bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–09–06
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Septic Cardiomyopathy and Mitochondrial Quality Control.
  2. Reprogramming Autoimmune Immunity via Mitochondrial Quality Control: Mechanisms, Biomarkers, and Windows for Intervention.
  3. Mitophagy and Cellular Homeostasis in Kidney Diseases: Mechanisms and Potential Therapeutics.
  4. SLC25A39: A Guardian against Cadmium-Induced Pleiotropic Disruption of Mitochondrial Homeostasis in Rat Neuronal Cells.
  5. Decoding the bile acid-mitochondria axis: Implications for disease management and therapeutic opportunities.
  6. AS160 Overexpression Protects Against β-Cell Failure in Hyperglycemic Mice by Interacting With HSPA8 to Regulate Mitophagy.
  7. Mitophagy: a regulator and therapeutic target in cerebral ischemia/reperfusion injury.
  8. Mild Hypothermia Alleviates Ischemia and Reperfusion Injury by Activating PINK1/Parkin Mitophagy.
  9. PINK1-Parkin pathway-mediated mitophagy in sepsis: friend or foe?
  10. Empagliflozin Improves Atherosclerosis by Promoting Mitophagy in Endothelial Cells.
  11. Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
  12. ASIV Attenuates Cisplatin-Induced Proximal Tubular Injury by Enhancing Mitochondrial Biogenesis and Mitophagy Through the ADRA1A/AMPK/FOXO3A Pathway.
  13. Algebraic Representation of Mitochondrial Dynamics.
  14. RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.
  15. EPS8 Differentially Regulates Antioxidant Defense and Mitochondrial Homeostatic Signaling in LNCaP and Enzalutamide-resistant LNCaP Cells.
  16. Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
  17. [Mechanical stimulation disrupts mitochondrial homeostasis and compromises biological functions of inflamed human periodontal ligament cells].
  18. Mitophagy-mediated ferroptosis involved in 2,5-hexanedione-induced neurotoxicity in rats.
  19. MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
  20. [Therapeutic effect comparison and mechanisms of Hedysari Radix, Astragali Radix, and Hedysari Radix polysaccharides in improving non-alcoholic fatty liver via regulating mitophagy].
  21. [Aberrant mitochondrial dynamics in myeloid neoplasms].
  22. Glutathione Primes Mitochondrial Autophagy to Guide Pulp-Dentine Complex Repair.
  23. Eriodictyol regulates LDHB to trigger mitophagy-mediated NLRP3 inflammasome inactivation as a therapeutic strategy for bone loss.
  24. Melatonin Improves Cognitive Function and Suppresses Excessive Mitophagy in Rats With Vascular Dementia.
  25. Mitochondrial damage and post-translational modifications in radiation-induced heart disease: mechanisms and emerging therapeutic targets.
  26. Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.
  27. PFKM acts as a metabolic switch initiating donut-shaped mitochondrial remodeling to promote osteogenesis.
  28. Intensity-dependent effects of interval training on brain mitophagy, metabolic signaling pathways, and neuroinflammation in a rat model of type 2 diabetes.
  29. Metformin activates the mitochondrial unfolded protein response via the AMPK/SIRT1 pathway to delay intervertebral disc degeneration.
  30. Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
  31. IFITM1 enhances anti-tumor function of unconventional TCRαβ double negative T cells by upregulating mitophagy.
  32. HMOX1-mediated ferroptosis participates in gangrenous mastitis in dairy goats.
  33. Celastrol-Based Hybrid Prodrug Ameliorates ALI by Spatiotemporally Consecutive Dual-Targeting GLUT1/Drp1 to Reestablish Mitochondrial Homeostasis.
  34. ACSL5 drives pancreatic ductal adenocarcinoma by suppressing mitophagy and enhancing ferroptosis resistance via the JAK1-STAT1-OASL axis.
  35. Inhibition of METTL14 Alleviates OGD/R-Induced Neuronal Differentiation Injury in Neural Stem Cells Through Suppressing the Tp53inp2/Ptgs2 Axis: Potential Benefits for the Mouse MCAO Model.
  36. Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.
  37. UBE2N flips the switch on for mitophagy and off for MASH.
  38. SRT1720-loaded exosome-mimetic nanovesicles promote mitophagy via SIRT1/PARKIN activation to ameliorate diabetic cerebral infarction in a preclinical rat model.
  39. Rosmarinic Acid Attenuates Isoniazid-Induced Neurotoxicity by Restoring Mitochondrial Dynamics and Suppressing Oxidative Stress, Ferroptosis, Neuroinflammation, and Apoptosis.
  40. Aβ-induced CaMKII hyperactivation is associated with impaired lysosomal maturation and mitophagy.
  41. The role of tryptophan hydroxylase-1 in metabolic dysfunction-associated steatotic liver disease.
  42. RETRACTION: Kruppel-Like Factor 4 Improves Obesity-related Nephropathy Through Increasing Mitochondrial Biogenesis and Activities.
  43. Maslinic Acid Alleviates Obesity-Associated Skeletal Muscle Atrophy and Adipose Tissue Dysfunction in Obese Mice.
  44. Mechanistic insights into andrographolide-mediated cardioprotective action through mitochondrial homeostasis: a network pharmacology and in vivo approach.
  45. Broccoli-licorice-passionflower blend improves mitochondrial function and exerts senotherapeutic effects.
  46. Identification of 2,4-dihydroxy-azaflavanone as an allosteric activator of SIRT1 and its potential role in cellular models of Parkinson's disease.
  47. Cancer-intrinsic SIRPα Signaling Triggers Mitochondrial Fission and Immune Tolerance to Promote TNBC Breast-to-Brain Metastasis.
  48. Neurons and Glia Exhibit Distinct Age-Associated MitoTimer-Based Mitochondrial Dynamics in the Drosophila Mushroom Body Calyx.
  49. UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.
  50. Structure and protection of Cichorium glandulosum polysaccharides against sarcopenic obesity through activating mitophagy via butyrate-GPR43-AMPK pathway.
  51. 4-phenylbutyric acid alleviated sepsis-induced myocardial dysfunction by inhibition of MAM formation to improve mitochondrial dynamic balance in myocardial cells.
  52. Research progress on terpenoids alleviating Alzheimer's disease through the Keap1/Nrf2/ARE pathway by exerting antioxidant effects and promoting mitophagy.
  53. [Mechanism study of Linggui Zhugan Decoction in improving post-myocardial infarction heart failure by modulating MAOA/4-HNE/MCU pathway].
  54. Liuwei Dihuang pills attenuates cognitive dysfunction in APP/PS1 mice through restoring mitochondrial homeostasis and activating the IRS/AKT/GSK3β insulin signaling pathway.
  55. Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.
  56. Targeting Mitochondrial PD-L1 O-GlcNAcylation to Sensitize HBV-Related HCC to Immunotherapy: Modulating Golgi-mitochondrial Crosstalk and mTOR/PGC-1α-Driven Mitochondrial Biogenesis to Overcome Resistance.
  57. Exercise-Induced Intercellular Mitochondrial Transfer: Redox Signaling as a Candidate Regulatory Mechanism.
  58. CRISPR/Cas9-Driven Fndc5 Knockout Reveals Augmented Mitochondrial Structural and Dynamic Alterations in Diabetic Nephropathy.
  1. Front Biosci (Landmark Ed). 2026 Jul 31. 31(8): 47390
    Septic Cardiomyopathy and Mitochondrial Quality Control.
    Xiangyi Pu, Zhaoqi Yan, Zhiming Liu, Xing Chang, Ruxiu Liu.
      Septic cardiomyopathy (SCM) is a prevalent and serious cardiac complication arising from sepsis-induced multiple organ dysfunction syndrome (MODS). The pathogenesis of SCM is complex and primarily involves immune-inflammatory responses, oxidative stress, programmed cell death, and mitochondrial dysfunction. In recent years, mitochondrial quality control (MQC) has attracted growing interest as a central mechanism for maintaining cellular homeostasis and myocardial energy metabolism in SCM. This review systematically summarizes recent advances in four key MQC mechanisms involved in SCM: (1) phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy; (2) mitochondrial dynamics, including dynamin-related protein 1 (Drp1)/fission protein 1 (FIS1)-driven fission and optic atrophy protein 1 (OPA1)/mitofusin (MFN)-regulated fusion; (3) mitochondrial biogenesis under the regulatory control of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/mitochondrial transcription factor A (TFAM) axis; and (4) the mitochondrial unfolded protein response (UPRmt), which maintains mitochondrial proteostasis through mediators such as C/EBP homologous protein (CHOP), YME1-like protease (YME1L), and Overlapping activity with m-AAA protease 1 (OMA1). These mechanisms have been shown to work synergistically to regulate mitochondrial clearance, renewal, and functional maintenance. Any imbalance among them can exacerbate myocardial injury. This review also emphasizes the redox crosstalk between oxidative stress and immune inflammation, with an emphasis on the pivotal contributions of NADPH oxidase 2 (NOX2), high mobility group box 1 (HMGB1), and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in vascular endothelial dysfunction and cardiac depression. In conclusion, preserving the dynamic equilibrium of MQC is crucial for preventing or reversing SCM and may present novel molecular targets and therapeutic strategies.
    Keywords:  cardiomyopathies; inflammation; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; oxidative stress; sepsis
    DOI:  https://doi.org/10.31083/FBL47390
  2. Int Immunopharmacol. 2026 Sep 01. pii: S1567-5769(26)01163-X. [Epub ahead of print]188 117316
    Reprogramming Autoimmune Immunity via Mitochondrial Quality Control: Mechanisms, Biomarkers, and Windows for Intervention.
    Xiao Chen, Jie Ding, Liu-Qing Meng, Shu-Fang Li, Yong Chen, Xin Wei, Wei-Rong Hu, Ke Wang, Feng Yao, Ying-Jie Zhao, Wei Hu, Ren-Peng Zhou.
       SIGNIFICANCE: In the case of heterogeneous autoimmune diseases (AIDs), the efficacy of single-pathway immunosuppression is limited, the toxicity is substantial, and the problem of cell type-specific metabolic vulnerability cannot be addressed.
    MECHANISM: New evidence highlights mitochondrial quality control (MQC) as an important regulatory axis of the immune set point. MQC is a coordinated network involving mitochondrial biogenesis, dynamics, mitophagy, proteostasis, protein import machinery, and selective removal of damaged mitochondrial components, including mitochondria-derived vesicles. Dysregulation across these interconnected MQC modules may contribute to key pathological events: impaired biogenesis compromises the metabolic fitness of regulatory T cells; an altered fission-fusion balance can influence macrophage inflammatory polarization; and defective mitophagy may increase the accumulation or release of immunostimulatory mitochondrial components, including mitochondrial DNA (mtDNA), triggering cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING)-driven type I interferon (IFN-I) amplification and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome hyperactivation. In parallel, impaired mitochondrial proteostasis, defective mitochondrial protein import machinery, dysregulated mitochondrial unfolded protein response (UPRmt) signaling, and altered Mitochondrial-derived vesicle (MDV)-mediated cargo disposal may further shape mitochondrial stress and immune-cell function.
    INNOVATION: We propose a conceptual shift from blanket immunosuppression to potential precision metabolic-immune reprogramming. This framework proposes that accessible MQC-related readouts, including transcription factor A (TFAM), Dynamin-related protein1 (Drp1) phosphorylation patterns, and Microtubule-associated protein 1A/1B-light chain 3 (LC3), may help inform treatment timing and therapeutic windows in future translational studies.
    FUTURE DIRECTIONS: To advance potential medicine in AIDs, prospective clinical studies should evaluate whether MQC-related biomarkers can identify treatment-responsive subgroups. For example, future studies should assess whether disease-stage and cell-specific modulation of mitophagy or mitochondrial dynamics improves treatment responses in rheumatoid arthritis (RA) patients stratified according to synovial Translocase of Outer Mitochondrial Membrane 7 (TOMM7) expression and metabolic state. These studies should test whether fission inhibition, restoration of regulated fission, or normalization of dysregulated fusion is beneficial in specific patient subgroups.
    Keywords:  Autoimmune diseases; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.intimp.2026.117316
  3. Int J Biol Sci. 2026 ;22(13): 7332-7348
    Mitophagy and Cellular Homeostasis in Kidney Diseases: Mechanisms and Potential Therapeutics.
    Hao Lu, Shenyu Yan, Baoyi Shao, Jianbo Guo, Yifan Wang, Rui Hou, Shen Chen, Meicen Wu, Biao Wei, Fei Li, Xiaoming Meng, Haiyong Chen.
      Mitochondrial homeostasis has attracted increasing interest and is now recognized as playing a significant role in both kidney development and the progression of kidney disease. Among these, the latest approach, mitophagy, has been shown to be activated dynamically and reversibly under various physiological conditions, including reactive oxygen stress, nutrient deficiency, and cellular senescence, to maintain mitochondrial homeostasis and function. Moreover, findings indicate that mitophagy can also maintain mitochondrial quality through interactions and mutual regulation with mitochondrial dynamics. Crucially, a growing number of kidney diseases, such as acute kidney injury, diabetic kidney disease, and other chronic kidney diseases, are linked to abnormal levels of mitophagy. In this review, we comprehensively examined the vital role of mitophagy in kidney diseases, discussed the potential of mitophagy-targeted therapies, and described the detailed alterations in specific mitophagy-related proteins associated with kidney diseases.
    Keywords:  kidney disease; mitochondrial quality control; mitophagy; targeted therapy
    DOI:  https://doi.org/10.7150/ijbs.138435
  4. J Agric Food Chem. 2026 Aug 26. 74(33): 26699-26713
    SLC25A39: A Guardian against Cadmium-Induced Pleiotropic Disruption of Mitochondrial Homeostasis in Rat Neuronal Cells.
    Li Wang, Tao Wang, Xianzu Luo, Yunhua Yao, Yonggang Ma, Xishuai Tong, Hui Zou, Jianhong Gu, Xuezhong Liu, Jianchun Bian, Zongping Liu, Yan Yuan.
      Cadmium (Cd) is a neurotoxic heavy metal, and mitochondrial homeostasis disruption is a key mechanism underlying its neurotoxicity. SLC25A39, a mitochondrial transporter, maintains the mitochondrial homeostasis. This study investigated the role of SLC25A39 in the Cd-induced disruption of mitochondrial homeostasis in rat neuronal cells. The results revealed that Cd exposure markedly upregulated the SLC25A39 protein levels in neuronal cells. SLC25A39 deficiency further aggravated Cd-induced mitochondrial oxidative-stress-related abnormalities, including mitochondrial glutathione (mtGSH) depletion, elevated lipid peroxidation, mitochondrial reactive oxygen species (mtROS) accumulation, and reduced mitochondrial SOD2 protein levels. Moreover, SLC25A39 deficiency aggravated Cd-induced mitochondrial dysfunction, suppressed biogenesis, disrupted the dynamic balance, and hyperactivated mitophagy. Notably, DRP1 inhibition suppressed the Cd-induced upregulation of Pink1 and Parkin in SLC25A39-deficient PC12 cells. Collectively, SLC25A39 confers resistance to Cd-induced pleiotropic mitochondrial injuries, including oxidative stress, dysfunction, impaired biogenesis, dynamic imbalance, and excessive mitophagy. In PC12 cells, SLC25A39 may limit excessive mitophagy by negatively regulating the DRP1 activity.
