bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–07–27
sixty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. Hepatic ischemia-reperfusion and mitochondrial quality control: potential therapeutic targets.
  2. ROS-Drp1-mitophagy feedback loop regulates myogenic differentiation via actin cytoskeleton remodeling-mediated MRTF-A/SRF axis.
  3. Age-Dependent Changes in Mitochondrial Regulatory Mechanisms in the Spinal Cord of SOD1-G93A-Transgenic Mice with the Phenotype of Amyotrophic Lateral Sclerosis.
  4. Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.
  5. Astragaloside IV Alleviates H2O2-Induced Mitochondrial Dysfunction and Inhibits Mitophagy Via PI3K/AKT/mTOR Pathway.
  6. Mitochondrial dynamics in diabetic peripheral neuropathy: Pathogenesis, progression, and therapeutic approaches.
  7. Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.
  8. Mitochondrial autophagy inhibits nucleotide-binding oligomerization domain-like receptor protein 3-mediated pyroptosis and alleviates endothelial cell injury in pregnancy-induced hypertension.
  9. MeCP2 dysregulation inhibits mitophagy and impairs neural development in cortical organoids.
  10. GNPAT/USP30 Stabilizes DRP1 Protein to Promote Mitochondrial Fission and Functional Damage in COPD Progression.
  11. Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
  12. Parkin aggravates symptoms of preeclampsia through promoting mitophagy and apoptosis.
  13. PHLPP1 regulates region-specific astroglial mitochondrial fission in response to oxidative stress in the male rat hippocampus.
  14. Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.
  15. UCP2 MEDIATES MITOCHONDRIAL DYNAMICS TO INDUCE AgRP NEURONAL ACTIVITY.
  16. Yoda1/Piezo1 Alleviates Lipopolysaccharide-Induced Cardiac Injury via AMPK-Mediated Mitophagy.
  17. Oxymatrine attenuates pulmonary fibrosis via APE1‑mediated regulation of the PINK1/Parkin pathway.
  18. Bidirectional Regulation of Neuronal Autophagy in Ischemic Stroke: Mechanisms and Therapeutic Potential.
  19. Voluntary exercise alleviates ischemic brain injury in mice by modulating mitochondrial dysfunction.
  20. Erythropoietin (EPO) Alleviates Chronic Stress-Induced Depression by Modulating SIRT1-Mediated Mitochondrial Function.
  21. Stressful situations: molecular insights on mitochondrial quality control pathways.
  22. Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.
  23. RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer.
  24. Caffeic acid phenethyl ester protects renal tubular epithelial cells against ferroptosis in diabetic kidney disease via restoring PINK1-mediated mitophagy.
  25. Corrigendum to "Qishentaohong granules alleviate heart failure by modulating mitochondrial fission and mitophagy balance" [J. Ethnopharmacol. 352 (2025) 120190].
  26. PTEN-L dephosphorylates Parkin and Ub Ser65 to aggravate mitophagy dysfunction in prion disease cell models.
  27. The Evolution of Alzheimer's Disease: From Mitochondria to Microglia.
  28. AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.
  29. Novel mitophagy inducer TJ0113 alleviates pulmonary inflammation during acute lung injury.
  30. Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
  31. [Mechanism of Jiming Powder in improving mitophagy for treatment of myocardial infarction based on PINK1-Parkin pathway].
  32. Role of Mitochondria-Associated ER in Apoptosis.
  33. Mortalin and PINK1/Parkin-Mediated Mitophagy Represent Ovarian Cancer-Selective Targets for Drug Development.
  34. EphrinB2 alleviates tubulointerstitial fibrosis in diabetic kidney disease.
  35. PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning.
  36. Retraction notice to "Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease" [Pharmacol. Res., Vol. 174 (2021) 105973].
  37. Inhibiting MARCH5/Mfn2 signaling as an alternative strategy to protect cardiomyocytes from hypoxia-induced mitochondrial dysfunction.
  38. Mammalian Sterile 20-Like Kinase 2 Knockdown Alleviates Neuropathic Pain in Rats by Mitochondrial Protection.
  39. DNAJC6 in Acute Kidney Injury: A Novel Target for Protecting Renal Tubular Epithelial Cells Through PGC-1α-Mediated Mitochondrial Homeostasis.
  40. NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.
  41. Single-Cell Sequencing Identifies the Crucial Role of Mitochondrial Fission-Fusion Imbalance in Heart Failure Progression.
  42. Mitochondrial bioenergetic failure in SLE immunocytes: Targeting fitness for therapy.
  43. Engineering a cell-based orthogonal ubiquitin transfer cascade for profiling the substrates of RBR E3 Parkin.
  44. Increased ROS levels activate AMPK-ULK1-mediated mitophagy to promote pseudorabies virus replication.
  45. Enhanced Mitochondrial Dynamics and Reactive Oxygen Species Levels with Reduced Antioxidant Defenses in Human Epicardial Adipose Tissue.
  46. Mitophagy: A key regulator of radiotherapy resistance in the tumor immune microenvironment.
  47. Reversal of neurodevelopmental toxicity induced by combined exposure to the neonicotinoid insecticides acetamiprid and imidacloprid in zebrafish through targeting DRP-1: insights into mitophagy and apoptosis mechanisms.
  48. Rett syndrome: Pathogenicity and regulation of MECP2 (human) and Mecp2 (mouse) genes and their protein products through various molecular mechanisms.
  49. [Alleviation of hypoxia/reoxygenation injury in HL-1 cells by ginsenoside Rg_1 via regulating mitochondrial fusion based on Notch1 signaling pathway].
  50. IL-1β-Mediated Immunometabolic Adaptation in Corneal Epithelial Cells.
  51. Magnolin Promotes PINK1-Parkin-mediated Mitophagy in Diffuse Large B-cell Lymphoma Cells via PPAR-γ Pathway.
  52. Natural Products in Regulating Mitophagy for the Intervention of Atherosclerosis and Its Risk Factors: Mechanisms and Therapeutic Potential.
  53. Determination of Mitochondrial Morphology in Live Cells Using Confocal Microscopy.
  54. [MiR-1-3p inhibits mitophagy in esophageal squamous cell carcinoma by targeting SLC7A11].
  55. MITF promotes MFN2-dependent mitochondrial fusion to protect retinal pigment epithelial cells from mitochondrial damage.
  56. Critique of "Repression of PGC-1α leads to loss of mitochondrial homeostasis, contributing to maladaptive kidney repair".
  57. Alpha-Heredin targets CAMKⅡ/DRP1-Mediated mitochondrial fission to trigger ferroptosis in pancreatic ductal adenocarcinoma.
  58. The DRP1 receptor FIS1 is critical to the expansion of triple-negative breast cancer tumor-initiating cells.
  59. SARS-CoV-2-Induced Phosphorylation of HSPA9 at Ser627: Potential Implications for Mitochondrial Function, Cell Cycle Regulation, and Immune Evasion.
