NF-κB; PGC-1α; TAPSE; lipid peroxidation; monocrotaline
    DOI:  https://doi.org/10.1016/j.mce.2026.112760
  65. FASEB J. 2026 Feb 28. 40(4): e71549
    Mitochondrial-Localized FABP4 Inhibits Ferroptosis-Dependent Mycobacterium tuberculosis Dissemination by Maintaining Mitochondrial Homeostasis.
    Tingting Zhao, Xinyu Hu, Ju Li, Mingying Liu, Qinzhou Dong, Zecheng Chang, Jianting Xu, Guoqing Wang.
      Mycobacterium tuberculosis (Mtb) is an intracellular parasitic pathogen that infects humans and potentially causes tuberculosis. In addition, emerging evidence suggests that Mtb infection can elicit distinct immune responses in different subcellular organelles; however, the underlying molecular mechanisms remain poorly understood. In this study, we determined that Mtb infection can suppress the expression of mitochondrial-localized fatty acid-binding protein 4 (FABP4), promote lipid peroxidation, and induce ferroptosis, thereby facilitating the intracellular proliferation and dissemination of the pathogen. Upon overexpressing mitochondrial FABP4, we discovered that the downregulation of PPARG coactivator 1 alpha (PGC-1α) and uncoupling protein 2 (UCP2) induced by Mtb infection were inhibited, resulting in lower mitochondrial superoxide levels, reduced reactive oxygen species levels, and suppressed lipid peroxidation. In addition, FABP4 overexpression in mitochondria resulted in normalization of the expression of ferroptosis marker glutathione peroxidase 4, thereby suppressing the proliferation of Mtb and the resulting cellular damage. In summary, our findings provide new insights into the molecular mechanisms of tuberculosis pathogenicity, suggesting that studying the immune responses elicited by pathogen infection in different organelles holds significant potential for guiding future research.
    Keywords:  Fabp4; ferroptosis; lipid peroxidation; mitochondrial homeostasis; tuberculosis
    DOI:  https://doi.org/10.1096/fj.202503899R
  66. Mitochondrion. 2026 Feb 11. pii: S1567-7249(26)00022-X. [Epub ahead of print] 102132
    Dysregulated iron homeostasis Drives mitochondrial Injury and ferroptosis susceptibility in MELAS fibroblasts.
    Yu-Han Lin, Xiao-Wen Wang, Yu-An Li, Ting-Ya Chen, Wei-Shiung Lian, Feng-Sheng Wang, Min-Yu Lan, Chia-Wei Liou, Tsu-Kung Lin.
      Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, caused by mtDNA mutations, disrupts mitochondrial function and triggers oxidative stress. This study explores ferroptosis playing a key role in cell death in MELAS patient-derived fibroblasts harboring low (MELASLow) or high (MELASHi) heteroplasmy levels, subjected to rotenone-induced mitochondrial stress (a Complex I inhibitor). Rotenone crucially curtailed cell viability in MELAS fibroblasts relative to normal human dermal fibroblasts (NHDF), alongside elevated cellular/mitochondrial reactive oxygen species (ROS), lipid peroxidation, stable SOD1, and mildly diminished SOD2 in MELASHi cells. Rotenone induced selective Fe2+ accumulation in MELASLow cells, while MELASHi showed exacerbated Fe2+ elevation both at baseline and rotenone-treated conditions. Ferroptosis susceptibility was evident in rotenone-treated MELASHi via suppressed glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter (xCT); ferroptosis suppressor FSP1 was downregulated across MELAS subtypes versus NHDF. Iron homeostasis was dysregulated, with compensatory transferrin receptor (TFRC) and divalent metal transporter 1 (DMT1) reductions in MELAS cells. Non-toxic deferoxamine (DFO; 1-100 μM) pretreatment reversed cell survival, attenuated mitochondrial fragmentation, and restored elongated morphology in the stressed MELAS fibroblasts. These data establish the imbalance of Fe2+ and mitochondrial damages are central amplifier of MELAS pathology, positioning iron chelation as a viable therapeutic to mitigate oxidative harm and safeguard cellular viability.
    Keywords:  DFO; Ferroptosis; MELASsyndrome; Mitochondria; Mitochondrial fragmentation
    DOI:  https://doi.org/10.1016/j.mito.2026.102132
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒08 at 17:38.