    Keywords:  Cadmium; Mitochondrial homeostasis; Rat neuronal cells; SLC25A39
    DOI:  https://doi.org/10.1021/acs.jafc.6c05935
  5. Pharmacol Res. 2026 Aug 30. pii: S1043-6618(26)00330-0. [Epub ahead of print]232 108415
    Decoding the bile acid-mitochondria axis: Implications for disease management and therapeutic opportunities.
    Xueru Jia, Zehan Zhang, Xiaoyu Lin, Xiangyue Dong, Ruixue Chen, Nan Liang, He Ding, Feng Li.
      Bile acids, as cholesterol metabolites, orchestrate a regulatory network with mitochondrial quality control through nuclear receptor FXR, membrane receptor TGR5, and other signaling molecules, modulating mitochondrial biogenesis, dynamic equilibrium, selective autophagy, and redox homeostasis. TGR5 promotes PGC-1α-mediated mitochondrial biogenesis via the cAMP-PKA-CREB pathway, while concurrently regulating mitochondrial fission and calcium homeostasis through the PKCδ/Drp1 and GRP75-MAMs pathways. FXR, acting through transcriptional reprogramming and epigenetic mechanisms, governs fatty acid oxidation, antioxidant defense, and apoptotic pathways, and has been shown to restore PINK1/Parkin-dependent autophagy and suppress NLRP3 inflammasome activation in alcoholic liver disease. Noncanonical receptors, including S1PR2, VDR, and PXR, also participate in the regulation of mitochondrial dynamics and autophagy. Dysregulation of this network is closely associated with metabolic dysfunction-associated fatty liver disease, diabetic retinopathy, pancreatic β-cells injury, alcoholic liver disease, and sepsis-induced immunoparalysis. Agonists targeting the aforementioned receptors, such as INT-777, INT-767, and Fexaramine, have demonstrated the capacity to restore mitochondrial function and alleviate tissue damage in animal models. Future investigations should employ multi-omics and structural biology approaches to elucidate receptor crosstalk and concentration-dependent bidirectional effects, and to develop tissue-selective modulators, thereby facilitating clinical translation.
    Keywords:  Bile acids; FXR; Metabolic diseases; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; TGR5
    DOI:  https://doi.org/10.1016/j.phrs.2026.108415
  6. Acta Physiol (Oxf). 2026 Oct;242(10): e70304
    AS160 Overexpression Protects Against β-Cell Failure in Hyperglycemic Mice by Interacting With HSPA8 to Regulate Mitophagy.
    Wenli Chen, Yanting Lu, Xiangxiang Liu, Bangrui Huang, Daowei Liu, Bilian He, Zhiming Zhao, Qian Wang, Jixi Li, Wenyong Xiong.
       AIM: Insulin deficiency due to pancreatic β-cell loss and dysfunction is a key event in the pathogenesis of T1DM and a progressive driver of T2DM. This study aims to investigate the role of AS160 in regulating mitochondrial homeostasis and insulin secretion in pancreatic β-cells, and to elucidate the underlying molecular mechanism involving its interaction with HSPA8 and activation of PINK1-Parkin-mediated mitophagy.
    METHODS: Insulin and AS160 levels in islets were analyzed by immunofluorescence staining. β cell-specific AS160 overexpression mice were generated via lentivirus injection, and their metabolic phenotypes were characterized. In vitro, AS160 was overexpressed or knocked down to assess its impact on cell proliferation, insulin secretion, and mitochondrial function. AS160-interacting proteins were identified by immunoprecipitation-mass spectrometry (IP-MS).
    RESULTS: AS160 expression was significantly decreased in islet and correlated positively with insulin levels in hyperglycemic mice. Specific overexpression of AS160 in β-cells exhibited novel protective effects for the islets and insulin levels in hyperglycemic mice. Mechanistically, AS160 overexpression in β-cells increased mitophagy and preserved mitochondrial biogenesis to maintain healthy mitochondrial homeostasis and insulin secretion. At the molecular level, HSPA8 was identified as a novel AS160-interacting protein that enhances PINK-dependent mitophagy. Knockdown of HSPA8 reversed the overexpression of AS160-induced mitophagy and mitochondrial biogenesis.
    CONCLUSION: Collectively, this work identifies the AS160-HSPA8 interaction as a key mechanism that sustains mitochondrial homeostasis through regulating mitophagy and mitochondrial biogenesis, thus preserving β-cell mass and function. These findings suggest that AS160 emerges as a pivotal regulator of mitochondrial homeostasis in pancreatic β-cell in vivo.
    Keywords:  AS160; diabetes; hyperglycemia; mitochondrial biogenesis; mitophagy
    DOI:  https://doi.org/10.1111/apha.70304
  7. Mitochondrion. 2026 Sep 04. pii: S1567-7249(26)00102-9. [Epub ahead of print] 102212
    Mitophagy: a regulator and therapeutic target in cerebral ischemia/reperfusion injury.
    Chalton Manengu, Zhen Tian, Huifeng Zhu.
      Cerebral ischemia/reperfusion (I/R) injury refers to the exacerbation of tissue damage following the restoration of blood flow to ischemic brain regions. This condition remains a major challenge in the clinical management of ischemic stroke due to limited therapeutic options. At present, no approved drugs specifically target cerebral I/R injury. Multiple mechanisms contribute to its pathogenesis, with mitochondrial dysfunction playing a central role. During cerebral I/R injury, mitochondria generate excessive reactive oxygen species (ROS), leading to impaired mitochondrial function and further tissue damage. In addition, mitochondrial calcium overload triggers neuronal apoptosis, which promotes disease progression. Given the critical role of mitochondrial dysfunction, preservation of mitochondrial homeostasis may attenuate cerebral I/R injury. Mitophagy, a selective process that removes damaged mitochondria, has been shown to mitigate cerebral I/R injury by limiting the release of harmful mitochondrial-derived factors. Therefore, mitophagy represents a potential therapeutic target for maintaining mitochondrial homeostasis in cerebral I/R injury treatment. This review summarizes the molecular regulation of mitophagy, its role in cerebral I/R injury, and current therapeutic strategies aimed at modulating mitophagy.
    Keywords:  Cerebral I/R injury; Mitochondrial dysfunction; Mitophagy; Neurological diseases
    DOI:  https://doi.org/10.1016/j.mito.2026.102212
  8. Neurochem Res. 2026 Sep 03. pii: 260. [Epub ahead of print]51(5):
    Mild Hypothermia Alleviates Ischemia and Reperfusion Injury by Activating PINK1/Parkin Mitophagy.
    Kailan Deng, Di Zhang, Yidan Chen, Qiumin Shao, Qian Zhang, Dan Wang, Fangyan Gong, Qin Li, Yue Wan, Mingmin Yan.
      Ischemia-reperfusion (IR) injury is characterized by significant neuronal apoptosis and mitochondrial damage.Despite significant advancements in understanding the pathophysiological mechanisms of IR, effective therapeutic strategies remain limited. Previous studies have shown that mild hypothermia (MH) can significantly alleviate brain IR injury by reducing neuronal apoptosis and mitochondrial damage, while mitophagy plays a crucial role in maintaining cellular self-protection and mitochondrial homeostasis. However, the involvement of the PINK1/Parkin signaling pathway, a classical regulatory route for mitophagy, in the protective effects of MH against IR remains unclear. To investigate this phenomenon, we used neuron-like SH-SY5Y cells and employed an oxygen-glucose deprivation/reoxygenation (OGD/R) model to simulate the in vitro IR process, and conducted a series of cell experiments. Our results demonstrated that under MH conditions, the expression levels of PINK1 and Parkin were upregulated after 5 h of ischemia-hypoxia followed by 24 h of reoxygenation, and the protective effect on cells was also significant. Furthermore, the inhibition of the mitophagy pathway may partially eliminate the protective effect provided by MH against OGD/R-induced damage.These findings indicate that the protective effects of MH against IR is mediated, at least in part, through the PINK1/Parkin-dependent mitophagy pathway.This study provides new insights into the mechanisms by which MH mitigates IR injury and may offer potential therapeutic targets for treating IR-related diseases.
    Keywords:  Ischemia-reperfusion injury; Mild hypothermia; Mitophagy; Oxygen-glucose deprivation; PINK1; Parkin
    DOI:  https://doi.org/10.1007/s11064-026-04878-5
  9. Mol Biol Rep. 2026 Aug 29. pii: 1488. [Epub ahead of print]53(1):
    PINK1-Parkin pathway-mediated mitophagy in sepsis: friend or foe?
    Xiaoyan Wu, Ke Ma, Junshuai Wang, Yang He.
      The PINK1-Parkin pathway is well-known for its role in canonical mitophagy, which is involved in various mitophagy-related biological and pathological processes, including pathogen infection, inflammasome activation, oxidative stress, inflammatory response, and even sepsis-induced multiorgan dysfunction. However, the precise mechanisms by which mitophagy is orchestrated during mitochondrial damage and its role in sepsis-induced multiple organ dysfunction are not yet fully elucidated, and there is even controversy. This review proposes four key mechanistic pathways-oxidative stress, the cGAS-STING axis, NF-κB signaling, and inflammasome activation-that interact with mitophagy and contribute to sepsis pathogenesis. Another objective of the work is to explore potential candidate agents that regulate the PINK1-Parkin pathway in mitophagy, by therapeutic mechanism (e.g. PINK1 activators, Parkin recruiters, deubiquitinase inhibitors and upstream pathway modulators). The therapeutic benefits can be achieved by regulating mitophagy, which has promising protective effects against multi-organ injuries, including septic encephalopathy, cardiac dysfunction, acute lung injury, and acute kidney injury.
    Keywords:  Mitophagy; Multiorgan dysfunction; PINK1-Parkin pathway; Sepsis
    DOI:  https://doi.org/10.1007/s11033-026-12690-1
  10. Cardiovasc Drugs Ther. 2026 Sep 01.
    Empagliflozin Improves Atherosclerosis by Promoting Mitophagy in Endothelial Cells.
    Longlong Yan, Jingjing Lu, Wendong Xu, Ruoyu Dong.
       PURPOSE: To investigate whether empagliflozin (EMPA) delays the progression of atherosclerosis (AS) by promoting mitophagy in endothelial cells.
    METHODS: In vivo and in vitro AS models were established using ApoE-/- mice fed a high-fat diet (HFD) and HUVECs treated with oxLDL, respectively. Models received EMPA intervention alone or combined with the autophagy inhibitor 3-MA. To specifically confirm the pivotal role of Pink1, siRNA-mediated knockdown was performed in HUVECs. Aortic plaque area was evaluated by Oil Red O staining. Serum lipids, mitochondrial function, and endothelial markers were assessed. Mitophagy-related proteins were detected by Western blot, and the co-localization of TOM20 with LC3 and CD31 with LC3 was observed via immunofluorescence.
    RESULTS: EMPA significantly reduced aortic plaque area and ameliorated lipid metabolism in mice, independent of hypoglycemic effects. In vitro, EMPA restored mitochondrial membrane potential and ATP levels while reducing ROS production. Furthermore, EMPA upregulated Pink1/Parkin expression and the LC3-II/LC3-I ratio, and promoted TOM20-LC3 co-localization. Critically, both 3-MA treatment and Pink1 knockdown reversed EMPA-induced improvements in endothelial viability and migration, abolished its inhibition of inflammatory cytokine release, and negated its regulatory effects on endothelial function, demonstrating that mitophagy is essential for EMPA's action.
    CONCLUSION: EMPA inhibits the progression of AS by activating Pink1/Parkin-mediated mitophagy, thereby improving mitochondrial function and alleviating endothelial injury. This finding provides a novel basis for the cardiovascular protective mechanisms of EMPA.
    Keywords:  Empagliflozin; atherosclerosis; cardiovascular diseases; endothelial cells; mitochondrial autophagy
    DOI:  https://doi.org/10.1007/s10557-026-07938-8
  11. J Clin Invest. 2026 Sep 01. pii: e199847. [Epub ahead of print]136(17):
    Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
    Bishal Basak, Julia F Riley, Neha M Nataraj, Erika Lf Holzbaur.
      Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
    DOI:  https://doi.org/10.1172/JCI199847
  12. FASEB J. 2026 Sep 15. 40(17): e72261
    ASIV Attenuates Cisplatin-Induced Proximal Tubular Injury by Enhancing Mitochondrial Biogenesis and Mitophagy Through the ADRA1A/AMPK/FOXO3A Pathway.
    Meng Wang, Wang Peng, Yani Wei, Hangxing Yu, Yan Luo, Qin Zhang, Xu Guan, Ying Li, Jianwei Wang, Qiurui Li, Weijian Xiong.
      Cisplatin causes nephrotoxicity by accumulating in renal tubular epithelial cells (RTECs). Astragaloside IV (ASIV) shows renoprotective potential, but its mechanisms remain poorly understood. Cisplatin induced nephrotoxicity was established in 8-week-old male C57BL/6 mice via intraperitoneal administration of cisplatin at 20 mg/kg for 48 h. For in vitro studies, HK-2 human proximal tubular epithelial cells were exposed to 50 μM cisplatin for 24 h. Multi-omics approaches were employed to identify novel mechanisms by which ASIV ameliorates cisplatin-induced proximal tubular injury. ASIV markedly reduced serum creatinine and urea nitrogen levels in mice, and ameliorated cisplatin-induced proximal tubular injury both in vivo and in vitro. Moreover, ASIV restored mitochondrial damage, upregulated protein expression of PGC-1α, TOMM20, and PINK1 in RTECs. Mechanistically, RNA-seq and scRNA-seq revealed that cisplatin predominantly affected ADRA1A-mediated mitochondrial biogenesis and mitophagy in proximal tubular cells, accompanied by suppression of the AMPK/FOXO3A pathway. Notably, ASIV upregulated ADRA1A expression, thereby facilitating AMPK and FOXO3A phosphorylation and consequently enhancing mitochondrial biogenesis and mitophagy. Furthermore, dabuzalgron (a selective ADRA1A agonist) recapitulated the protective effects of ASIV. In contrast, the renoprotective action of ASIV against cisplatin-induced proximal tubular injury was largely abrogated by the ADRA1A antagonist tamsulosin in vivo and by ADRA1A-specific siRNA in vitro. These findings identify ASIV as a highly promising renoprotective agent that upregulates ADRA1A expression and activates the AMPK/FOXO3A axis to enhance mitochondrial biogenesis and mitophagy, thereby counteracting cisplatin-induced proximal tubular injury.
    Keywords:  Astragaloside IV; acute kidney injury; alpha‐1A adrenergic receptor (ADRA1A); cisplatin; renal tubular epithelial cells
    DOI:  https://doi.org/10.1096/fj.202602118R
  13. Bull Math Biol. 2026 Sep 04. pii: 176. [Epub ahead of print]88(10):
    Algebraic Representation of Mitochondrial Dynamics.
    Raphael Mostov, Greyson Lewis, Gabriel Sturm, Wallace F Marshall.