  60. Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control.
  61. A protein-specific priority code in presequences determines the efficiency of mitochondrial protein import.
  62. LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
  63. TRAP1 Improves Diabetic Retinopathy by Preserving Mitochondrial Function.
  64. The mammalian protein MTCH1 can function as an insertase.
  1. Int Immunopharmacol. 2025 Jul 23. pii: S1567-5769(25)01257-3. [Epub ahead of print]163 115267
    Hepatic ischemia-reperfusion and mitochondrial quality control: potential therapeutic targets.
    Junqi Wang, Wenkai Fu, Nan Lu, Zhijiang Guo, Ong Sang Bing, Hongshuo Shi, Hao Zhou, Xing Chang, Miao Meng.
       BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) represents a significant challenge in liver surgical procedures. This complex pathology arises from the interplay of inflammation, oxidative damage, and regulated cell death cascades. Compromised mitochondrial function critically contributes to HIRI progression. Consequently, maintaining cellular equilibrium necessitates effective mitochondrial quality control (MQC), a fundamental axis encompassing mitochondrial autophagy, dynamic remodeling, biogenesis, and the mitochondrial unfolded protein response (UPRmt).
    KEY MECHANISMS: Mitophagy: Selectively removes damaged mitochondria via PINK1/Parkin (ubiquitin-dependent) and BNIP3/FUNDC1 (ubiquitin-independent) pathways. Impaired mitophagy during ischemia-reperfusion exacerbates mitochondrial damage, while enhancing it (e.g., via PEG35, Sirtuin activators) mitigates injury. Mitochondrial Dynamics: The stability of the mitochondrial network is critically dependent on the equilibrium between fusion, regulated by Mfn1, Mfn2, and Opa1, and fission, mediated by Drp1. HIRI disrupts this equilibrium, promoting fragmentation and apoptosis. Pharmacological agents (e.g., DEX, exogenous irisin) restore dynamics by modulating Drp1 and fusion proteins. Biogenesis: The PGC-1α/NRF-1/TFAM axis drives mitochondrial renewal. HIRI suppresses biogenesis, but interventions (e.g., ADSC-exo, genipin) enhance ATP production and mitochondrial DNA replication.
    THERAPEUTIC INTERVENTIONS: Pharmacological strategies targeting MQC components demonstrate efficacy: Mitophagy: PEG35 enhances ALDH2-mediated LC3 conversion; quercetin regulates SIRT1/TMBIM6. Dynamics: COX-2 inhibitors and SIRT3 deacetylate Opa1 to promote fusion. Biogenesis: Irisin and NRF2 activators upregulate PGC-1α/TFAM, restoring mitochondrial mass.
    CONCLUSION: MQC mechanisms are pivotal in HIRI pathogenesis. Targeting mitophagy, dynamics, and biogenesis offers promising therapeutic avenues to attenuate inflammation, oxidative stress, and cell death. Translational research on MQC modulators (e.g., PEG35, Sirt1 activators) may yield novel treatments.
    Keywords:  Apoptosis; HIRI; Inflammation; MQC; Oxidative stress
    DOI:  https://doi.org/10.1016/j.intimp.2025.115267
  2. Redox Rep. 2025 Dec;30(1): 2536400
    ROS-Drp1-mitophagy feedback loop regulates myogenic differentiation via actin cytoskeleton remodeling-mediated MRTF-A/SRF axis.
    Aiwen Jiang, Luyao Wang, Xinyu Liu, Jialong Li, Haifei Wang, Shenglong Wu, Wenbin Bao.
       BACKGROUND: Mitochondrial division is one of the main characteristics for the initiation of myogenic differentiation. However, the role and mechanism of Dynamin-related protein 1 (Drp1), the most important protein that regulates mitochondrial fission in mammals, in regulating myogenic differentiation are not well understood.
    METHODS: Drp1 siRNAs were transfected to C2C12 cells, or AAV9-shDrp1 were injected to C57BL/6J mice to knockdown Drp1 expression. Then, mitochondrial damage, ROS level, myogenic differentiation, mitophagy and actin/MRTF-A/SRF pathway was detected by quantitative real-time PCR, western blotting, immunofluorescence staining and flow cytometry.
    RESULTS: The results showed that Drp1 was upregulated after C2C12 differentiation; Drp1 knockdown by siRNA transfection impaired myotube formation. ROS are the upstream activators for Drp1 expression, and Drp1 inversely reduces ROS by facilitating mitophagy to form a ROS-Drp1-mitophagy feedback loop during myogenic differentiation. Knockdown of Drp1 disrupted the ROS-Drp1-mitophagy feedback loop-mediated ROS homeostasis, thereby accelerating F-action depolymerization and blocking MRTF-A nuclear translocation by reducing the phosphorylation of cofilin. A decrease in MRTF-A nuclear translocation impaired SRF activity and hindered myogenic differentiation.
    CONCLUSION: In summary, this study revealed the functional mechanism of Drp1 and clarified the interactions among ROS, Drp1-mediated mitophagy and actin cytoskeleton remodeling during myogenic differentiation.
    Keywords:  Drp1; MRTF-A; ROS; SRF; actin cytoskeleton; cofilin; mitophagy; myogenic differentiation
    DOI:  https://doi.org/10.1080/13510002.2025.2536400
  3. Bull Exp Biol Med. 2025 May;179(1): 34-40
    Age-Dependent Changes in Mitochondrial Regulatory Mechanisms in the Spinal Cord of SOD1-G93A-Transgenic Mice with the Phenotype of Amyotrophic Lateral Sclerosis.
    N V Belosludtseva, I B Mikheeva, V S Starinets, M V Dubinin, K N Belosludtsev.
      Age-dependent changes in the expression level of genes encoding proteins responsible for mitochondrial homeostasis were studied in relation to ultrastructural abnormalities in the mitochondria of motor neurons in the anterior horns of the spinal cord in a transgenic model of amyotrophic lateral sclerosis (SOD1-G93A mice). The expression of the Drp1, Mfn2, Ppargc1a, and Nefl genes was reduced, and the expression of the Nfe2l2, Pink1, and Parkin genes was enhanced in mice with the genotype of the familial form of the disease at the age of 22 weeks corresponding to the symptomatic stage in comparison with wild-type mice (C57BL6 × SJL) and non-transgenic littermates (SOD1-G93A(Tg-)) of the same age. Comparative analysis of spinal cord tissue samples from 8 and 12 weeks-old animals revealed no significant differences in the expression levels of genes encoding proteins responsible for mitochondrial dynamics, biogenesis, and mitophagy. Electron microscopic examination showed pronounced structural alterations in mitochondria in the soma of lower motor neurons of SOD1-G93A(Tg+) mice at the symptomatic stage, which manifested in the appearance of "ring-like" mitochondrial structures, matrix swelling, destruction of membranes in the cristae, and increased number of autophagolysosomes. The role of mitochondrial homeostasis disorders in the progression of amyotrophic lateral sclerosis is discussed.