      This paper addresses the increasing need for comprehensive mathematical descriptions of cell organization by examining the algebraic structure of mitochondrial network dynamics. Mitochondria are cellular structures involved in metabolism that take the form of a network of membrane-based tubes that undergo continuous re-arrangement by a set of morphological processes, including fission and fusion, carried out by protein-based machinery. Because of their network structure, mitochondria can be represented as graphs, and the morphological operations that take place in the cell, referred to as mitochondrial dynamics, can be represented by changes to the graphs. Prior studies have classified mitochondrial graphs based on graph-theoretic features, but an alternative approach is to focus not on the graphs themselves but on the set of morphological operations inducing mitochondrial dynamics, since this may provide a simpler representation. Moreover, the operations are what determine the graphs that will be generated in a biological system. Here we show that mitochondrial dynamics give rise to a category in which the objects are equivalence classes of graphs defined by one of the morphological operations and morphisms are mappings between these equivalence classes defined by the remaining morphological operations. For mitochondria consisting of a single component this gives rise to a particularly simple representation. Using these formalisms we define a distance metric for similarity between mitochondrial structures based on an edit distance, and demonstrate how this representation can be used for visualization and statistical analysis of biological data. In the course of defining these structures we provide a mathematical motivation for new experimental questions regarding mitochondrial fusion, the impacts of cell division on mitochondrial morphology, and the presence of a single giant component in some cell types. This work points to a general strategy for formulating a cell structure state-space, based not on the shapes of cellular structures, but on relations between the dynamic operations that produce them.
    Keywords:  Algebraic graph theory; Budding yeast; Cell representation; Mitochondrial fission; Mitochondrial fusion; Morpholomics; Planar graphs; Spatial statistics
    DOI:  https://doi.org/10.1007/s11538-026-01738-9
  14. Autophagy. 2026 Sep 01.
    RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.
    Waka Kojima, Ryu Endo, Kei Okatsu, Hiroki Kinefuchi, Tomoko Tokita, Reika Kikuchi, Noriyuki Matsuda, Shuya Fukai, Koji Yamano.
      Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the precise molecular mechanisms governing this recruitment remain poorly understood. In this study, we identify the small RAB GTPases RAB1A and RAB1B as direct binding partners of the OPTN leucine zipper (LZ) domain. We demonstrate that RAB1A/1B is required for the recruitment of ATG9A vesicles to mitochondria during the initial stages of mitophagy. Knockdown of RAB1A and RAB1B significantly impaired the assembly of OPTN at phagophore formation sites, leading to a profound inhibition of mitophagy progression. Mechanistically, we found that RAB1A/1B associate with ATG9A-positive vesicles via their C-terminal prenylation, thereby tethering these vesicles to the OPTN-bound mitochondria. Our findings establish a novel OPTN-RAB1-ATG9A axis that drives the de novo synthesis of phagophore membranes in close proximity to damaged mitochondria. This work clarifies how selective autophagy receptors spatially coordinate membrane trafficking to ensure the efficient clearance of dysfunctional organelles.
    Keywords:  Autophagy; Optineurin; PINK1; Parkin; RAB GTPase; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2026.2728346
  15. Cancer Genomics Proteomics. 2026 Sep-Oct;23(5):23(5): 964-981
    EPS8 Differentially Regulates Antioxidant Defense and Mitochondrial Homeostatic Signaling in LNCaP and Enzalutamide-resistant LNCaP Cells.
    Sih-Han Chen, Chun-Hsien Wu, Pei-Fang Hsieh, Wen-Chi Huang, Yu-Lin Yang, Victor C Lin, Ming-Wei Lin.
       BACKGROUND/AIM: Epidermal growth factor receptor pathway substrate 8 (EPS8) is an adaptor protein implicated in tumor progression and therapeutic resistance; however, its role in mitochondrial homeostatic signaling and antioxidant regulation remains unclear. This study examined the effects of EPS8 modulation in lymph node carcinoma of the prostate (LNCaP) and enzalutamide-resistant LNCaP (LNCaP-Enz) cells.
    MATERIALS AND METHODS: LNCaP-Enz cells were generated by long-term exposure to enzalutamide and maintained in 5 μM enzalutamide. EPS8 expression was modulated by plasmid-mediated overexpression or shRNA-mediated knockdown. Superoxide dismutase (SOD) activity and cellular adenosine triphosphate (ATP) levels were measured using colorimetric assays. Mitochondrial membrane potential (ΔΨm) was evaluated using JC-1 fluorescence, and mitochondrial staining patterns were qualitatively examined using MitoTracker Green staining. Protein expression associated with antioxidant defense, mitochondrial dynamics, mitochondrial stress response, mitochondrial biogenesis, and AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling was analyzed by western blotting.
    RESULTS: EPS8 overexpression increased SOD activity and the expression of SOD1 and SOD2, whereas EPS8 knockdown reduced these antioxidant parameters. Conversely, EPS8 silencing increased cellular ATP levels and enhanced JC-1 red fluorescence patterns. EPS8 silencing increased MFN1 and OPA1 expression and reduced DRP1 expression, consistent with a fusion-associated mitochondrial profile. EPS8 silencing also increased SIRT1, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-mTOR/mTOR, but reduced HSP60, LONP1, ATF5, and CEBPβ expression.
    CONCLUSION: EPS8 differentially regulates SOD-associated antioxidant capacity and mitochondrial homeostatic signaling in LNCaP-based cell models. Further studies are required to determine whether EPS8 modulation affects enzalutamide responsiveness.
    Keywords:  AMPK–mTOR signaling; EPS8; LNCaP; antioxidant defense; enzalutamide resistance; mitochondrial homeostasis
    DOI:  https://doi.org/10.21873/cgp.20611
  16. Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00432-5. [Epub ahead of print] 103015
    Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
    Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin.
      High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.
    Keywords:  DHODH; LOX; MERCS; TNBC; ferroptosis; glucose metabolism; lysyl oxidase; mitochondria-ER contacts; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103015
  17. Zhonghua Kou Qiang Yi Xue Za Zhi. 2026 Sep 01. 61(9): 1345-1355
    [Mechanical stimulation disrupts mitochondrial homeostasis and compromises biological functions of inflamed human periodontal ligament cells].
    J R Li, H Wang, S S Zhang, R F Song, S B Zhang, M Zhang.
      Objective: To investigate the effect and mechanism of mechanical stimulation on the proliferation, migration, and osteogenic differentiation of periodontal ligament cells (PDLC) under inflammatory microenvironment by regulating mitochondrial homeostasis. Methods: An inflammatory cell model was established by treating PDLC with tumor necrosis factor-α (TNF-α, 10 ng/ml) combined with interleukin-1β (IL-1β, 5 ng/ml) for 12 h. Normal and inflamed cells were exposed to pressures of 0, 60, 120 and 180 kPa using a multi-functional pressure loading system. The expression of the osteogenic transcription factor Osterix (OSX) was detected by Western blotting and real-time fluorescence quantitative PCR to identify the most inhibitory pressure condition. PDLC were divided into control, pressure, inflammation, and inflammation+pressure groups. The mitochondrial fission inhibitor Mdivi-1 was used for intervention. The following parameters were measured: apoptosis rate by flow cytometry; indicators of mitochondrial homeostasis by fluorescence staining; and the expression of runt-related transcription factor 2 (RUNX2), OSX, collagen type I (COL-Ⅰ), interleukin-6 (IL-6), dynamin-related protein 1 (DRP1), mitofusin 1/2(MFN1/2), PTEN-induced putative kinase 1 (PINK1) and Parkin by Western blotting. Results: Under inflammatory conditions, the 180 kPa pressure group showed the most significant reduction in the relative protein and mRNA expression levels of OSX (t=8.34, P<0.05; t=4.91, P<0.05), whereas no significant differences were observed under other pressure conditions.Therefore, 180 kPa was used for the subsequent experiments. Compared with the control group, the pressure group showed no significant changes in mitochondrial homeostasis parameters. Compared with the inflammation group, the inflammation+pressure group showed disruption of mitochondrial homeostasis, and significantly elevated expression of DRP1, PINK1, and Parkin (t=3.21,P<0.05,t=2.84,P<0.05;t=3.70, P<0.05), and significantly decreased expression of MFN1 and MFN2(t=3.50,P<0.05;t=3.68,P<0.05) After Mdivi-1 treatment, the migration rate (at 3, 6, and 12 h) and proliferation rate of PDLC were significantly increased (migration: t=6.52, P<0.05;t=5.97, t=10.07, P<0.05; proliferation: t=4.73, P<0.05), and the apoptosis rate was significantly decreased (t=4.53, P<0.05). Moreover, the protein expression levels of RUNX2, OSX, and COLI were significantly increased (t=6.11, P<0.05;t=4.97, t=3.22, P<0.05), while the protein expression level of IL-6 was significantly decreased (t=3.98, P<0.05). Conclusions: Mechanical stimulation can inhibit the migration, proliferation and osteogenic differentiation of inflammatory periodontal ligament cells by disrupting mitochondrial homeostasis.
    DOI:  https://doi.org/10.3760/cma.j.cn112144-20260121-00037
  18. J Environ Sci (China). 2026 Oct;pii: S1001-0742(26)00104-X. [Epub ahead of print]168 632-643
    Mitophagy-mediated ferroptosis involved in 2,5-hexanedione-induced neurotoxicity in rats.
    Wenqiong Wang, Yu Ma, Su Li, Qingshan Wang, Liyan Hou.
      n-Hexane, a widespread environmental and industrial pollutant, poses serious health risks, particularly neurotoxicity. Chronic exposure primarily induces sensorimotor neuropathy via its metabolite 2,5-hexanedione (HD), yet the mechanisms underlying HD-induced neuronal injury remain unclear. Recent evidence implicates ferroptosis, an iron-dependent form of regulated cell death, in neurodegenerative processes. In this study, Sprague-Dawley (SD) rats were exposed to HD to establish a neuropathy model. Ferroptosis involvement was assessed using the iron chelator deferoxamine (DFO) and the ferroptosis inhibitor Ferrostatin-1. The potential role of mitophagy in HD-induced ferroptosis was evaluated by monitoring mitophagy markers and by autophagy inhibition with chloroquine (CQ). In vitro, SH-SY5Y cells were transfected with PINK-1 siRNA to explore mitophagy-mediated regulation of ferroptosis. HD exposure led to iron accumulation, lipid peroxidation, mitochondrial abnormalities, and decreased GPX4 in rat spinal neurons. DFO or ferrostatin-1 treatment ameliorated these changes and preserved mitochondrial integrity. Mechanistic analyses revealed HD-induced activation of mitophagy, as shown by upregulation of Beclin-1, LC3II, Drp-1, and PINK-1, with concomitant downregulation of P62 in spinal mitochondria. CQ suppressed mitophagy, reduced iron deposition and lipid peroxidation, and improved motor function. Similarly, PINK-1 knockdown in SH-SY5Y cells mitigated HD-induced mitophagy and ferroptosis. These findings demonstrate that HD induces neuronal ferroptosis via mitophagy activation. Inhibition of ferroptosis or mitophagy effectively attenuates HD-induced neurotoxicity, suggesting potential therapeutic strategies to reduce neural damage from environmental n-hexane exposure.
    Keywords:  2,5-hexanedione (HD); Chloroquine (CQ); Ferroptosis; Mitophagy; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.jes.2026.02.007
  19. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930
    MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
    Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.
      Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.
    Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117930
  20. Zhongguo Zhong Yao Za Zhi. 2026 Aug;51(15): 4429-4438
    [Therapeutic effect comparison and mechanisms of Hedysari Radix, Astragali Radix, and Hedysari Radix polysaccharides in improving non-alcoholic fatty liver via regulating mitophagy].
    Zi-Qi Jia, Qiang Xu, Yu-Chun Han, Li He, Lei Zhang, Rong-Ke Li.
      This study aims to compare the therapeutic effects of Hedysari Radix, Astragali Radix, and Hedysari Radix polysaccharide(HPS) in non-alcoholic fatty liver disease(NAFLD) and to investigate the mechanisms of action by which these TCMs improve NAFLD through the regulation of mitophagy. NAFLD mouse models were established by feeding C57BL/6J mice a high-fat diet for 12 weeks. The mice were then randomly divided into a model group, a metformin group, a Hedysari Radix decoction group, an Astragali Radix decoction group, and an HPS group. The mice in the treatment groups received intragastric administration for four consecutive weeks. C57BL/6J mice fed a normal diet served as the control group. The mice in the control and model groups were administered an equal volume of distilled water by gavage. General conditions of the mice were observed, and at week 16, serum and liver tissues were collected. Serum biochemical indices were measured to evaluate liver function. The pathological changes in the liver were observed by hematoxylin-eosin(HE) and oil red O stainings. Mitochondrial morphological changes in the liver were observed by using a transmission electron microscope. The contents of reactive oxygen species(ROS), malondialdehyde(MDA), and superoxide dismutase(SOD) were measured using kits. Fasting insulin(FINS) levels were measured by enzyme-linked immunosorbent assay(ELISA). The mRNA and protein expression levels of PTEN-induced putative kinase 1(PINK1), parkin, microtubule-associated protein 1 light chain 3(LC3), and sequestosome 1(P62) were detected by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot. The results show that, compared with those in the control group, mice in the model group exhibit significantly increased body weight, liver weight, liver index, fasting blood glucose, insulin, alanine aminotransferase(ALT), aspartate aminotransferase(AST), total cholesterol(TC), triglyceride(TG), low-density lipoprotein(LDL), and triglyceride-glucose index(TyG), while high-density lipoprotein(HDL) levels are significantly decreased. Marked hepatocellular steatosis was observed, accompanied by mitochondrial structural damage and morphological abnormalities. ROS and MDA levels in liver tissue were significantly increased, whereas SOD activity was significantly decreased. RT-qPCR and Western blot results show that the expression levels of PINK1, parkin, and LC3 are decreased in the model group, whereas the expression level of ubiquitin-binding protein P62 is increased. Compared with those in the model group, after treatment with Hedysari Radix, Astragali Radix, and HPS, the mice in these groups exhibited significantly reduced body weight, liver weight, liver index, fasting blood glucose, insulin, ALT, AST, TC, TG, LDL, and TyG levels and significantly increased HDL levels. Hepatic tissue steatosis was markedly alleviated; mitochondrial morphology tended to normalize; ROS and MDA contents were significantly decreased; SOD activity was significantly increased. RT-qPCR results show that the mRNA expression levels of PINK1, parkin, and LC3 are increased in the Hedysari Radix and Astragali Radix decoction groups, while the mRNA expression level of P62 is decreased. In the HPS group, the mRNA expression of LC3 was increased, whereas that of P62 was decreased. Western blot results show that protein expression levels of PINK1, parkin, and LC3 were significantly increased in the Hedysari Radix and Astragali Radix decoction groups, whereas the expression level of P62 was significantly decreased. In the HPS group, the expression level of LC3 was increased, while that of P62 was decreased. In conclusion, Hedysari Radix and Astragali Radix can improve oxidative stress and liver injury of NAFLD mice by regulating mitophagy through the PINK1/Parkin pathway, with Hedysari radix showing superior efficacy. Although HPS can increase LC3 expression and decrease P62 expression, it does not exert a significant regulatory effect on the core proteins of the PINK1/Parkin pathway, and its specific mechanism requires further investigation.
    Keywords:  Astragali Radix; Hedysari Radix; Hedysari Radix polysaccaride; PINK1/Parkin pathway; mitophagy; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20260407.901
  21. Rinsho Ketsueki. 2026 ;67(8): 940-944
    [Aberrant mitochondrial dynamics in myeloid neoplasms].
    Yoshihiro Hayashi.