    Keywords:  amyotrophic lateral sclerosis; lower motor neurons; mitochondrial biogenesis; mitochondrial dynamics; spinal cord
    DOI:  https://doi.org/10.1007/s10517-025-06429-4
  4. Mol Cell Biochem. 2025 Jul 24.
    Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.
    Francisco Alejandro Lagunas-Rangel.
      Mitochondria are highly dynamic organelles essential for cellular energy production. However, they are also a primary source of reactive oxygen species, making them particularly vulnerable to oxidative damage. To preserve mitochondrial integrity, cells employ quality control mechanisms such as mitophagy, a selective form of autophagy that targets damaged or dysfunctional mitochondria for degradation. Among the key regulators of mitophagy are the sirtuins, a family of NAD+-dependent deacetylases. SIRT1, SIRT3, and SIRT6 generally promote mitophagy, whereas SIRT2, SIRT4, SIRT5, and SIRT7 often act as negative regulators. Sirtuin-mediated regulation of mitophagy is critical for maintaining cellular homeostasis and is implicated in a variety of physiological and pathological conditions. The aim of this review is to provide an overview focused on describing how sirtuins influence the mitophagy process. It highlights the different molecular mechanisms by which individual members of the sirtuin family modulate mitophagy, either by promoting or suppressing it, depending on the context. In addition, the review explores the relevance of sirtuin-regulated mitophagy in health and disease, emphasizing some conditions under which altered sirtuin activity could be harnessed for therapeutic benefit.
    Keywords:  FOXO transcription factors; Mitochondria; PINK1-PARKIN pathway; Receptor-mediated mitophagy; Ubiquitin-mediated mitophagy
    DOI:  https://doi.org/10.1007/s11010-025-05358-0
  5. Cardiovasc Ther. 2025 ;2025 9549175
    Astragaloside IV Alleviates H2O2-Induced Mitochondrial Dysfunction and Inhibits Mitophagy Via PI3K/AKT/mTOR Pathway.
    Miaomiao Qi, Qiongying Wang, Runmin Sun, Zeyi Cheng, Mingze Li, Xin Fan, Feng Bai, Jing Yu.
      Oxidative stress and mitochondrial dysfunction play critical roles in the pathology of cardiovascular diseases. However, the effects of Astragaloside IV (As-IV) on mitochondrial function remain unclear. This study is aimed at evaluating the protective effects and mechanism of As-IV against H2O2-induced mitochondrial dysfunction in H9c2 cells. H9c2 cells were exposed to 200 μM H2O2 with or without As-IV. The level of apoptosis and reactive oxygen species (ROS) was measured by flow cytometry. Confocal microscopy and transmission electron microscopy were performed to detect the changes in mitochondrial membrane potential (MMP), mitochondrial morphology, and autophagosome. Mitochondrial dynamics and mitophagy-related proteins were measured by Western blot. The results indicated that As-IV decreased H2O2-induced apoptosis and ROS generation. Meanwhile, As-IV significantly increased MMP, exerted regulatory effects on mitochondrial dynamics, and ameliorated the damaged mitochondrial morphology in H2O2-injured cardiomyocytes. Additionally, As-IV decreased the amount of autophagosome and expressions of PINK1 and Parkin, but upregulated the expressions of PI3K, p-AKT, and p-mTOR proteins. However, cotreatment with LY294002 diminished the upregulation of PI3K, p-AKT, and p-mTOR induced by As-IV. In the study, we demonstrated that As-IV protected H9c2 cells from H2O2-induced mitochondrial dysfunction by inhibiting mitophagy, which might be related to the PI3K/AKT/mTOR pathway.
    Keywords:  Astragaloside IV; PI3K/AKT/mTOR; mitochondrial dysfunction; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1155/cdr/9549175
  6. Medicine (Baltimore). 2025 Jul 18. 104(29): e42748
    Mitochondrial dynamics in diabetic peripheral neuropathy: Pathogenesis, progression, and therapeutic approaches.
    Honghai Yu, Cunqing Yang, Guoqiang Wang, Xiuge Wang.
      Diabetic peripheral neuropathy (DPN) is a chronic complication resulting from late-stage peripheral nerve damage in diabetes. It is associated with pain and can lead to foot ulcers and even amputations. Currently, there are no reversible treatments for DPN. The pathophysiology of DPN is extremely complex and involves multiple mediating factors. Despite extensive research by scholars worldwide, the exact mechanisms underlying DPN remain incompletely understood. Recent evidence increasingly supports the notion that dysregulation of mitochondrial fission and fusion proteins, which regulate mitochondrial morphology and quantity in neurons under hyperglycemic conditions, may be a key pathological mechanism of DPN. In fact, processes such as metabolism, energy production, inflammation, reactive oxygen species generation, and apoptosis rely on the balance between fission and fusion. Pathological alterations in this balance can lead to bioenergetic dysfunction and mitochondrial-mediated cell death, thus contributing to the progression of DPN. Mitochondria regulate their number, quality, and function through mitochondrial dynamics (fission and fusion) to maintain homeostasis and cope with structural and functional impairments under high-glucose conditions. This article discusses the pathophysiological changes in DPN, the role of mitochondrial dynamics in its pathogenesis, and current targeted mitochondrial therapies, aiming to enhance the understanding of the mechanisms involved in DPN and to explore more effective treatment methods and intervention strategies.
    Keywords:  diabetic peripheral neuropathy; mitochondrial dynamics; pathologic mechanisms; pathophysiological
    DOI:  https://doi.org/10.1097/MD.0000000000042748
  7. Inflammopharmacology. 2025 Jul 22.
    Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.
    Pouya Goleij, Mohammad Amin Khazeei Tabari, Mohadeseh Poudineh, Pantea Majma Sanaye, Haroon Khan, Alan Prem Kumar, Danaé S Larsen, Maria Daglia.
      Neurons rely heavily on functional mitochondria for energy production. Mitochondrial dysfunction is a key player in age-related neurodegenerative diseases like Alzheimer's disease (AD). In AD, damaged mitochondria accumulate early, worsening the disease. This dysfunction disrupts cellular balance in neurons, leading to energy deficiencies, calcium imbalances, and oxidative stress. These issues further aggravate the harmful effects of amyloid beta (Aβ) plaques and tau tangles, ultimately leading to synaptic dysfunction, memory loss, and cognitive decline. While a complex link exists between mitochondrial dysfunction and AD hallmarks like Aβ plaques and tau tangles, the exact cause-and-effect relationship remains unclear. Additionally, recent evidence suggests impaired mechanisms for mitophagy in AD. Mitophagy is crucial for neuronal health, and studies have found changes to proteins involved in this process, mitochondrial dynamics, and mitochondrial production in AD. Impaired mitophagy might also be linked to problems with how cells fuse waste disposal compartments (autophagosomes) with lysosomes, and issues with maintaining proper acidity within lysosomes. Interestingly, melatonin, a hormone known for regulating sleep, has recently emerged as a potential neuroprotective agent. Studies using a mouse model of AD showed that melatonin treatment improved cognitive function by enhancing mitophagy. These findings suggest that melatonin's ability to improve mitophagy may be a promising avenue for future AD therapies. Therefore, in this review, we discuss the therapeutic effect of melatonin on mitochondrial dysfunction, especially mitophagy, in AD.
    Keywords:  Alzheimer’s disease; Amyloid-beta; Melatonin; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Tau pathology
    DOI:  https://doi.org/10.1007/s10787-025-01859-y
  8. Cytojournal. 2025 ;22 60
    Mitochondrial autophagy inhibits nucleotide-binding oligomerization domain-like receptor protein 3-mediated pyroptosis and alleviates endothelial cell injury in pregnancy-induced hypertension.
    Mengsi Zhang, Xiangzhen Zhang, Leilei Mao.
       Objective: Pregnancy-induced hypertension (PIH) is a common complication during pregnancy and is closely associated with vascular endothelial cell damage and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis. This study aimed to investigate whether mitophagy alleviates vascular endothelial cell damage in PIH by inhibiting NLRP3-mediated pyroptosis. The regulatory mechanisms of pyroptosis-related pathways were systematically investigated by establishing a cellular model of PIH and incorporating mitophagy intervention.
    Material and Methods: An Nω-nitro-L-arginine methyl ester (L-NAME)-induced gestational hypertension model was established, and the cell samples were grouped as follows: Control group (Control), L-NAME-induced gestational hypertension group (L-NAME), mitochondrial autophagy inhibition group (L-NAME+ 3-methyladenine [3-MA]), and mitochondrial autophagy activation group (L-NAME+ rapamycin [Rapa]). Cell viability was assessed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, lactate dehydrogenase (LDH) levels were measured to evaluate cell damage, and reactive oxygen species (ROS) kits were used to quantify ROS accumulation. Cell death was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling staining to detect apoptotic cells. Immunofluorescence, Western blot analysis, and quantitative real-time polymerase chain reaction were performed to assess the expression levels of proteins and genes associated with mitophagy (e.g., microtubule-associated protein 1 light chain 3 and sequestosome 1) and those linked to pyroptosis (e.g., NLRP3, gasdermin D (GSDMD), cysteinyl aspartate-specific proteinase 1 (caspase-1), interleukin (IL)-1β, and IL-18). The role of NLRP3 in pyroptosis regulation through mitochondrial autophagy was further examined using NLRP3 small interfering RNA (siNLRP3) transfection experiments.
    Results: L-NAME treatment substantially decreased vascular endothelial cell viability, elevated LDH release and ROS levels, and upregulated pyroptosis-related proteins (NLRP3, GSDMD, and caspase-1) and inflammatory factors (IL-1β and IL-18). The inhibition of mitochondrial autophagy with 3-MA further enhanced pyroptosis and aggravated cell damage, and its activation with Rapa reduced pyroptosis, improved cell survival, and decreased LDH release and ROS levels. NLRP3 silencing (siNLRP3) significantly inhibited pyroptosis and alleviated the cell damage caused by 3-MA. Meanwhile, Rapa enhanced the protective effect of NLRP3 silencing.
    Conclusion: This study demonstrates that mitophagy can effectively alleviate the vascular endothelial cell damage associated with PIH by inhibiting NLRP3-mediated pyroptosis. The findings provide new theoretical support for the treatment of PIH and suggest potential intervention targets.
    Keywords:  Mitophagy; Nucleotide-binding oligomerization domain-like receptor protein 3; Pregnancy-induced hypertension; Pyroptosis; Vascular endothelial cell injury
    DOI:  https://doi.org/10.25259/Cytojournal_52_2025
  9. J Adv Res. 2025 Jul 19. pii: S2090-1232(25)00560-0. [Epub ahead of print]
    MeCP2 dysregulation inhibits mitophagy and impairs neural development in cortical organoids.
    Jing Zhou, Yuchun Liu, Xintao Jing, Hang Peng, Fang Li, Li Cao, Wen Li, Rufeng Li, Jinyuan Zhang, Xiaofei Wang, Jiangfang Lian, Dongdong Tong, Chen Huang.
       INTRODUCTION: Methylated CpG-binding protein 2 (MeCP2) plays a critical role in the normal development and function of the nervous system. Mutations in MeCP2 have been linked to neurodevelopmental disorders, potentially because of mitochondrial dysfunction and impaired mitophagy. However, the underlying mechanisms remain poorly understood. Investigating the role of MeCP2 in the regulation of mitophagy is essential for elucidating the pathogenesis of these disorders.
    OBJECTIVES: The aim of the present study was to explore the molecular mechanisms by which MeCP2 regulates mitophagy and determine how its dysfunction contributes to neurodevelopmental abnormalities using cortical organoids (COs) derived from MeCP2 mutant induced pluripotent stem cells (iPSCs).
    METHODS: CRISPR-Cas9 technology was used to generate MeCP2 mutant iPSCs, which were then differentiated into cortical organoids. Growth, proliferation, and differentiation of neural stem cells in these organoids were analysed. Single-cell RNA sequencing was performed to assess the changes in gene expression, focusing on mitophagy-related genes. MeCP2 occupancy at the BNIP3L transcription start site (TSS) was also examined.
    RESULTS: MeCP2 mutant COs exhibited growth inhibition, abnormal proliferation, and disrupted neural stem cell differentiation. Single-cell RNA sequencing revealed a significant downregulation of BNIP3L, a key mitophagy receptor. MeCP2 was found to occupy the BNIP3L TSS, leading to suppressed BNIP3L expression and impaired mitophagy in COs.
    CONCLUSION: The obtained findings demonstrate that MeCP2 regulates mitophagy by modulating BNIP3L expression, and its dysfunction leads to mitochondrial accumulation and neurodevelopmental abnormalities. The present study highlights the critical role of MeCP2 in maintaining mitochondrial homeostasis and provides insights into the molecular mechanisms underlying MeCP2-related neurodevelopmental disorders.
    Keywords:  BNIP3L; Cortical organoids; MeCP2; Mitophagy; Neural development
    DOI:  https://doi.org/10.1016/j.jare.2025.07.035
  10. Kaohsiung J Med Sci. 2025 Jul 25. e70080
    GNPAT/USP30 Stabilizes DRP1 Protein to Promote Mitochondrial Fission and Functional Damage in COPD Progression.
    Xin-Gui Cheng, Yun-Chan Liu, Fei Chen, Ji-Wei Li, Xiao-Zhou Yao, Qing-Yun Chen.