      Growing evidence has revealed that mitochondria are not merely bioenergetic organelles but also critical regulators of inflammation, cell death, and stem cell maintenance. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid malignancies that arise from hematopoietic stem and progenitor cells harboring genetic alterations; however, their fundamental disease phenotypes are distinct. Notably, hematopoietic stem and progenitor cells in MDS, which are characterized by chronic inflammation and ineffective hematopoiesis, exhibit excessive mitochondrial fragmentation independent of the underlying mutational profile. In contrast, AML, a malignancy driven primarily by uncontrolled proliferation, is associated with mitochondrial fusion and an increase in mitochondrial mass. These distinct mitochondrial dynamics appear to reflect disease-specific biological demands rather than incidental cellular abnormalities. This review focuses on the differences in mitochondrial dynamics and function between MDS and AML and discusses how these mitochondrial alterations contribute to the pathogenesis of myeloid neoplasms.
    Keywords:  Acute myeloid leukemia; Mitochondrial dynamics; Myelodysplastic neoplasms; Myeloid malignancies
    DOI:  https://doi.org/10.11406/rinketsu.67.940
  22. Int Endod J. 2026 Sep 02.
    Glutathione Primes Mitochondrial Autophagy to Guide Pulp-Dentine Complex Repair.
    Haiyun Luo, Siying Li, Qinglu Tian, Jiahui Gao, Ziyu Li, Liwei Zheng, Yachuan Zhou.
       AIM: Pulp-dentine complex repair following injury is fundamental to preserving tooth vitality and function. Despite advances in understanding reparative dentinogenesis, the molecular mechanisms orchestrating odontogenic differentiation of human dental pulp stem cells (hDPSCs) remain fragmented, lacking systematic integration across transcriptomic, proteomic and metabolomic levels. This study employs integrated multi-omics approaches to identify key regulatory pathways during odontogenic differentiation and elucidate the underlying mechanisms controlling pulp-dentine complex repair.
    METHODOLOGY: Single-cell RNA sequencing was performed on human carious and healthy pulp tissues. Temporal proteomic and metabolomic profiling was conducted during hDPSCs' odontogenic differentiation. Based on multi-omics integration revealing glutathione metabolism as a central regulatory node, hDPSCs were treated with L-buthionine-sulfoximine (BSO) or exogenous glutathione (GSH). Intracellular reactive oxygen species (ROS), GSH levels, mitochondrial membrane potential and mitophagy markers (PINK1/Parkin) were quantified. siRNA-mediated PINK1 knockdown was performed to assess the involvement of PINK1 in GSH-regulated odontogenic differentiation. A mouse molar injury model evaluated GSH effects on tertiary dentine formation in vivo.
    RESULTS: Single-cell transcriptomic analysis revealed enrichment of oxidative stress response pathways in mesenchymal stem cells from injured pulp. Multi-omics integration identified glutathione metabolism as a central regulatory pathway, with glutamate-cysteine ligase catalytic subunit (GCLC) progressively upregulated during differentiation. BSO treatment depleted intracellular GSH, elevated ROS levels, suppressed PINK1/Parkin-mediated mitophagy and impaired odontogenic differentiation. GSH supplementation restored mitophagy activity and rescued differentiation capacity in vitro. PINK1 depletion impaired odontogenic differentiation and markedly attenuated the pro-differentiation effects of exogenous GSH. In vivo, GSH administration enhanced tertiary dentine formation and activated mitophagy pathways in injured dental pulp.
    CONCLUSIONS: Our findings establish that the GCLC-mediated GSH antioxidant system orchestrates the odontogenic differentiation of dental pulp cells and pulp-dentine complex repair via the PINK1/Parkin-mitophagy axis, revealing a novel metabolic-oxideative signalling circuit as a potential therapeutic target for regenerative endodontics.
    Keywords:  glutathione; mitophagy; odontoblastic differentiation; pulp‐dentine complex; vital pulp therapy
    DOI:  https://doi.org/10.1111/iej.70240
  23. Pharmacol Res. 2026 Aug 29. pii: S1043-6618(26)00333-6. [Epub ahead of print]232 108418
    Eriodictyol regulates LDHB to trigger mitophagy-mediated NLRP3 inflammasome inactivation as a therapeutic strategy for bone loss.
    Yiyuan Wang, Wen Pu, Yuangang Su, Zhijuan Liu, Baihui Yang, Junliang Lu, Xiangde Li, Qian Liu, Jiake Xu, Fangming Song.
       BACKGROUND: Imbalance of bone homeostasis triggers abnormal activation of osteoclasts and impaired osteogenic function, which further exacerbates bone resorption, reduces bone mass, and ultimately induces bone loss. Eriodictyol (ERI) possesses a wide range of biological activities and can effectively inhibit excessive bone destruction. Nevertheless, its role in ameliorating bone loss remains to be further elucidated. In this study, we identified ERI as a natural inhibitor of lactate dehydrogenase B (LDHB) that protects against bone loss, and revealed the molecular mechanism whereby ERI inhibits NLRP3 inflammasome activation via enhancing mitophagy.
    METHODS: To explore the relationship between ERI and osteoclast development and bone resorption, we performed CCK-8 assays, TRAcP staining, and scanning electron microscopy (SEM). RNA sequencing, western blotting, and qPCR were then carried out to dissect the molecular mechanisms by which ERI regulates osteoclast activity. The interaction between ERI and LDHB was evaluated using molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA). Functional manipulation of LDHB through both silencing and overexpression confirmed its regulatory role in osteoclasts. Finally, the protective effect of ERI against systemic bone loss was assessed in vivo using a lipopolysaccharide (LPS)-induced mouse model, with micro-CT analysis and histological immunostaining.
    RESULTS: Transcriptomic profiling indicated that ERI exerted suppressive impacts on osteoclast biological behavior, which was tightly linked to mitochondrial autophagy as well as the NLRP3 inflammatory complex. Mechanistically, ERI inactivated the NLRP3 inflammasome by enhancing mitophagy and reducing reactive oxygen species (ROS) formation. In addition, ERI directly and stably targets LDHB. Functional assays demonstrated that altered LDHB expression modulates the activation status of osteoclasts. Notably, ERI modulated osteoclast activity and mitophagy activation in a LDHB‑dependent manner. In vivo experiments further verified that ERI effectively alleviated bone loss triggered by LPS in mice.
    CONCLUSIONS: Collectively, our findings confirm that ERI maintains bone homeostasis by regulating PINK1/Parkin-mediated mitophagy and suppressing NLRP3 inflammasome activation, which may provide a novel natural candidate for the treatment of bone loss-related diseases.
    Keywords:  Eriodictyol; LDHB; Mitophagy; NLRP3 inflammasome; Osteoclast
    DOI:  https://doi.org/10.1016/j.phrs.2026.108418
  24. CNS Neurosci Ther. 2026 Sep;32(9): e71141
    Melatonin Improves Cognitive Function and Suppresses Excessive Mitophagy in Rats With Vascular Dementia.
    Si-Jia Hou, Xing-Yi Guo, Zhi-Gang Wang, Ting-Yan Chen, Yang Li, Sui-Yi Xu.
       AIMS: Melatonin has shown neuroprotective potential in various models of cerebrovascular diseases, but its effects on mitophagy in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH) remain unclear.
    METHODS: Eighteen adult male Sprague-Dawley rats underwent bilateral common carotid artery occlusion (BCCAO) to induce CCH. Animals were randomly assigned to three groups (n = 6 per group): sham-operated controls, BCCAO model animals receiving vehicle injection, and BCCAO animals treated with daily melatonin (10 mg/kg, intraperitoneally for 14 days). Cognitive performance was evaluated using the Morris water maze. Regional cerebral blood flow (rCBF) was measured with high-resolution laser Doppler imaging. Mitophagy was assessed via Western blot analysis of LC3BII/I, TOMM20, COX IV, caspase-3, and immunofluorescence colocalization of LC3B with TOMM20 in the hippocampal CA1 subfield.
    RESULTS: BCCAO rats exhibited significant cognitive deficits in the Morris water maze, along with persistently reduced rCBF. BCCAO also induced a significant upregulation of hippocampal mitophagy, as indicated by an elevated LC3BII/I, decreased TOMM20 and COX IV levels, and increased colocalization of TOMM20 and LC3B immunofluorescence signals. Caspase-3 expression was markedly higher in the BCCAO group. Melatonin treatment improved rCBF recovery at day 14, mitigated the spatial learning and memory impairments, decreased the LC3BII/I, increased mitochondrial protein markers (TOMM20, COX IV), reduced the colocalization of TOMM20 and LC3B puncta, and attenuated caspase-3 levels.
    CONCLUSION: These findings indicate that CCH in the VaD model induces excessive hippocampal mitophagy and cognitive impairment. The cognitive improvement observed with melatonin treatment is closely correlated with restored cerebral perfusion and attenuated mitophagic activity.
    Keywords:  chronic cerebral hypoperfusion; cognitive dysfunction; melatonin; mitophagy; vascular dementia
    DOI:  https://doi.org/10.1002/cns.71141
  25. Front Pediatr. 2026 ;14 1914384
    Mitochondrial damage and post-translational modifications in radiation-induced heart disease: mechanisms and emerging therapeutic targets.
    Na Zuo, Yaling Li, Jun Yang.
       Background: Radiation-induced heart disease (RIHD) is a major late complication of thoracic radiotherapy. However, the mechanisms responsible for its long-term progression remain poorly understood. Conventional explanations, such as DNA damage, and oxidative stress, mainly focus on early radiation responses and fail to fully account for the prolonged latency and progressive myocardial remodeling observed in RIHD over years to decades.
    Main content: This review proposes that persistent disruption of mitochondrial homeostasis represents a central link between early radiation-induced injury and late cardiac remodeling. We systematically summarize the major processes involved in radiation-induced mitochondrial dysfunction. These processes include mtDNA damage, respiratory chain impairment, sustained mitochondrial reactive oxygen species (mitoROS) accumulation, metabolic network remodeling, and defective mitochondrial clearance through mitophagy. We further discuss how acetylation, SUMOylation, and lactylation regulate these processes and contribute to the development and progression of RIHD. Building on this framework, we highlight emerging molecular targets, including NDP52, ATP5F1C, P4HB, and SH3GLB1, as well as the potential protective effects of bioactive compounds derived from traditional Chinese medicine, such as aloe-emodin and astragaloside IV, through restoration of mitochondrial homeostasis. By integrating mitochondrial dysfunction, post-translational modifications, and mitophagy into a unified pathological framework, this review provides new perspectives for early identification and therapeutic intervention in RIHD.
    Key conclusions: RIHD is not simply an oxidative stress-driven disorder but rather a chronic remodeling process shaped by the interplay among mitochondrial injury, post-translational modifications, and mitophagy dysregulation. This integrated framework links early subcellular alterations to late cardiac remodeling and provides a potential biological explanation for the long latency and progressive nature of RIHD. However, most current evidence is derived from adult models. Future research should specifically address childhood cancer survivors, as radiation exposure during critical periods of cardiac development may result in distinct long-term cardiovascular outcomes.
    Keywords:  mitochondrial damage; mitophagy; post-translational modifications; radiation-induced heart disease; therapeutic targets
    DOI:  https://doi.org/10.3389/fped.2026.1914384
  26. Antioxid Redox Signal. 2026 Sep 02. 15230864261481794
    Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.
    Huijia Zhang, Ying Chen, Junjie Jiang, Yarong Ding, Si Hu, Zhongzhi Zhou, Li Chen.
      Background:Mitochondrial quality control has traditionally been attributed to mitophagy. However, emerging evidence indicates that mitochondrial microautophagy represents a distinct quality control pathway. This pathway enables selective removal of damaged mitochondrial subdomains while preserving overall organelle integrity. Therefore, mitochondrial microautophagy can be viewed as a redox-adaptive, sub-organelle quality control system that responds to localized mitochondrial stress.Scope of Review: In this review, we integrate recent mechanistic, imaging, and molecular studies to establish an updated framework of mitochondrial microautophagy. We describe this process as a sequential pathway involving damage sensing, mitochondria-lysosome contact formation, lysosomal membrane remodeling, selective degradation, and metabolic recycling. Localized reactive oxygen species (ROS) serve as important signals during this process. ROS define specific damage microdomains and facilitate selective mitochondrial component recognition. Subsequent cargo delivery and degradation are regulated by multiple molecular modules. These modules include the ubiquitin-autophagy-related protein 8 system, vacuolar-type H+-ATPase-dependent membrane remodeling, Ras-related in brain-endosomal sorting complexes required for transport signaling, the spermatogenesis-associated 18/mitochondria-eating protein pathway, and the mechanistic target of rapamycin complex 1-transcription factor EB and nuclear factor erythroid 2-related factor 2 stress-response networks.Outstanding Questions: Despite substantial progress, several fundamental questions remain unresolved. The mechanisms underlying cargo recognition require further clarification. The existence of specific redox-sensitive receptors remains to be determined. In addition, future technological advances will provide deeper insights into this pathway.Conclusions: Understanding mitochondrial microautophagy may reveal new therapeutic opportunities for mitochondrial dysfunction-associated disorders, including neurodegeneration, ischemic injury, metabolic disorders, and aging. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  ESCRT complex; Rab GTPase; SPATA18/Mieap; TFEB; V-ATPase; autophagy; lysosomal membrane remodeling; mitochondrial microautophagy; mitochondrial quality control
    DOI:  https://doi.org/10.1177/15230864261481794
  27. Int J Oral Sci. 2026 Aug 31. pii: 60. [Epub ahead of print]18(1):
    PFKM acts as a metabolic switch initiating donut-shaped mitochondrial remodeling to promote osteogenesis.
    Nengwen Huang, Yang Li, Jie Lu, Yifeng Xing, Weiping Chen, Kaidi Chen, Geyuan Zheng, Pengyuan Hu, Kaixun He, Hanyu Lin, Wenxiu Yuan, Yuwei Zhou, Zhenzhu Xue, Junjin Lin, Wen Li, Sihui Zhang, Yanjing Ou, Jiang Chen.
      Osteogenic differentiation requires sophisticated mitochondrial adaptation to meet bioenergetic demands, yet regulatory checkpoints governing this organelle reorganization remain poorly defined. Through single-cell RNA sequencing reanalysis and metabolic intervention, this study unveils a non-canonical signaling role for PFKM, traditionally recognized solely as a glycolytic enzyme, in orchestrating mitochondrial remodeling during bone formation. Beyond its established metabolic function, Pfkm suppression triggers distinctive donut-shaped mitochondria through a novel signaling cascade. Mechanistically, Pfkm knockdown expands mitochondria-endoplasmic reticulum contacts (MERCs), facilitating mitochondrial calcium influx. Concomitantly, elevated CD38 suppresses protein kinase A (PKA) activity, inducing DRP1 dephosphorylation at Serine 656. This signaling integration promotes DRP1 mitochondrial translocation, driving the characteristic donut architecture. This structural transformation initiates comprehensive mitochondrial quality control (MQC) encompassing enhanced biogenesis, selective mitophagy, and mitochondrial-derived vesicles (MDVs) secretion, collectively optimizing the osteogenic microenvironment and cellular mineralization capacity. In vivo validation demonstrates that AAV-mediated Pfkm knockdown accelerates bone repair in rat calvarial and femoral defect models. This work establishes PFKM as a dual-function regulator bridging metabolism and mitochondrial signaling, offering a potent therapeutic avenue for bone regeneration.
    DOI:  https://doi.org/10.1038/s41368-026-00460-5
  28. Metab Brain Dis. 2026 Aug 29. pii: 196. [Epub ahead of print]41(1):
    Intensity-dependent effects of interval training on brain mitophagy, metabolic signaling pathways, and neuroinflammation in a rat model of type 2 diabetes.
    Babak Esmealy, Kosar Zeinizadeh, Elaheh Piralaiy, Farnaz Derakhti, Mahdi Hayati.
      Type 2 diabetes mellitus impairs brain metabolic and mitochondrial homeostasis, yet the intensity-dependent neuroprotective effects of exercise remain poorly defined. This study examined the intensity‑dependent effects of interval training on brain mitophagy, metabolic signaling, oxidative stress, and neuroinflammation in a type 2 diabetes model. Fifty male rats were assigned to five groups (n = 10 each): healthy control (HC), diabetic control (DC), diabetic + low-intensity interval training (LIIT), diabetic + moderate-intensity interval training (MIIT), and diabetic + high-intensity interval training (HIIT). Following the intervention, hippocampal and cortical tissues were analyzed for metabolic signaling markers (AMPK, ULK1, mTOR), mitophagy-related proteins (PINK1, Parkin, LC3-II/I, p62), oxidative and antioxidant indices (MDA, SOD, CAT, TAC), pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lipid peroxidation (4-HNE). Statistical significance was set at p < 0.05. MIIT and HIIT activated AMPK-ULK1 signaling and suppressed mTOR in the hippocampus and cortex, leading to enhanced mitophagy, particularly in the hippocampus. These adaptations were accompanied by improved redox balance, reduced lipid peroxidation, and attenuated neuroinflammation, with effects increasing in an intensity-dependent manner (LIIT < MIIT < HIIT). Interval training may support neuroprotective adaptations in type 2 diabetes, with moderate- and high-intensity protocols potentially offering greater benefits than low intensity. Still, these effects require confirmation in broader experimental contexts.
    Keywords:  Brain metabolism; Exercise intensity; Interval training; Mitophagy; Neuroinflammation; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s11011-026-01944-3
  29. Free Radic Biol Med. 2026 Sep 02. pii: S0891-5849(26)01138-X. [Epub ahead of print]256 323-342
    Metformin activates the mitochondrial unfolded protein response via the AMPK/SIRT1 pathway to delay intervertebral disc degeneration.
    Shanzhong Shao, Zhiwei Huang, Jinrun Liu, Jie Li, Ziyu Wang, Ruoyu Yang, Shengxuan Chang, Guoqing Bao, Ming Zhu, Songsen Gao, Shengquan Zhang, Sumei Zhang, Xiaochuan Li, Hui Tao.
      Intervertebral disc degeneration (IDD) is associated with the loss of nucleus pulposus derived mesenchymal stem cell (NP-MSC) function, but the contribution of the mitochondrial unfolded protein response (UPRmt) to this process is not well understood. We found that SIRT1 and the UPRmt-related proteins HSP60, ATF5, and CLPP decreased as degeneration progressed in human disc tissues and primary NP-MSCs. In NP-MSCs exposed to tert-butyl hydroperoxide, metformin increased AMPK phosphorylation and SIRT1 expression, enhanced UPRmt signaling, and reduced apoptosis and senescence. Metformin also improved mitochondrial membrane potential and morphology, lowered reactive oxygen species, restored NAD + levels, and favored extracellular matrix synthesis. Blocking SIRT1 with EX527 or SIRT1 siRNA weakened UPRmt activation and largely reversed the mitochondrial, cellular, and matrix effects of metformin. In a rat needle-puncture model, intradiscal metformin preserved disc height and T2 signal, reduced histological degeneration, and increased matrix and UPRmt-related protein expression; these effects were diminished by EX527. Together, these results suggest that reduced AMPK/SIRT1/UPRmt activity contributes to NP-MSC dysfunction during IDD and that metformin may slow disc degeneration by restoring this mitochondrial stress response.
    Keywords:  Apoptosis; Intervertebral disc degeneration; Metformin; Mitochondrial unfolded protein response; SIRT1; Senescence; Stem cells
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.004
  30. Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00380-0. [Epub ahead of print]97 104381
    Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
    Tanvi Chaudhary, Sharath Mohan Bhat, Priyadarshika Pradhan, Manjunath B Joshi, Devanjan Sinha.
      Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.
    DOI:  https://doi.org/10.1016/j.redox.2026.104381
  31. Sci China Life Sci. 2026 Aug 26.
    IFITM1 enhances anti-tumor function of unconventional TCRαβ double negative T cells by upregulating mitophagy.
    Xiaotong Han, Xiaonan Du, Longyang Zhou, Zihan Zhang, Jingjing Zhu, Xiyu Wang, Yuan Jiang, Jie Sun, Yue Tian, Songlin Wang, Zhongtao Zhang, Guangyong Sun, Dong Zhang.
      Unconventional TCRαβ+ CD4-CD8- double negative T cells (DNT) can effectively impede the progression of leukemia, lymphoma, and solid tumors, highlighting their potential as a novel and effective cell therapy approach for cancer. However, the intrinsic mechanisms regulating DNT homeostasis and anti-tumor functions remain unclear. In this study, we discovered that DNT highly expressed IFITM1 (interferon-induced transmembrane protein 1) and further demonstrated that IFITM1 actively regulated the anti-tumor function of DNT both in vitro and in vivo. Furthermore, our investigation revealed that IFITM1+ DNT exhibited elevated expression of key molecules involved in immune cell-mediated anti-tumor responses, such as perforin, granzyme B, and NKG2D. Overexpression of IFITM1 promoted DNT anti-tumor activity. Notably, IFITM1 regulated mitophagy, which contributed to the improved mitochondrial function in DNT. Mechanistically, IFITM1 in the mitochondria of DNT interacts with the autophagosomal cargo protein p62/SQSTM1, recruiting more p62/SQSTM1 to the mitochondria, thereby promoting mitophagy. It is worth noting that IFITM1 is also highly expressed in activated human DNT (hDNT), and its regulatory effect on DNT mitophagy, homeostasis, and anti-tumor function has been validated. In conclusion, IFITM1 has emerged as a crucial player in enhancing DNT-mediated anti-tumor activity by regulating mitophagy and mitochondrial function. These findings suggested that upregulating IFITM1 expression in DNT may enhance mitophagy and promote DNT survival and cytotoxic functions, ultimately providing better control over cancer.
    Keywords:  IFITM1; immunotherapy; mitophagy; unconventional CD4−CD8− double negative T cells
    DOI:  https://doi.org/10.1007/s11427-025-3424-5
  32. Vet J. 2026 Sep 02. pii: S1090-0233(26)00306-0. [Epub ahead of print] 106849
    HMOX1-mediated ferroptosis participates in gangrenous mastitis in dairy goats.
    Xuewen Tan, Mingzhe Fu, Huicong Li, Jiajun Gao, Xingchen Wang, Nishang Liu, Yingqiu Liu, Weimin Zhang, Shen Zhuang, Xiaopeng An, Yunpeng Fan.
      Gangrenous mastitis is a severe disease caused by bacterial infection. It can lead to sepsis and even death in affected goats, posing a significant threat to the development of the dairy goat industry. The pathogenesis of this disease is not fully understood. In this study, a Staphylococcus aureus isolate obtained from a goat with gangrenous mastitis was used to establish in vivo and in vitro models. Using omics sequencing and detection of iron, MDA, GSH, and ROS levels, along with RT-qPCR and western blot, the occurrence of ferroptosis was assessed. Furthermore, by employing ferrostatin-1 (Fer-1), siRNA to inhibit HMOX1, and mitochondrial division inhibitor-1 (Mdivi-1), we explored the role of HMOX1 in regulating ferroptosis and the inflammatory response, as well as its association with mitophagy. The results showed the gangrenous mastitis model had typical symptoms, including mammary gland cyanosis, and bloody milk. Gene Set Enrichment Analysis (GSEA) revealed significant enrichment of the ferroptosis pathway, with HMOX1 being the most differentially expressed gene. Both gangrenous mastitis tissues and goat mammary epithelial cells infected with Staphylococcus aureus showed ferroptosis features, such as iron, MDA, and ROS accumulation, GSH depletion, and upregulation of HMOX1, along with downregulation of GPX4 and SLC7A11, while Fer-1 reversed these processes. Mitophagy-related proteins BNIP3, FUNDC1, and LC3 were upregulated, while Mdivi-1 inhibited them and alleviated ferroptosis. Inhibiting HMOX1 reduced ferroptosis, mitophagy and reduced inflammation. This study demonstrated that HMOX1 drives ferroptosis via mitophagy, providing new insights into the disease's pathogenesis and potential treatment strategies.
    Keywords:  Dairy goats; Ferroptosis; Gangrenous mastitis; HMOX1; Mitophagy
    DOI:  https://doi.org/10.1016/j.tvjl.2026.106849
  33. Int J Biol Sci. 2026 ;22(13): 7427-7446
    Celastrol-Based Hybrid Prodrug Ameliorates ALI by Spatiotemporally Consecutive Dual-Targeting GLUT1/Drp1 to Reestablish Mitochondrial Homeostasis.
    Hong Xu, Hongyu Chen, Fengling He, Xinlan Li, Wanxin Li, Qingqing Yang, Tingting Zhang, Jin Liu, Xiaoke Shi, Shilin Chen, Defang Li, Jun Lu.
      Aberrant activation of macrophages and their amplification of inflammatory responses constitute the core pathological basis driving the progression of acute lung injury (ALI). Celastrol (CE), despite its potent anti-inflammatory activity, suffers from poor aqueous solubility and substantial systemic toxicity, which severely limit its clinical translation. Capitalizing on the metabolic signature of pro-inflammatory M1 macrophages, specifically their high expression of glucose transporter 1 (GLUT1), we designed a glucose-modified CE prodrug that self-assembled into carrier-free nanoparticles CG NPs. With markedly improved solubility and systemic stability, CG NPs rapidly and persistently accumulated in the inflammatory lungs of LPS-induced ALI mice facilitated by GLUT1-mediated targeting and uptake by M1 macrophages. Compared with free CE, CG NPs exhibited enhanced overall therapeutic efficacy while significantly reducing hepatorenal toxicity. Mechanistic studies revealed that by targeting Drp1, CG NPs disrupt Drp1-MiD51 interaction, thus inhibiting excessive mitochondrial fission and ROS accumulation, which blocks NF-κB-mediated inflammatory signaling and M1-driven cytokine release. Molecular docking suggested that glucose conjugation may confer CG with a superior ability to regulate mitochondrial homeostasis over CE, potentially driven by its unique U-shaped conformation that inserts into Drp1 and forms a denser hydrogen-bond network, which could contribute to enhanced binding affinity. In summary, this study proposes a nanoprodrug strategy that combines precise targeting with mitochondrial protection, offering a promising therapeutic avenue for inflammatory diseases such as ALI.
    Keywords:  Acute lung injury; Celastrol; Drp1; M1 macrophage glucose metabolism; Mitochondrial homeostasis
    DOI:  https://doi.org/10.7150/ijbs.133756
  34. Cancer Lett. 2026 Sep 03. pii: S0304-3835(26)00573-2. [Epub ahead of print]660 218809
    ACSL5 drives pancreatic ductal adenocarcinoma by suppressing mitophagy and enhancing ferroptosis resistance via the JAK1-STAT1-OASL axis.
    Jingjing Dong, Mengting Dai, Yiming Zhou, Mengde Wu, Wei Wu, Linling Zhou, Zhaoyang Ji, Tongtong Ye, Jiaying Qin, Jialu Luo, Chenhuan Yu, Mingzhi Xu.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. Here, we identify long-chain acyl-CoA synthetase 5 (ACSL5) as a key oncogenic driver and prognostic biomarker in PDAC. Combined transcriptomic analysis of 51 PDAC samples and three public databases (GSE183795, GSE28735, GSE62452) reveals that ACSL5 is markedly upregulated in PDAC, and its overexpression is significantly associated with shorter patient survival and high diagnostic accuracy (AUC = 0.899), suggesting robust diagnostic potential. Functional assays demonstrate that ACSL5 promotes PDAC cell proliferation, migration, and tumor growth while inhibiting apoptosis. Mechanistically, ACSL5 activates the JAK1-STAT1 signaling pathway, leading to transcriptional upregulation of oligoadenylate synthetase-like protein (OASL). The ACSL5-OASL axis concurrently suppresses PINK1/Parkin-mediated mitophagy and enhances ferroptosis resistance by modulating GPX4, SLC7A11, and ACSL4 expression. Notably, the mitophagy activator CCCP effectively reverses ACSL5-driven tumor progression and restores ferroptosis sensitivity. Our findings establish ACSL5 as a promising diagnostic and therapeutic target and reveal that targeting mitophagy represents a potential strategy for ACSL5-high PDAC.
    Keywords:  ACSL5; Ferroptosis; JAK-STAT signaling; Mitophagy; OASL; Pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.canlet.2026.218809
  35. CNS Neurosci Ther. 2026 Sep;32(9): e71099
    Inhibition of METTL14 Alleviates OGD/R-Induced Neuronal Differentiation Injury in Neural Stem Cells Through Suppressing the Tp53inp2/Ptgs2 Axis: Potential Benefits for the Mouse MCAO Model.
    Dan Hou, Yujie Hu, Tian Yun, Dan Yu, Guoshuai Yang.
       BACKGROUND: Ischemic stroke (IS) is an acute cerebrovascular disease characterized by high morbidity and mortality, with limited current treatment options. Tumor protein p53-inducible nuclear protein 2 (Tp53inp2) is known to be a positive regulator of autophagy under physiological conditions, but the mechanism of Tp53inp2 in IS remains unclear. In this study, we aimed to explore the mechanism of Tp53inp2 in IS.
    METHODS: Primary neural stem cells (NSCs) were extracted and identified. An OGD/R cell model was constructed. Tp53inp2 was knocked down and rapamycin was added. A middle cerebral artery occlusion (MCAO) animal model was constructed, and then 5 μL of 5 × 105 NSCs, either untreated or transfected with sh-NC or sh-Tp53inp2, were injected. Additionally, at the cellular level, Ptgs2 or Tp53inp2 was overexpressed, and METTL14 was knocked down.
    RESULTS: Inhibition of Tp53inp2 mitigated OGD/R-induced mitophagy and ROS levels in vitro. Moreover, inhibition of Tp53inp2 mediated neuronal differentiation of OGD/R treated NSCs by suppressing mitophagy. At the animal level, the transplantation of NSCs with a knockdown of Tp53inp2 increased neuronal differentiation, thereby alleviating the effects of MCAO and mitigating cognitive impairments in MCAO model mice. Ptgs2 was further screened and validated as a downstream target mediating the effect of Tp53inp2 on NSCs. At the cellular level, Tp53inp2 alleviated OGD/R-induced mitophagy and ROS levels by regulating Ptgs2 expression. METTL14 could regulate Tp53inp2 expression by modulating the functional m6A modification sites on Tp53inp2 mRNA. Inhibition of METTL14 alleviated OGD/R-induced mitophagy and the rise of ROS levels in NSCs by inhibiting the Tp53inp2/Ptgs2 axis.