      Our previous study revealed the role of glycerol phosphate O-acyltransferase (GNPAT) in regulating chronic obstructive pulmonary disease (COPD). However, its further mechanisms remained unclear. In this study, COPD models were established by exposing mice to cigarette smoke particulates. H&E staining and immunohistochemistry assays were performed on COPD tissue. A549 cells were stimulated with 5% cigarette smoke extract (CSE) and transfected with GNPAT, ubiquitin-specific protease 30 (USP30), and dynamin-related protein 1 (DRP1) plasmids. Cell viability, cell apoptosis, lactate dehydrogenase (LDH) release, ATP production, and reactive oxygen species (ROS) levels were determined using commercial kits. Quantitative real-time PCR and western blotting were used to evaluate mRNA and protein expression. Mitochondrial morphology was examined by transmission electron microscopy. A co-immunoprecipitation assay determined the binding relationships among GNPAT, USP30, and DRP1. Our results showed that GNPAT and DRP1 were highly expressed in the COPD model mice. CSE promoted mitochondrial fission, mitochondrial dysfunction, and cell apoptosis, which were further enhanced by treatment with a mitochondrial fission inducer (TA9). GNPAT promoted mitochondrial fission, mitochondrial dysfunction, and cell apoptosis by enhancing DPR1 protein stability, which depended on USP30. DRP1 enhanced mitochondrial fission, mitochondrial dysfunction, and cell apoptosis, which were both reversed by GNPAT/USP30 inhibition. Collectively, our present study found that GNPAT recruited USP30 and stabilized DRP1, thereby mediating mitochondrial fission and mitochondrial dysfunction that contributed to cell apoptosis in COPD. This study suggests a promising therapeutic biomarker for COPD.
    Keywords:  DRP1; GNPAT; USP30; chronic obstructive pulmonary disease; mitochondrial fission
    DOI:  https://doi.org/10.1002/kjm2.70080
  11. bioRxiv. 2024 Oct 27. pii: 2024.10.27.620333. [Epub ahead of print]
    Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
    Ryan M Mendel, Sofie Matsuno, Alex Lu, Marni J Falk, Suraiya Haroon.
      S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPR mt ) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.
    DOI:  https://doi.org/10.1101/2024.10.27.620333
  12. Adv Clin Exp Med. 2025 Jul 23.
    Parkin aggravates symptoms of preeclampsia through promoting mitophagy and apoptosis.
    Li Wang, Xue Wang, Ying Zheng, Jiao Kong, Lin-Mei Zheng, Ai-Hua He, Xiao-Ju Chen.
       BACKGROUND: Preeclampsia is a serious pregnancy complication with significant maternal and fetal morbidity. Mitophagy plays a crucial role in its pathogenesis. The importance of this study lies in evaluating the role of parkin in preeclampsia, which may offer new insights into the management of this disease.
    OBJECTIVES: This study was designed to evaluate the role of parkin in preeclampsia.
    MATERIAL AND METHODS: To induce a preeclampsia model, pregnant female rats were administered N-nitro-L-arginine methyl ester (L-NAME) subcutaneously at a dose of 50 mg/(kg·day) starting on gestational day 14 for 7 consecutive days. Uteroplacental tissues were then collected, and chorionic trophoblast cells were isolated. Systolic blood pressure (SBP) and urine protein content were measured on days 12 and 20 of pregnancy. Hematoxylin-eosin (H&E) staining and TUNEL staining were employed to assess pathological changes and apoptosis in uteroplacental tissues, respectively. Reverse transcription polymerase chain reaction (RT-qPCR) and western blot analysis were performed to evaluate mRNA and protein expression levels associated with cellular function, mitophagy and the PINK1/parkin signaling pathway.
    RESULTS: Compared to the negavtive control (NC) group, rats in the model group showed elevated SBP and urine protein levels (p < 0.01). Chorionic trophoblast cells exhibited substantial damage, with significantly increased levels of apoptosis and autophagy. Moreover, parkin mRNA and protein expression levels were markedly upregulated in the model group. Overexpression of parkin in chorionic trophoblast cells enhanced apoptosis and mitophagy, while the autophagy inhibitor 3-methyladenine (3-MA) significantly alleviated the damage caused by overexpression of parkin.
    CONCLUSIONS: Parkin aggravates the symptoms of preeclampsia by increasing mitophagy and apoptosis.
    Keywords:  3-methyladenine (3-MA); apoptosis; mitophagy; parkin; preeclampsia
    DOI:  https://doi.org/10.17219/acem/200059
  13. Sci Rep. 2025 Jul 18. 15(1): 26077
    PHLPP1 regulates region-specific astroglial mitochondrial fission in response to oxidative stress in the male rat hippocampus.
    Ji-Eun Kim, Su Hyeon Wang, Tae-Cheon Kang.
      Astrocytes have specialized functions depending on their localization. This region-dependent heterogeneity of astrocytes shows marked difference in astroglial responses to various stimuli. In the hippocampus, the populations of astrocytes in the stratum radiatum of the CA1 region (CA1 astrocytes) and the molecular layer of the dentate gyrus (DG astrocytes) have more complex structures than other regions. In the present study, we investigated whether oxidative stress induces distinct regulation of mitochondrial dynamics in CA1- and DG astrocytes, and which signaling pathways are relevant to these region-specific events in male rats. L-Buthionine sulfoximine (BSO)-induced oxidative stress led to mitochondrial fission in DG astrocytes concomitant with increased leucine-rich repeat protein phosphatase 1 (PHLPP1) expression and dynamin-related protein 1 (DRP1) S616 phosphorylation without altering AKT S473 and glycogen synthase kinase 3β (GSK3β) S9 phosphorylation, which were inhibited by PHLPP1 siRNA and SC79 (an AKT activator). BSO increased AKT S473 and GSK3β S9 phosphorylation in CA1 astrocytes without affecting their mitochondrial length or PHLPP1 expression, which was attenuated by 3-chloroacetyl-indole (an AKT inhibitor). These findings suggest that PHLPP1 may facilitate mitochondrial fragmentation in response to oxidative stress through the AKT-GSK3β-DRP1 pathway in DG astrocytes, but not in CA1 astrocytes, highlighting the region-specific heterogeneity in astrocytes.
    Keywords:  3CAI; Astrocyte; BSO; Mitochondrial dynamics; Oxidative stress; SC79
    DOI:  https://doi.org/10.1038/s41598-025-12214-0
  14. Autophagy. 2025 Jul 24. 1-3
    Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.
    Xiaowei Song, Yifei Wang, Kai Zheng.
      Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the accumulation of damaged mitochondria via defective mitophagy in vitro and in brain tissue of mice. The viral proteins ICP34.5 and US11 inhibit the EIF2S (eukaryotic translation initiation factor 2 subunit alpha)-ATF4 (activating transcription factor 4) axis to transcriptionally suppress PRKN/Parkin expression and subsequently impede PRKN-dependent mitophagy. Consequently, modulation of mitophagy significantly affects HSV-1 infection and NFKB/NF-κB-mediated neuroinflammation, as well as the severity of viral encephalitis in mice. Moreover, taurine, a metabolite differentially regulated by HSV-1 infection, transcriptionally promotes PRKN-mediated mitophagy, thereby limiting HSV-1 infection both in vitro and in vivo. This work reveals a protective function of mitophagy in restricting viral encephalitis and highlights the ATF4-PRKN axis as a potential therapeutic approach for the treatment of neurotropic virus-related diseases.Abbreviations: Aβ: amyloid β protein; AD: Alzheimer disease; ATF4: activating transcription factor 4; EIF2AK2/PKR: eukaryotic translation initiation factor 2 alpha kinase 2; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1.
    Keywords:  EIF2S1-ATF4 axis; PRKN; herpes simplex encephalitis; mitophagy; neuroinflammation; taurine
    DOI:  https://doi.org/10.1080/15548627.2025.2538767
  15. Mol Metab. 2025 Jul 17. pii: S2212-8778(25)00122-X. [Epub ahead of print] 102215
    UCP2 MEDIATES MITOCHONDRIAL DYNAMICS TO INDUCE AgRP NEURONAL ACTIVITY.
    Sungho Jin, Nal Ae Yoon, Zhong-Wu Liu, Ciro Menale, Jung Dae Kim, Nadia Diano, Sabrina Diano.
       OBJECTIVE: The hypothalamic agouti-related protein (AgRP)- expressing neurons regulate feeding and whole-body energy homeostasis. A growing body of evidence indicates that changes in mitochondrial dynamics, such as fission and fusion, play a crucial role in regulating AgRP neuronal activity. However, the mechanisms underlying this process remain to be elucidated. Here, we showed a role of mitochondrial UCP2-mediated mitochondrial dynamics in AgRP neurons in regulating AgRP neuronal activity and fasting-induced feeding behavior.
    METHODS: We analyzed mitochondrial morphology, expression of activated dynamin-related protein 1 (DRP1), and mRNA expression levels of uncoupling protein 2 (Ucp2) in AgRP neurons of mice that were either in fed or fasted states. We then generated a mouse model in which Ucp2 was selectively deleted from adult AgRP neurons to assess the role of this mitochondrial protein in feeding behavior and whole-body energy metabolism.
    RESULTS: We show fasting-induced AgRP neuronal activation is associated with UCP2-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking UCP2 in AgRP neurons (Ucp2AgRPKO) show attenuated fasting- or ghrelin-induced AgRP neuronal activation and feeding behaviors and exhibited a significant decrease in body weight and fat mass accompanied by a significant increase in energy expenditure.
    CONCLUSIONS: Altogether, our data revealed that UCP2-mediated mitochondrial dynamics and fatty acids oxidation in the hypothalamic AgRP neurons is necessary for AgRP neuronal function and fasting-induced food intake.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102215
  16. Cardiovasc Toxicol. 2025 Jul 24.
    Yoda1/Piezo1 Alleviates Lipopolysaccharide-Induced Cardiac Injury via AMPK-Mediated Mitophagy.
    Yiheng Yang, Qingshan Tian, Feng Qiu, Jiangfeng Tang, Zhenzhong Zheng, Peng Yang.
      The role of the mechanosensitive ion channel Piezo1 in septic cardiomyopathy remains unclear. This study investigated the role of Piezo1 in septic cardiomyopathy, focusing on the effects of its activation by Yoda1, an effective selective Piezo1 agonist, in LPS-induced cardiac injury models. In vivo, Yoda1 treatment improved cardiac function, enhanced mitophagy, and activated AMPK signaling in LPS-treated mice. In vitro, Yoda1 protected primary cultured cardiomyocytes from LPS-induced oxidative stress, improved mitochondrial function, and increased PINK1/Parkin-mediated mitophagy, whereas the Piezo1 inhibitor GsMTx4 had minimal effects. Western blot analysis confirmed the activation of the PINK1/Parkin and AMPK pathways by Yoda1 in cardiomyocytes. Notably, inhibiting AMPK signaling reduced the protective effects of Yoda1, underscoring the crucial role of AMPK in mitophagy regulation. These findings indicate that Yoda1 may serve as a potential therapeutic agent for LPS-induced cardiac injury, acting primarily through the regulation of mitophagy via the Piezo1/AMPK/PINK1/Parkin signaling pathway.
    Keywords:  AMPK; Peizo1; Septic cardiomyopathy; Yoda1
    DOI:  https://doi.org/10.1007/s12012-025-10045-z
  17. Mol Med Rep. 2025 Oct;pii: 262. [Epub ahead of print]32(4):
    Oxymatrine attenuates pulmonary fibrosis via APE1‑mediated regulation of the PINK1/Parkin pathway.
    Wenya Xu, Tian Xie, Bingli Zhang, Jie Zhao, Lei Zhang, Yamei Zheng, Yipeng Ding.
      Pulmonary fibrosis (PF) is a chronic, progressive lung disease characterized by impaired gas exchange and respiratory difficulties, which can ultimately lead to respiratory failure and mortality. The present study explored the therapeutic effects and underlying mechanisms of oxymatrine (OMT) in an 8‑week‑old C57BL/6 mouse model of bleomycin‑induced PF. The results demonstrated that OMT alleviated lung tissue damage, inflammation and collagen deposition, while promoting autophagy and restoring mitochondrial function. OMT achieved these effects by upregulating apurinic/apyrimidinic endonuclease‑1 (APE1) and activating the PTEN‑induced kinase 1 (PINK1)/Parkin pathway, both of which are key for mitochondrial autophagy. Furthermore, Lewis lung carcinoma mouse lung cancer cells were transduced with an adeno-associated virus containing small interfering RNA APE1 and a negative control, and the silencing efficiency was validated by reverse transcription‑quantitative PCR and western blotting. The results revealed a significant reduction in APE1 expression in the APE1 knockdown group compared with that in the negative control knockdown group. Immunohistochemistry and immunofluorescence confirmed that OMT increased the expression of APE1, PINK1 and Parkin while reducing markers of fibrosis, such as α‑smooth muscle actin and collagen type I α 1. However, silencing APE1 or inhibiting mitochondrial autophagy with mitochondrial division inhibitor‑1 reversed the beneficial effects of OMT, suggesting a key role for APE1 and the PINK1/Parkin pathway in its mechanism of action. These findings provide insights into the antifibrotic potential of OMT and highlight its potential as a basis for the development of new therapies for PF.
    Keywords:  APE1; OMT; PF; PINK1/Parkin pathway; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2025.13627
  18. Ageing Res Rev. 2025 Jul 22. pii: S1568-1637(25)00188-6. [Epub ahead of print] 102842
    Bidirectional Regulation of Neuronal Autophagy in Ischemic Stroke: Mechanisms and Therapeutic Potential.