    CONCLUSIONS: Inhibition of METTL14 alleviated OGD/R-induced neuronal differentiation injury in NSCs by inhibiting the Tp53inp2/Ptgs2 axis. By elucidating the mechanisms involving Tp53inp2, Ptgs2, and METTL14, this research offers a foundation for developing new strategies to enhance neuronal differentiation and mitigate cognitive impairments in stroke patients.
    Keywords:  METTL14; Tp53inp2; cerebral ischemia‐reperfusion; m6A; mitophagy; neural stem cell differentiation
    DOI:  https://doi.org/10.1002/cns.71099
  36. Adv Sci (Weinh). 2026 Aug 31. e77529
    Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.
    Shiyang Liu, Chenguang Liu, Weihong Zheng, Xiaofei Tong, Zhengwei Gui, Zonghong Lu, Sun Ieong, Lin Zhang.
      Doxorubicin remains an important component of chemotherapy for triple-negative breast cancer (TNBC), yet chemoresistance severely limits its clinical efficacy. Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin-treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1-SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN-induced putative kinase 1 (PINK1). This suppresses PINK1/Parkin-mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.
    Keywords:  DNA methylation; TNFRSF19; doxorubicin; mitophagy; triple‐negative breast cancer
    DOI:  https://doi.org/10.1002/advs.77529
  37. Nat Metab. 2026 Sep 04.
    UBE2N flips the switch on for mitophagy and off for MASH.
    Emily D Madigan, Sandro L Matos, Michael J Jurczak.
      
    DOI:  https://doi.org/10.1038/s42255-026-01604-x
  38. Int J Pharm X. 2026 Dec;12 100639
    SRT1720-loaded exosome-mimetic nanovesicles promote mitophagy via SIRT1/PARKIN activation to ameliorate diabetic cerebral infarction in a preclinical rat model.
    Qifeng Huang, Fang Zhao, Bo Sun, Xie Yang, Miao Chen.
      Mitochondrial dysfunction and impaired mitophagy-a key event in diabetic hyperglycemia-aggravated ischemic injury - lead to accumulation of dysfunctional mitochondria and neuronal apoptosis, which are vital processes involved in diabetic cerebral infarction (DCI). Herein, we developed SRT1720-loaded exosome-mimetic nanovesicles (SRT1720@M) to leverage the potential of SIRT1/PARKIN pathway activation to inhibit these processes and counteract DCI. The lipid fusion approach was used to fabricate exosome-loaded SRT1720@M. The properties of SRT1720@M were established by employing UV-Vis, transmission electron microscopy (TEM), dynamic light scattering, and Fourier-transform infrared (FTIR) spectroscopy. Oxygen-glucose deprivation/reperfusion (OGD/R) and high-glucose (HG)-treated primary hippocampal neurons were used as an in vitro DCI model treated with SRT1720@M. qPCR, Western blotting and immunofluorescence were used for expression analyses, whereas cell viability, phagocytosis, inflammation, and ATP/L-LA levels were assessed by CCK-8, ELISA and TEM. A rat model of DCI was obtained by establishing middle cerebral artery occlusion (MCAO), from which infarct volume, neurological deficits, histopathology, behavioral indexes, and molecular markers were detected. SRT1720@M average size was ∼68 nm, with an encapsulation efficiency of 78.19%, loading capacity of 8.52%, and zeta potential of -54 mV. In vitro, SRT1720@M markedly improved cell viability (P < 0.01), decreased IL-1β, TNF-α, and L-LA, but increased ATP levels, and promoted mitophagy and suppressed inflammatory responses compared with the DCI group. In the DCI model, SRT1720@M improved neurological deficits, reduced infarct volume, and alleviated behavioral disorders by inhibiting apoptosis and inflammation and promoting mitophagy and mitochondrial function through activation of the SIRT1/PARKIN pathway. SRT1720@M alleviates DCI by activating the SIRT1/PARKIN pathway and promoting mitophagy, highlighting its potential as a promising preclinical therapeutic strategy.
    Keywords:  Diabetic cerebral infarction; Exosome-mimetic nanovesicles; Mitophagy; Neuronal protection; SIRT1/PARKIN pathway; SRT1720
    DOI:  https://doi.org/10.1016/j.ijpx.2026.100639
  39. Tissue Cell. 2026 Aug 27. pii: S0040-8166(26)00573-2. [Epub ahead of print]104(Pt 2): 103878
    Rosmarinic Acid Attenuates Isoniazid-Induced Neurotoxicity by Restoring Mitochondrial Dynamics and Suppressing Oxidative Stress, Ferroptosis, Neuroinflammation, and Apoptosis.
    Merve Bolat, Tuba Karaarslan, Samet Teki̇n, Esra Derelİ, Aslıhan Atasever, Burak Batuhan Laçi̇n, Esra Aktaş Şenocak, Furkan Aykurt, Emin Şengül, Fikret Çelebi̇, İsmail Bolat.
      Despite the continued global burden of tuberculosis and the essential role of isoniazid (INH) in first-line antituberculosis therapy, INH-induced neurotoxicity remains a major clinical challenge that compromises treatment adherence, and effective, well-characterized neuroprotective strategies are still lacking. This study investigated the neuroprotective effects of rosmarinic acid (RA) against INH-induced neurotoxicity, evaluating oxidative stress, inflammation, iron metabolism, energy homeostasis, mitochondrial dynamics, ferroptosis, and apoptosis using biochemical, molecular, and histopathological approaches. INH markedly increased malondialdehyde while reducing superoxide dismutase and glutathione, and increased TNF-α, IL-1β, and IL-6 while decreasing IL-10. INH also disturbed iron homeostasis (increased Fe²⁺), impaired energy metabolism (reduced ATP), and disrupted mitochondrial dynamics (increased Drp-1; decreased Mfn-2 and PGC-1α). NF-κB activation was accompanied by increased ACSL4 and decreased GPX4 and FTH1, reflecting ferroptosis, alongside increased Bax, Caspase-3, and Cytochrome c and reduced Bcl-2, indicating mitochondrial apoptosis. RA treatment suppressed oxidative stress, enhanced antioxidant defense, attenuated inflammation, restored iron and energy homeostasis, improved mitochondrial dynamics, and inhibited NF-κB activation, ferroptosis, and apoptosis. These findings demonstrate that RA exerts potent neuroprotective effects against INH-induced brain injury by simultaneously targeting oxidative stress, mitochondrial dysfunction, iron dyshomeostasis, neuroinflammation, ferroptosis, and apoptosis. To our knowledge, this is among the first studies to comprehensively address these interconnected pathways, including ferroptosis and iron dyshomeostasis, in INH-induced neurotoxicity. RA may thus represent a promising therapeutic candidate for preventing INH-induced neurotoxicity.
    Keywords:  Ferroptosis; Iron homeostasis; Isoniazid; Mitochondrial dynamics; Neurotoxicity; Rosmarinic acid
    DOI:  https://doi.org/10.1016/j.tice.2026.103878
  40. Neurochem Int. 2026 Sep 01. pii: S0197-0186(26)00143-9. [Epub ahead of print]200 106252
    Aβ-induced CaMKII hyperactivation is associated with impaired lysosomal maturation and mitophagy.
    Eun Cheng Suh, Yul A Kim, Kyung Eun Lee, Eun-Mi Park.
      Alzheimer's disease (AD) is characterized by amyloid-β (Aβ)-associated synaptic failure, intracellular Ca2+ dysregulation, and progressive impairment of lysosome-dependent clearance pathways. Aβ induces sustained Ca2+ overload, resulting in pathological hyperactivation of CaMKII, which normally participates in the regulation of autophagy. However, whether CaMKII hyperactivation contributes to Aβ-induced late-stage autophagy-lysosomal dysfunction and mitophagy failure remains unclear. This study aimed to examine the effects of the CaMKII inhibitor KN93 in Aβ25-35-exposed rat organotypic hippocampal slice cultures (OHSCs, ex vivo model) and the mouse brain in vivo. The results showed that Aβ25-35 induced intracellular Ca2+ elevation, CaMKII hyperactivation, and marked accumulation of LC3-II and p62. Ultrastructural and biochemical analyses revealed impaired lysosomal maturation, defective autophagosome-lysosome coupling, and accumulation of autophagic vacuoles, consistent with a blockade of late-stage autophagic flux. Increased levels of immature cathepsin D and reduced colocalization of LC3 with lysosomal markers further supported compromised lysosomal competence. Damaged mitochondria were recruited to lysosomal compartments but failed to undergo effective degradation, indicating abortive mitophagy under Aβ25-35 exposure. KN93 attenuated Aβ25-35-induced defects in lysosomal protease maturation, autophagosome-lysosome fusion, and mitochondrial clearance in both the ex vivo OHSCs model and the in vivo mouse brain. KN93 also ameliorated cognitive impairment in Aβ25-35-exposed mice. Taken together, these findings indicate that CaMKII hyperactivation contributes to Aβ25-35-induced autophagy-lysosomal dysfunction and neuronal damage, and that pharmacological inhibition of CaMKII with KN93 restores intracellular degradative capacity and ameliorates cognitive impairment under Aβ stress.
    Keywords:  Amyloid beta; Autophagic flux; CaMKII; Calcium dysregulation; Lysosomal dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.neuint.2026.106252
  41. Pediatr Investig. 2026 Aug 31.
    The role of tryptophan hydroxylase-1 in metabolic dysfunction-associated steatotic liver disease.
    Shuangzhen Jia, Xiaolin Ye, Zhaoxia Wang, Jie Wu.
       Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by dysregulated lipid metabolism, inflammation, and mitochondrial dysfunction. Given the rising burden of MASLD in children and adolescents, identifying experimentally tractable mechanisms relevant to pediatric diseases is of considerable interest. Tryptophan hydroxylase-1 (TPH1), the rate-limiting enzyme for peripheral serotonin synthesis, has been implicated in metabolic disorders, but its hepatic role in MASLD remains unclear.
    Objective: To investigate whether Tph1 suppression alleviates lipid accumulation, mitochondrial dysfunction, and hepatocyte injury through changes associated with Parkin-mediated mitophagy.
    Methods: MASLD was induced in young adult male C57BL/6J mice by a 12-week high-fat diet (HFD). At HFD onset, mice received a single tail-vein injection of liver-tropic AAV8-shTph1 or the control AAV8. The HFD feeding was continued for 12 weeks until the end of the experiment. Hepatic histology, serum biochemistry, oxidative stress, inflammatory responses, apoptosis, and mitochondrial function were also evaluated. Mechanistic studies were conducted in palmitic acid/oleic acid-treated AML12 hepatocytes using siRNA targeting Tph1 and Parkin.
    Results: Hepatic TPH1 expression was elevated in MASLD mice. Tph1 knockdown alleviated diet-induced steatosis, reduced serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and transaminase levels, suppressed oxidative stress, and attenuated inflammatory and fibrotic markers. Tph1 silencing decreased hepatocyte apoptosis and restored mitochondrial function. Transmission electron microscopy and fractionated Western blotting analyses revealed increased Parkin-associated mitophagy. In AML12 cells, siTph1 reduced lipid accumulation and apoptosis, whereas co-silencing Parkin partially reversed these effects.
    Interpretation: Hepatic TPH1 is associated with MASLD progression and impaired Parkin-mediated mitophagy. Tph1 suppression may represent a potential therapeutic strategy for experimental MASLD, with possible translational relevance to pediatric MASLD, though direct clinical validation is still needed.
    Keywords:  Children; Metabolic dysfunction‐associated steatotic liver disease (MASLD); Parkin‐dependent mitophagy; Tryptophan hydroxylase‐1 (TPH1)
    DOI:  https://doi.org/10.1002/ped4.70078
  42. J Cell Mol Med. 2026 Sep;30(17): e71314
    RETRACTION: Kruppel-Like Factor 4 Improves Obesity-related Nephropathy Through Increasing Mitochondrial Biogenesis and Activities.
       RETRACTION: L. Jin, H. Ye, M. Pan, Y. Chen, B. Ye, Y. Zheng, W. Huang, S. Pan, Z. Shi, and J. Zhang, "Kruppel-Like Factor 4 Improves Obesity-related Nephropathy Through Increasing Mitochondrial Biogenesis and Activities," Journal of Cellular and Molecular Medicine 24, no. 2 (2019): 1200-1207, https://doi.org/10.1111/jcmm.14628. The above article, published online on 4 December 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Stefan N. Constantinescu; the Foundation for Cellular and Molecular Medicine; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties. Specifically, image elements in Figure 3C were found to have been previously published by a different author group in a different scientific context. Further investigation by the publisher identified undeclared splicing sites in the IκB blot in Figure 2F and in the α-porin blot in Figure 4c. Finally, the tubulin blot in Figure 4c was also found to have been previously published by a different author group in a different scientific context. The first author stated that the overlap of data with a previous publication lacking shared authorship was due to data theft from their laboratory. However, no further clarification or supporting raw data was provided for the remaining concerns. As a result, the article has been retracted as the editors have lost confidence in the integrity and reliability of the whole body of data and consider the article's conclusions invalid.
    DOI:  https://doi.org/10.1111/jcmm.71314
  43. Biomol Ther (Seoul). 2026 Sep 01. 34(5): 1267-1280
    Maslinic Acid Alleviates Obesity-Associated Skeletal Muscle Atrophy and Adipose Tissue Dysfunction in Obese Mice.
    Shu-Ju Wu, Chian-Jiun Liou, Ya-Ling Chen, Hui-Ling Peng, Wen-Chung Huang.
      Maslinic acid, a triterpenoid isolated from Olea europaea L., has been reported to exert anti-tumor and anti-inflammatory effects. Previous studies have shown that maslinic acid promotes skeletal muscle hypertrophy via mTORC1 and TGR5 signaling. Here, we examined the effects of maslinic acid on obesity-associated skeletal muscle atrophic changes and adipose tissue dysfunction. Male C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity and subsequently received maslinic acid via intraperitoneal injection. In parallel, differentiated C2C12 myotubes were exposed to palmitic acid to induce lipotoxic stress-associated atrophic changes and were treated with maslinic acid to examine related cellular responses. Maslinic acid increased gastrocnemius muscle weight and attenuated obesity-associated myofiber atrophic changes in HFD-fed mice. In skeletal muscle, maslinic acid treatment was associated with increased myosin IIa expression and AKT phosphorylation, reduced expression of the atrophy-related proteins MuRF1 and Atrogin-1, and changes in mitochondrial morphology and mitochondrial dynamics-related protein expression, including increased mitofusin-2 expression and decreased phosphorylation of dynamin-related protein 1 (DRP1). Consistently, in palmitic acid-treated C2C12 myotubes, maslinic acid treatment was associated with increased myosin IIa and mitofusin-2 levels and reduced MuRF1, Atrogin-1, and DRP1 phosphorylation. In addition, maslinic acid reduced epididymal fat mass in obese mice and altered macrophage-associated marker expression in epididymal adipose tissue. Collectively, these findings suggest that maslinic acid may ameliorate obesity-associated skeletal muscle atrophic changes and adipose tissue dysfunction, accompanied by reduced adiposity and treatment-associated changes in atrophy-related, mitochondrial dynamics-related, and macrophage-associated marker expression.
    Keywords:  Adipose dysfunction; Maslinic acid; Mitochondrial dynamics; Obesity; Skeletal muscle atrophy
    DOI:  https://doi.org/10.4062/biomolther.2026.072
  44. Naunyn Schmiedebergs Arch Pharmacol. 2026 Sep 02.
    Mechanistic insights into andrographolide-mediated cardioprotective action through mitochondrial homeostasis: a network pharmacology and in vivo approach.
    Pratiksha Jamadade, Krushna Ch Maharana, Sanjiv Singh.
      Cardiovascular aging is the progressive deterioration of heart and blood vessel function with advancing age. Despite advances in cardiovascular research, no specific therapy is currently available to prevent cardiac aging. Andrographolide, a bioactive diterpenoid, has shown cardioprotective potential, but its role in cardiac aging remains inadequately explored. To evaluate the mechanistic role of andrographolide in attenuating cardiac aging, with a particular focus on mitochondrial homeostasis. Cardiac aging was induced in male C57BL/6J mice by intraperitoneal administration of D-galactose (50 mg/kg/day). Mice were divided into control, andrographolide (50 mg/kg), D-galactose, and D-galactose + andrographolide (50 mg/kg). Andrographolide was administered orally for 8 weeks. Cardiac tissues were analyzed for oxidative stress, inflammation, apoptosis, and mitochondrial biogenesis-related markers TFAM, PGC-1α, and SIRT-1. Andrographolide treatment significantly improved cardiac function in D-galactose-induced aged mice. It enhanced antioxidant defenses while reducing inflammation and apoptosis. Immunohistochemical analysis demonstrated increased expression of SIRT1, PGC-1α, TFAM, and Nrf2, suggesting that andrographolide may promote mitochondrial biogenesis and antioxidant defense. Andrographolide confers significant cardioprotection against induced cardiac aging by modulating oxidative, inflammatory, and mitochondrial regulatory pathways. Thus, andrographolide can act as an ameliorative therapeutic drug for management of cardiac aging, warranting further mechanistic and translational investigations.
    Keywords:  Andrographolide; Apoptosis; Cardiac aging; Cardioprotection; D-Galactose
    DOI:  https://doi.org/10.1007/s00210-026-05853-1
  45. Food Sci Biotechnol. 2026 Sep;35(11): 3409-3421
    Broccoli-licorice-passionflower blend improves mitochondrial function and exerts senotherapeutic effects.
    So-Hyun Park, Hee Soo Kim, Pyeong Geun Choi, Eunyoung Lee, Do Yun Cho, Sun Ho Kim, Hui Yun Kim, Ahjin Kim, Jiyun Ahn, Chang Hwa Jung.
      Aging is driven by multiple interconnected mechanisms, necessitating interventions that target multiple hallmarks of aging. Using a data-driven prioritization strategy, we screened 16 extract combinations generated from four candidate extracts (broccoli, licorice, passionflower, and lemon balm) and identified an optimized formulation, Blend 2, composed of broccoli, licorice, and passionflower extracts. Blend 2 restored mitochondrial respiration, ATP production, and citrate synthase activity under DNA damage-induced mitochondrial dysfunction through activation of the SIRT1-AMPK-PGC-1α pathway and enhanced mitophagy. It also exhibited dual senotherapeutic activity by suppressing the senescence-associated secretory phenotype via NF-κB inhibition and selectively eliminating senescent cells through the Bax/caspase pathway. These findings demonstrate that data-driven formulation strategies can identify multifunctional natural product combinations and establish Blend 2 as a promising candidate for targeting multiple hallmarks of aging.
    Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10068-026-02265-y.
    Keywords:  Cellular senescence; Mitochondrial biogenesis; Mitophagy; Natural product blend; Senotherapeutics
    DOI:  https://doi.org/10.1007/s10068-026-02265-y
  46. Methods Enzymol. 2026 ;pii: S0076-6879(26)00199-0. [Epub ahead of print]734 121-149
    Identification of 2,4-dihydroxy-azaflavanone as an allosteric activator of SIRT1 and its potential role in cellular models of Parkinson's disease.
    Chitrakshi Pant, Vidya Jyothi Alli, Genji Sukumar, Abhijit Mohapatra, Surender Singh Jadav, Srihari Pabbaraja, Shasi V Kalivendi.
      Mitochondrial dysfunction is one of the significant aspects of Parkinson's disease (PD) pathophysiology, marked by a gradual decline in oxidative phosphorylation, an abnormal increase in free radical species, dysfunctional mitochondrial quality control, and faulty mitochondrial biogenesis. Sirtuin 1 (SIRT1), a NAD+-dependent class-III deacetylase, acts as a crucial metabolic sensor that orchestrates transcriptional programs related to mitochondrial biogenesis, respiratory chain assembly, and stress resilience, mainly by way of deacetylation and activation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). While screening for the small molecule activators, we have identified that 2,4-dihydroxy-Azaflavanone allosterically activates SIRT1. This chapter outlines a detailed, multi-layered methodological framework for assessing the allosteric activation of SIRT1 by 2,4-dihydroxy-azaflavanone and its downstream effects in a cellular models of PD. The validation process involves synthesis of small molecules, molecular docking studies utilizing crystallographic SIRT1 coordinates (PDB: 5BTR), in vitro fluorometric deacetylase assays with recombinant enzyme, and cellular thermal shift assays (CETSA) to confirm direct, isoform-selective target engagement. The activation of downstream pathways is evaluated by immunoblotting and quantitative PCR for PGC-1α, TFAM, and quantification of mitochondrial DNA (mtDNA) copy number. Functional restoration of mitochondria in cells is analyzed by assessing the overall mitochondrial bioenergetics parameters using Seahorse extracellular flux analyzer. Overall, this integrated approach offers robust, reproducible results for exploring SIRT1-activators in the mechanisms mediating neurodegenerative disease models.
    Keywords:  Azaflavanone; CETSA; Mitochondrial biogenesis; Mitochondrial membrane potential; MtDNA copy number; PGC-1α; Parkinson’s disease; SIRT1; Seahorse assay
    DOI:  https://doi.org/10.1016/bs.mie.2026.06.011
  47. Neuro Oncol. 2026 Aug 31. pii: noag202. [Epub ahead of print]
    Cancer-intrinsic SIRPα Signaling Triggers Mitochondrial Fission and Immune Tolerance to Promote TNBC Breast-to-Brain Metastasis.
    Yu-Ting Tsai, Jessica D Mackert, Adam Wilson, Mitra Kooshki, Valerie Payne, Jamie J Sagastume, Ashley Szymonski, Brian Westwood, Lance D Miller, Pierre L Triozzi, Dawen Zhao, Linda Metheny-Barlow, Masaki Terabe, Katherine L Cook, Glenn J Lesser, David R Soto-Pantoja.
       BACKGROUND: Triple negative breast cancer (require) new treatment strategies due to poor responses to current therapies. While myeloid SIRPα mediates immunosuppression, its cancer intrinsic role remains poorly understood.
    METHODS: Human breast cancer scRNAseq profiles were used to examine SIRPα expression across different cell populations and subtypes. TNBC brain-tropic cells were injected into the mouse mammary fat pad for the orthotopic tumor model, and intracardiac-injected for brain metastasis models. Bulk RNA sequencing was used to determine SIRPα-regulated pathway. Stably SIRPα overexpressed and knockout TNBC cell lines were established to determine SIRPα intracellular regulation. Digital spatial profiling was utilized to investigate the orthotopic and brain metastasis tumor immune microenvironment.
    RESULTS: Human single-cell data showed that SIRPα levels increased in malignant TNBC epithelial cells. We observed that SIRPα is upregulated in patient breast-to-brain metastatic lesions. SIRPα is overexpressed in TNBC brain-tropic cells compared to parental cells. Bulk RNA-Seq showed that targeting SIRPα affects genes involved in mitochondrial dynamics, and that SIRPα upregulates mitochondrial fission and induces metastasis through the SHP2/Erk/Drp1 signaling pathway. In vivo, overexpression of SIRPα in cancer cells significantly increases TNBC systemic metastasis. Next, spatial proteomics revealed changes in the immune microenvironment associated with the SIRPα-regulated ECM protein fibronectin. Fibronectin induces microglial tolerance by impairing inflammatory signaling and metabolic reprogramming, allowing cancer to escape microglial immunosurveillance. Most importantly, SIRPα inhibition reduced TNBC brain metastatic lesions in mouse metastasis models.
    CONCLUSION: : Cancer-intrinsic SIRPα promotes TNBC brain metastasis through increased mitochondria fission and triggering microglia tolerance, and targeting SIRPα reduces brain metastasis.
    Keywords:  TNBC brain metastasis; cancer-intrinsic SIRPα; microglia tolerance; mitochondria fission
    DOI:  https://doi.org/10.1093/neuonc/noag202
  48. MicroPubl Biol. 2026 ;2026
    Neurons and Glia Exhibit Distinct Age-Associated MitoTimer-Based Mitochondrial Dynamics in the Drosophila Mushroom Body Calyx.
    Allison Walsh, Abigail Wendland, Sofia Uriarte, Caroline Oliynyk, Anitej Akella, Lexxie Padron, Leonard Lorusso, Alice Tsybulski, Nahila Davis, Panteha Sartipi, Casey Spencer.
      Aging increases the prevalence of diseases with mitochondrial dysfunction, notably Alzheimer's and Parkinson's. This study assesses MitoTimer-based mitochondrial dynamics across the lifespan between neurons and glia. MitoTimer was expressed in neurons using nSyb-Gal4 and in glia using Repo-Gal4. MitoTimer red:green fluorescence ratios were quantified within or surrounding the mushroom body calyx of young, middle-aged, and old female Drosophila melanogaster . Paraquat-supplemented food increased red:green ratios relative to controls, supporting our use of MitoTimer. Neuronal red:green ratios peaked in middle age, whereas glial ratios were highest in young flies. These findings reveal distinct, age-dependent mitochondrial dynamics in neurons and glia.
    DOI:  https://doi.org/10.17912/micropub.biology.002249
  49. Nat Metab. 2026 Sep 04.
    UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.
    Feng Wang, Jin Lee, Jeong-Su Park, Meizhou Huang, Hwan Ma, Guoyan Sui, Zixiong Zhou, Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, Xuefeng Wu, Haram Lee, Soohwan Oh, Hanseul Park, Key-Hwan Lim, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, Michael Karin, Yoon Seok Roh, Ekihiro Seki.
      K63-linked ubiquitination (K63) is closely associated with the interaction, intracellular trafficking or activity of tagged proteins. However, its role during metabolic dysfunction-associated steatohepatitis (MASH) is largely unknown. Here we show that UBE2N, a ubiquitin-conjugating enzyme that specializes in creating K63, is downregulated by THAP11 in human and mouse hepatocytes with MASH. While hepatocyte-specific Ube2n deficiency exacerbates western diet-induced MASH and fibrosis via PANoptosis and impaired mitophagy, its overexpression reverses these pathological phenotypes and restores hepatic homeostasis. Mechanistically, UBE2N increases PARKIN-mediated K63-p62 at lysine 420, promoting K63-p62 translocation into damaged mitochondria for mitophagic clearance. Ube2n deficiency, conversely, induces cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis. Additional Sqstm1 deletion mitigates Ube2n deletion-induced pathologies, highlighting the importance of p62 accumulation for MASH progression. Thus, our results demonstrate that hepatocyte UBE2N is essential for regulation of metabolic stress-mediated mitophagy and PANoptosis, and that p62 is a proof-of-concept target for treating MASH and fibrosis.
    DOI:  https://doi.org/10.1038/s42255-026-01590-0
  50. Carbohydr Polym. 2026 Oct 15. pii: S0144-8617(26)00839-8. [Epub ahead of print]390 125722
    Structure and protection of Cichorium glandulosum polysaccharides against sarcopenic obesity through activating mitophagy via butyrate-GPR43-AMPK pathway.
    Chong Ma, Ruoyu Geng, Qiang Hou, Yao Zhao, Yanzhe Yue, Taotao Xue, Limei Wen, Tian Li, Jianhua Yang, Junping Hu.
      Sarcopenic obesity (SO) is a major complication of type 2 diabetes with limited therapeutic options. This study characterized CGP-A, a novel branched fructan (6.722 kDa) from Cichorium glandulosum. Its backbone consists of →1)-β-D-Fruf-(2→ and →6)-α-D-Glcp-(1→ residues, interspersed with →1,6)-β-D-Fruf-(2→ branching points. The side chains consist of terminal β-D-Fruf-(2→ units attached to the C-6 position of the fructofuranosyl residues in the backbone. In db/db mice, CGP-A dose-dependently ameliorated insulin resistance, hepatic steatosis, muscle loss and intestinal barrier dysfunction. Importantly, CGP-A significantly improved grip strength, reflecting an enhancement in muscle quality. Integrated multi-omics analysis combining metagenomics, multi-organ proteomics, and metabolomics revealed that CGP-A altered the gut microbiota, specifically enriching Ligilactobacillus, Bacteroides and Alistipes, while elevating serum butyrate. These findings suggest that butyrate may activate the GPR43-AMPK signaling pathway in both liver and skeletal muscle. Hepatic AMPK activation upregulated PPARα to enhance fatty acid oxidation; concurrently, muscular AMPK stimulated PINK1/Parkin-mediated mitophagy, restoring mitochondrial function and attenuating protein degradation. Antibiotic depletion abolished these effects, establishing the microbiota as a crucial mediator. These findings elucidate the gut microbiota-butyrate-GPR43-AMPK pathway through which CGP-A contributes to multi-organ metabolic improvements, offering a promising prebiotic strategy for managing SO.
    Keywords:  Cichorium glandulosum polysaccharide; Gut microbiota; Mitophagy; Sarcopenic obesity; Structural characterization
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125722
  51. Burns Trauma. 2026 ;14 tkag039
    4-phenylbutyric acid alleviated sepsis-induced myocardial dysfunction by inhibition of MAM formation to improve mitochondrial dynamic balance in myocardial cells.
    Yue Wu, Yijin Fang, Yuanqun Zhou, Qinghui Li, Liyong Zou, Xiaodan Wang, Li Wang, Ying Zheng, Liangming Liu, Yu Zhu.
       Background: Sepsis-related myocardial dysfunction significantly increases the mortality risk of sepsis. However, its underlying mechanism remains incompletely understood, and effective therapeutic strategies are still lacking. Transcriptomic profiling from septic patients showed endoplasmic reticulum stress (ERS) were the main pathways participating in the occurrence of sepsis myocardial dysfunction. Therefore, this study aimed to explore the protective effect of 4-phenylbutyric acid (4-PBA) on sepsis-induced myocardial injury and specify its molecular regulatory mechanism, to provide experimental basis for clinical intervention of septic myocardial dysfunction.
    Methods: In vivo and in vitro models of sepsis were used, and 4-PBA (5 mg/kg) was administered for intervention. Mitochondria-associated ER-membrane (MAM) formation, mitochondrial dynamics, mitochondrial function, glycolytic metabolism, and protein lactylation were systematically examined. Molecular docking and site-directed mutation were applied to verify the direct binding and catalytic sites of 4-PBA.
    Results: 4-PBA significantly alleviated sepsis-induced myocardial dysfunction (SIMD). The mechanism was closely related to 4-PBA inhibiting MAM formation and improving the mitochondrial dynamic balance and mitochondrial function. 4-PBA inhibited MAM formation mainly via decreasing the lactate production and lactylation of Arpc1b-K308 by inhibiting the glycolysis limiting enzyme HK2, and 4-PBA inhibited HK2 activity by binding K621 and K624 catalytic sites.