    Yige Wu, Zhu Li, Tao Ding, Yunqi Yang, Congmin Wei, Shanshan Zhang, Xiang Fan.
      Ischemic stroke, characterized by cerebral blood flow disruption, triggers complex pathophysiological responses where neuronal autophagy plays a bidirectional regulation role in neuroprotection and injury. Autophagy, activated by energy deprivation, hypoxia, and endoplasmic reticulum stress, dynamically regulates neuronal survival through selective autophagy (e.g., mitophagy, endoplasmic reticulum-phagy, ferritinophagy) of damaged organelles and protein aggregates. Early-stage moderate autophagy exerts neuroprotection by clearing cytotoxic aggregates and maintaining metabolic homeostasis, while excessive or prolonged autophagy exacerbates neuronal death via energy depletion and activation of apoptosis/ferroptosis pathways. Key regulatory mechanisms involve AMPK/mTOR, PI3K/AKT, HIF-1, and MAPK signaling, which modulate autophagic flux and crosstalk with oxidative stress, inflammation, and mitochondrial dynamics. Notably, selective autophagy pathways exhibit spatiotemporal specificity: mitophagy via PINK1/Parkin and BNIP3/FUNDC1 balances mitochondrial quality control, while ferritinophagy-mediated iron dysregulation drives ferroptosis. Pharmacological interventions targeting autophagy-related pathways (e.g., rapamycin, 3-MA, NCOA4 inhibitors) or natural compounds (e.g., Ginkgolide B, HSYA) demonstrate therapeutic potential by fine-tuning autophagic activity. However, challenges remain in defining optimal autophagy thresholds and translating preclinical findings to clinical applications. This review highlights the critical importance of spatiotemporal regulation of neuronal autophagy to develop precise neuroprotective strategies for ischemic stroke, with a particular focus on the interaction between autophagy modulators and the pathophysiological mechanisms of ischemia.
    Keywords:  Endoplasmic Reticulum Stress; Ferritinophagy; Ischemic Stroke; Mitophagy; Neurons; Selective Autophagy
    DOI:  https://doi.org/10.1016/j.arr.2025.102842
  19. Iran J Basic Med Sci. 2025 ;28(7): 846-851
    Voluntary exercise alleviates ischemic brain injury in mice by modulating mitochondrial dysfunction.
    Beibei Li, Ye Zhou, Guifen Yang, Bo Li, Mingjin Zhu, Dan Lu, Senge Dai, Guoyuan Pan.
       Objectives: The relationship between exercise and mitochondrial function is unclear. This study investigated the relationship between voluntary exercise and mitochondrial dynamics in ischemic stroke model mice.
    Materials and Methods: This experiment used 54 male C57BL/6 J mice to assess the therapeutic effect of voluntary exercise on ischemic stroke in a middle cerebral artery occlusion (MCAO) model. Body weight and the number of wheel turns were recorded to monitor the physiological condition of the mice. The degree of brain injury was evaluated via hematoxylin and eosin (H&E) staining and measurement of the cerebral infarction volume. Western blotting and immunofluorescence were used to measure dynein-1-like protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and optic atrophy type 1 (OPA1) levels to assess mitochondrial dynamics and analyze the degree of mitochondrial apoptosis by measuring cytochrome c (CYT-C), cleaved caspase-3, and caspase-3 expression.
    Results: Voluntary exercise positively affected the behavioral score and infarct volume. H&E staining revealed that voluntary exercise reversed MCAO-induced cortical damage. Furthermore, voluntary exercise improved mitochondrial dynamics by inhibiting DRP1 and FIS1 expression and inducing OPA1 expression. Additionally, the mitochondrial apoptosis pathway was inhibited by down-regulating the expression of CYT-C, cleaved caspase-3, and caspase-3.
    Conclusion: Voluntary exercise exerts a significant neuroprotective effect against MCAO-induced brain injury by regulating mitochondrial dynamics and the mitochondrial apoptotic pathway.
    Keywords:  Apoptosis; Cerebral Infarction; Exercise; Mitochondria; Mitochondrial dynamics; Voluntary exercise
    DOI:  https://doi.org/10.22038/ijbms.2025.80783.17488
  20. J Neuroimmune Pharmacol. 2025 Jul 21. 20(1): 73
    Erythropoietin (EPO) Alleviates Chronic Stress-Induced Depression by Modulating SIRT1-Mediated Mitochondrial Function.
    Yanhua Luo, Tahir Ali, Yue Hu, Qichao Gong, Chengyou Zheng, Ling Li, Shupeng Li, Liangliang Hao.
      Mitochondrial dysfunction is a hallmark of many psychiatric disorders, and SIRT1 signaling plays a critical role in regulating mitochondrial dynamics, function, and autophagy. This study investigated the interplays between erythropoietin (EPO), mitochondrial protection, and SIRT1 signaling in depression. Chronic restraint stress (CRS)- induced depression mouse model and CORT-treated HT22 cells were employed, which were subsequently treated with EPO. CRS mice exhibited depressive-like behaviors, which were alleviated by EPO treatment, as evidenced by decreased immobility and increased sucrose preference. EPO also enhanced mitochondrial function by stimulating mitophagy and improving mitochondrial homeostasis, as indicated by elevated ATP levels, reduced nitric oxide, and restored expression of mitochondrial-related genes in both the hippocampus of CRS mice and CORT-treated HT22 cells. Additionally, EPO restored suppressed SIRT1 expression, promoted dendritic spine density and synaptic gene expression in the hippocampus, increased p-STAT5 phosphorylation, and increased NAMPT expression and NAD + levels. Notably, pharmacological inhibition of SIRT1 via EX-527 counteracted EPO effects, exacerbating depressive symptoms and mitochondrial homeostasis. Furthermore, EX-527 treatment decreased ATP levels and mitochondrial DNA copy numbers in CRS + EPO-treated mice and reduced ATG5 expression. However, EX-527 did not significantly impact BNIP3, Parkin, PINK1, LC3B-II, Ace-FOXO1, or FOXO1 expression. EX-527 exposure significantly increased Ac-LC3B precipitation in the hippocampus of CRS + EPO-treated mice and the COXIV/LAMP1 ratio in the HT22 cells. In summary, these results suggested that EPO antidepressant effects were mediated through SIRT1 regulation, which influenced LC3B deacetylation, improving CRS-induced mitochondrial dysfunction and autophagy impairment.
    Keywords:  Depression; Erythropoietin; Mitochondrial dysfunction; SIRT1
    DOI:  https://doi.org/10.1007/s11481-025-10233-2
  21. J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02333-6. [Epub ahead of print] 110483
    Stressful situations: molecular insights on mitochondrial quality control pathways.
    Sabrina Romanelli, Jean-François Trempe.