    Conclusions: The results indicate that 4-PBA protects cardiac function following sepsis by recovering mitochondrial dynamics balance. This finding provides a novel therapeutic strategy and potential target for SIMD.
    Keywords:  4-phenylbutyric acid; Endoplasmic reticulum stress; Hexokinase 2; Lactylation; MAM; Mitochondrial dynamics; Myocardial dysfunction; Sepsis
    DOI:  https://doi.org/10.1093/burnst/tkag039
  52. J Alzheimers Dis. 2026 Aug 31. 13872877261480043
    Research progress on terpenoids alleviating Alzheimer's disease through the Keap1/Nrf2/ARE pathway by exerting antioxidant effects and promoting mitophagy.
    Wanting Zhang, Shan Wang, Xingchun Gou.
      The exact initiating causes of Alzheimer's disease (AD) remain inconclusive. Meanwhile, the causal sequence and interactions within its pathological network are still poorly understood, which limits the efficacy of single treatment strategies and impedes drug development. Oxidative stress, identified as a central intersection point within this network, drives the deposition of amyloid-β protein, excessive tau phosphorylation, neuroinflammation, and mitochondrial damage, creating a self-perpetuating cycle. Consequently, oxidative stress has become a focal point for multi-target interventions. This review systematically investigates the evidence of terpenoids in cellular and animal models, elucidating their protective effects via a dual antioxidant mechanism. Firstly, terpenoids activate the Keap1/Nrf2/ARE pathway, leading to the upregulation of antioxidant genes and reduced free radical generation. Secondly, they enhance PINK1/Parkin-mediated mitophagy, facilitating the clearance of damaged organelles and preventing the release of reactive oxygen species. The review also delves into the positive feedback regulatory network involving molecules like Nrf2 and key proteins of mitophagy, such as p62/SQSTM1, offering a detailed mechanistic insight into the synergistic effects of terpenoids. This study underscores the significance of natural terpenoids, with their unique regulatory role in oxidative stress, as a promising candidate library for Alzheimer's drug development due to their diverse structures, clear mechanisms, and high safety profile. Additionally, it establishes a theoretical and experimental basis for the development of novel intervention strategies targeting multiple pathways with a single drug.
    Keywords:  Alzheimer's disease; Keap1/Nrf2/ARE pathway; antioxidants; mitophagy; oxidative stress; terpenoids
    DOI:  https://doi.org/10.1177/13872877261480043
  53. Zhongguo Zhong Yao Za Zhi. 2026 Aug;51(15): 4387-4400
    [Mechanism study of Linggui Zhugan Decoction in improving post-myocardial infarction heart failure by modulating MAOA/4-HNE/MCU pathway].
    Rong Wang, Sheng-Yi Huang, Fang Wang, Jin-Ling Huang.
      Mitochondrial calcium(mtCa~(2+)) overload constitutes a core pathological process in the initiation and progression of heart failure(HF) following myocardial infarction(MI). Abnormal accumulation of the lipid peroxide 4-hydroxynonenal(4-HNE) mediated by monoamine oxidase A(MAOA), as well as dysfunction of the mtCa~(2+) uniporter(MCU), can both induce mtCa~(2+) overload. Linggui Zhugan Decoction(LGZGD), a classical traditional Chinese medicine prescription for the treatment of cardiovascular diseases, is extensively used to manage post-MI HF. However, its regulatory effects on mtCa~(2+) homeostasis and the underlying molecular mechanisms remain unclear. In the present study, a rat model of post-MI HF and a H_2O_2-induced oxidative stress model in H9C2 cardiomyocytes were established, combined with MAOA overexpression and knockdown validation experiments, to systematically investigate the cardioprotective mechanisms of LGZGD. The results revealed that LGZGD significantly improved cardiac systolic function in MI rats(P&lt;0.01), reduced creatine kinase(CK) and lactate dehydrogenase(LDH) activities(P&lt;0.05), alleviated myocardial pathological injury, and significantly decreased the level of the oxidative stress marker 4-HNE while restoring the content of the antioxidant glutathione(GSH)(P&lt;0.05). In vitro experiments further demonstrated that LGZGD-medicated serum effectively suppressed apoptosis in H9C2 cardiomyocytes, restored mitochondrial membrane potential(P&lt;0.01), and promoted mitophagy to eliminate damaged mitochondria. Moreover, LGZGD markedly inhibited MAOA expression and activation, reduced 4-HNE accumulation, subsequently downregulated MCU-mediated mtCa~(2+) overload, and effectively maintained mtCa~(2+) homeostasis(P&lt;0.01). MAOA functional modulation experiments further demonstrated that MAOA knockdown mimicked the protective effects of LGZGD, whereas MAOA overexpression exacerbated cardiomyocyte injury, and LGZGD partially reversed this adverse effect(P&lt;0.05). Collectively, this study confirms that LGZGD significantly ameliorates post-MI HF and oxidative stress-induced cardiomyocyte injury, with the underlying mechanism closely associated with modulation of the MAOA/4-HNE/MCU pathway, clearance of damaged mitochondria, and maintenance of mtCa~(2+) homeostasis.
    Keywords:  Linggui Zhugan Decoction; calcium homeostasis; heart failure; mitophagy; monoamine oxidase A; oxidative stress
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20260326.801
  54. Front Pharmacol. 2026 ;17 1873606
    Liuwei Dihuang pills attenuates cognitive dysfunction in APP/PS1 mice through restoring mitochondrial homeostasis and activating the IRS/AKT/GSK3β insulin signaling pathway.
    Junying Song, Yong Yuan, Mao Wang, Junlin Li, Rui Ding, Yaquan Jia, Zichuang Wang, Zhishen Xie, Zhonghua Li, Zhenqiang Zhang.
       Introduction: Alzheimer's disease (AD) features progressive cognitive decline, Aβ aggregation, neurofibrillary tangles, mitochondrial dysfunction and central insulin resistance, lacking effective disease-modifying treatments. Liuwei Dihuang Pills (LWDHP) exert neuroprotective effects, while its dual regulatory mechanisms targeting mitochondrial homeostasis and cerebral IRS/AKT/GSK3β insulin signaling remain unclear.
    Methods: APP/PS1 transgenic mice were used as AD models. Morris water maze assessed spatial cognition; immunofluorescence detected Aβ and MAP2; transmission electron microscopy observed neuronal/synaptic ultrastructure; western blot quantified synaptic proteins and insulin signaling cascade molecules.
    Results: LWDHP significantly rescued spatial learning and memory deficits, reduced cerebral Aβ plaques and tau hyperphosphorylation. LWDHP balanced mitochondrial fusion-fission via upregulating PGC-1α/MFN2 and downregulating FIS1, elevated synaptic structural proteins (MAP2, PSD-95, SYN), restored cerebral insulin sensitivity by elevating InsR, normalizing IRS-1/AKT/GSK3β phosphorylation, and suppressing tau hyperphosphorylation.
    Discussion: LWDHP alleviates AD cognitive impairment through dual regulation of mitochondrial homeostasis and IRS/AKT/GSK3β insulin signaling, providing solid preclinical evidence for its anti-AD application.
    Keywords:  IRS/AKT/GSK3β insulin signaling pathway; Liuwei Dihuang Pills (LWDHP); alzheimer’s disease (AD); cognitive deficits; mitochondrial homeostasis
    DOI:  https://doi.org/10.3389/fphar.2026.1873606
  55. NPJ Dement. 2026 ;2(1): 83
    Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.
    Shatakshi Shukla, Devin Kolmetzky, Shanikumar Goyani, Kunal Samantaray, Anupriya Sinha, Philip A Kramer, Dhanendra Tomar, Pooja Jadiya.
      Alzheimer's disease (AD) lacks effective therapies, partly due to an incomplete understanding of mitochondrial dysfunction, a key driver of neurodegeneration. Mitochondria activate the unfolded protein response (UPRmt) to maintain proteostasis, but the roles of matrix- and intermembrane space (IMS)-associated stress responses in AD remain unclear. Here, we used human microglial-like cells expressing mutant amyloid precursor protein together with compartment-targeted mitochondrial proteotoxic stressors to investigate matrix (UPRmt-MM) and IMS (UPRmt-IMS) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPRmt-MM promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPRmt-IMS preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPRmt signaling rescued mitochondrial dysfunction and reduced Aβ release. Together, these findings demonstrate that matrix- and IMS-targeted mitochondrial stress elicit distinct microglial responses and identify mitochondrial proteostasis as a potential therapeutic target in AD.
    Keywords:  Cell biology; Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1038/s44400-026-00137-0
  56. Int J Biol Sci. 2026 ;22(13): 6892-6913
    Targeting Mitochondrial PD-L1 O-GlcNAcylation to Sensitize HBV-Related HCC to Immunotherapy: Modulating Golgi-mitochondrial Crosstalk and mTOR/PGC-1α-Driven Mitochondrial Biogenesis to Overcome Resistance.
    Ze-Bang Du, Xin-Yu Ma, Han-Yu Zhang, Jia-Ming Lei, Xin-Xin He, Wen-Qi Xu, Wen-Dan Zhou, Xiao-Gang Xia, Ao-Bo Zhuang, Xiao-Xuan Chen, You-Liang Yao, Wen-Gang Li, Yu-Chun Lin, Zhong-Ning Lin.
      Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with chronic hepatitis B virus (HBV) infection representing its foremost risk factor. Although programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have entered clinical practice, response rates in HBV-related HCC remain limited, underscoring the urgent need for mechanism-based strategies to overcome intrinsic resistance and improve immune checkpoint blockade (ICB) efficacy by exploiting noncanonical PD-L1 functions. Here, we identify a non-canonical pathway in which the HBV-encoded X protein (HBx) drives O-GlcNAcylation (O-GlcNAc) of PD-L1 at S283 and T285, thereby promoting PD-L1 mitochondrial translocation via the GOLPH3/Drp1 axis. Mitochondrial PD-L1 (mtPD-L1) hijacks Golgi-mitochondria communication to activate the mTOR/PGC-1α axis, enhance mitochondrial biogenesis and translation, and reprogram cellular energy metabolism, ultimately conferring resistance to anti-PD-L1 antibody (αPD-L1) therapy in HBV-related HCC. Pharmacological inhibition of O-GlcNAcylation with OSMI-1 disrupts this mtPD-L1 regulatory axis, restores mitochondrial homeostasis, and sensitizes HBV-related HCC to αPD-L1 therapy. Collectively, these findings identify O-GlcNAcylated mtPD-L1 as a previously unrecognized immunometabolic checkpoint and establish the mtPD-L1-mTOR/PGC-1α axis as a key mechanism linking mitochondrial biogenesis to immunotherapy resistance. This study provides a rationale for combining αPD-L1 with OSMI-1-mediated O-GlcNAcylation inhibition as a therapeutic strategy to improve immunotherapy sensitivity in HBV-related HCC.
    Keywords:  HBV-related HCC; O-GlcNAcylation of mitochondrial PD-L1; immunotherapy resistance; mTOR/PGC-1α signaling axis; mitochondrial biogenesis; αPD-L1 combination therapy.
    DOI:  https://doi.org/10.7150/ijbs.126948
  57. Free Radic Biol Med. 2026 Sep 04. pii: S0891-5849(26)01137-8. [Epub ahead of print]
    Exercise-Induced Intercellular Mitochondrial Transfer: Redox Signaling as a Candidate Regulatory Mechanism.
    Mei Ma, Jinze Tian, Zhe Wang, Ziyi Zhang, Yong Zhang, Hai Bo.
      Intercellular mitochondrial transfer has been recognized as an important mechanism for maintaining tissue homeostasis and adapting to stress. Mitochondria can cross cellular boundaries through tunneling nanotubes, extracellular vesicles, and free mitochondrial release. However, the physiological signals coordinating these pathways remain poorly defined. Exercise is a potent inducer of transient redox signaling, generating superoxide and hydrogen peroxide while modulating mitochondrial dynamic remodeling. This review integrates exercise redox biology with redox regulation of transfer machinery characterized in non-exercise models, proposing that exercise-induced redox signaling may function as a candidate regulatory mechanism. The framework emphasizes bidirectional redox coordination, in which oxidant pulses may activate export in donor cells and prepare recipient cells for uptake and antioxidant defense. Exercise-induced mitochondrial transfer has been directly demonstrated in the brain, while observations in skeletal muscle, adipose tissue, and heart remain suggestive but have not been confirmed in exercise models. These findings support a framework in which intercellular mitochondrial transfer contributes to metabolic signaling, antioxidant defense, and distributed quality control across organs. This model represents a working hypothesis requiring direct experimental validation through lineage tracing, tissue-specific mitochondrial reporters, and intravital imaging.
    Keywords:  exercise; mitochondrial biogenesis; mitochondrial quality control; mitochondrial transfer; redox signaling; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.003
  58. Int J Med Sci. 2026 ;23(9): 2884-2898
    CRISPR/Cas9-Driven Fndc5 Knockout Reveals Augmented Mitochondrial Structural and Dynamic Alterations in Diabetic Nephropathy.
    Chien-Wei Huang, Hsin-Hung Chen, Tzu-Ming Jao, Chia-Jung Li, Junne-Ming Sung, Yau-Sheng Tsai, Jin-Shuen Chen.
      FNDC5 has been implicated in glucose homeostasis and is associated with mitochondrial function. Its role in diabetes and diabetic nephropathy (DN) remains unclear. This study hypothesizes that FNDC5 deficiency predisposes the kidney to accelerated mitochondrial dysfunction in diabetes and DN. Systemic Fndc5 knockout (KO) C57BL/6 mice were generated using CRISPR/Cas9. DN were induced in six-week-old Fndc5 wild-type (WT) and KO mice using high-fat diet combined with streptozotocin injection. Weekly blood and urine analyses assessed glucose, cholesterol, triglycerides, blood urea nitrogen, creatinine, and proteinuria. At 15 weeks, kidneys and metabolic tissues including pancreas, muscle and adipose were collected for histological and molecular analyses. Results showed that while both Fndc5 WT and KO mice were successfully induced with hyperglycemia, the Fndc5 KO DN group exhibited a slightly lower cumulative glycemic burden compared with the WT DN group. Despite this milder metabolic stress, proteinuria remained comparable between the two groups. Furthermore, histological analysis revealed that Fndc5 KO DN mice displayed more severe mesangial expansion, glomerular basement membrane thickening, and podocyte effacement compared with WT DN mice. The elevated lipid peroxidation, reduced PGC-1α expression, and increased DNA fragmentation were also evident in Fndc5 KO DN. More swollen mitochondria with a significantly higher percentage of disrupted cristae were observed in Fndc5 KO DN mice compared with WT DN mice. This was accompanied by the upregulation of mitochondrial fission-related genes (Dnm1l and Fis1), downregulation of the fusion-related gene (Mfn1), and reduced expression of ATP synthase subunits (ATP5A1 and ATP5B). Systemic analysis of other metabolic tissues, including the pancreas and muscle and adipose tissues, revealed increased lipid peroxidation and decreased PGC-1α expression. These findings underscore FNDC5's role in maintaining mitochondrial integrity and cellular health under diabetic conditions, positioning FNDC5 as a potential therapeutic target.
    Keywords:  Fndc5; diabetic nephropathy; irisin; mitochondrial dynamics; mitochondrial morphology; oxidative stress
    DOI:  https://doi.org/10.7150/ijms.131007
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