      Mitochondrial quality control has emerged as an important area of research over the past decade, with more than 2,000 publications exploring the molecular pathways that regulate it. Mitochondria are essential for energy production and various cellular functions but are highly susceptible to damage from stressors such as protein misfolding, reactive oxygen species, and chemicals that disrupt the electron transport chain. If left unresolved, mitochondrial dysfunction can lead to health complications, including neurodegenerative disorders, cardiovascular diseases, and cancer. To maintain cellular health, cells evolved quality control pathways to remove damaged mitochondrial components. This review focuses on three key quality control responses: the PINK1-Parkin pathway, the DELE1-HRI pathway, and the mitochondrial unfolded protein response (UPRmt). While these pathways have distinct functions, there is ongoing debate about how they overlap and which responds first in different contexts. In this review, we discuss the physiological and structural mechanisms behind each pathway, explore how they interconnect, and highlight their differences and relevance to disease. By summarizing this information in a single review, we aim to enhance the molecular understanding of mitochondrial quality control, which can help highlight avenues for novel therapeutics for diseases associated to dysfunctional mitochondria.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110483
  22. Cell Death Dis. 2025 Jul 21. 16(1): 539
    Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.
    Antigoni Diokmetzidou, Aurora Maracani, Anna Pellattiero, Mauricio Cardenas-Rodriguez, Erwan A Rivière, Luca Scorrano.
      In breast cancer, the inner mitochondrial membrane fusion protein Optic Atrophy 1 (OPA1) is upregulated and its inhibition reverses acquired chemoresistance. However, it remains unclear whether OPA1 inhibition also targets normal breast cells. We show that OPA1 upregulation is a hallmark of metastatic breast cancer cells, which are selectively susceptible to OPA1 inhibition compared to isogenic normal or localized tumor cells. In an isogenic model spanning normal, transformed, and metastatic breast cancer cells, levels of Mitofusin 1 (MFN1) progressively declined while dynamin related protein 1 (DRP1) became increasingly active, correlating with fragmented mitochondria during cancer progression. Meanwhile, OPA1 levels were elevated in invasive cells characterized by mitochondrial fragmentation, tight cristae, and high respiration. OPA1 deletion selectively reduced metastatic cells mitochondrial respiration, proliferation, and migration. Specific OPA1 inhibitors MYLS22 and Opitor-0 diminished migration and increased death of metastatic cells, underscoring OPA1 as a selective vulnerability of metastatic breast cancer.
    DOI:  https://doi.org/10.1038/s41419-025-07878-5
  23. Nat Commun. 2025 Jul 19. 16(1): 6666
    RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer.
    Peng Ding, Xing Wang, Chuan Gao, Yuehan Wei, Gan Li, Wenlei Zhu, Ni Wang, Wan Fu, Qihang Fang, Meng Yao, Yigang Huang, Chenyi Jiang, Youshui Gao, Jing Zhang, Junjie Gao, Qing Zhong, Changqing Zhang.
      Human RIPK4 mutation leads to Bartsocas-Papas syndrome (BPS), characterized by severe skin, craniofacial and limb abnormalities. Currently, our understanding of RIPK4's function has focused on epidermal differentiation and development, whether RIPK4 regulates skeletal homeostasis remains largely elusive. Herein, through global RIPK4 ablation in adult mice, we demonstrate that RIPK4 deficiency leads to osteoporosis, promotes myeloid-biased hematopoiesis and osteolineage RIPK4 plays a crucial role in bone formation and myeloid hematopoiesis. Further detailed investigation pinpoints that RIPK4 interacts with mitochondrial fusion protein MFN2 in a kinase-dependent manner. RIPK4 facilitates the phosphorylation of MFN2, which subsequently undergoes degradation through the proteasome pathway and disrupts the dynamic equilibrium of mitochondrial fission and fusion. Additionally, we also show that osteolineage RIPK4 maintains bone marrow myelopoiesis by MFN2-mediated mitochondrial transfer. More interestingly, while osteocytic RIPK4 could modestly influence the osteogenesis, it is insufficient to sustain bone marrow myelopoiesis owing to the limited amount of mitochondria transfer. These findings decipher the essential role of RIPK4 in maintaining skeletal homeostasis and unveil an unappreciated mechanism of RIPK4-MFN2 axis in regulating osteogenesis and bone marrow myelopoiesis.
    DOI:  https://doi.org/10.1038/s41467-025-61808-9
  24. Mol Med. 2025 Jul 24. 31(1): 264
    Caffeic acid phenethyl ester protects renal tubular epithelial cells against ferroptosis in diabetic kidney disease via restoring PINK1-mediated mitophagy.
    Ying Lu, Ye Zhu, Sheng Feng, Qifei Cong, Sixia Chen, Ying Zeng, Kai Song, Ji Hu.
      Mounting evidence indicates that renal tubular ferroptosis plays a crucial role in the progression of diabetic kidney disease (DKD). Caffeic acid phenethyl ester (CAPE), derived from propolis, a precious resinous substance synthesized by various bee species, has garnered broad attention in biomedical research. This study aims to explore the mechanism by which CAPE protects renal tubular epithelial cells (TECs) against ferroptosis in DKD. DBA/2J mice were administered streptozotocin (STZ) by intraperitoneal injection, fed a high-fat diet (HFD) and treated with CAPE. The findings revealed significant changes in ferroptosis markers. In diabetic mice and TECs under high-glucose (HG) conditions, levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased, while transferrin receptor 1 (TFR1) increased. These changes were accompanied by a reduction in antioxidant capability and the accumulation of malondialdehyde (MDA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the intersection targets of CAPE and ferroptosis were mainly located in the mitochondria and exhibited high enrichment values in mitophagy. Further investigations revealed that HG induced a depolarization of mitochondrial membrane potential and an excessive level of mitochondrial reactive oxygen species (ROS), accompanied by defective mitophagy. The administration of CAPE inhibited exacerbated ferroptosis and rescued defective mitophagy induced by DKD. In addition, CAPE restored PTEN-induced putative kinase 1 (PINK1) levels, which were markedly diminished in the kidneys of DKD mice and TECs subjected to HG. Molecular docking simulation experiments suggested that CAPE is steadily bound to the PINK1 active pocket. Cellular Thermal Shift Assay (CETSA) and Drug Affinity Responsive Target Stability assay (DARTS) showed that CAPE enhances the thermal stability of the PINK1 protein within a specific temperature range and protects the PINK1 protein from degradation by proteolytic enzymes. These results confirm that CAPE interacts with PINK1 as its specific target. However, the positive outcomes of CAPE treatment on ferroptosis were nullified by the PINK1 siRNA. This research indicates that CAPE has potential therapeutic benefits for DKD by protecting renal TECs against ferroptosis via rescuing PINK1-mediated mitophagy. These findings suggest that CAPE shows potential as a therapeutic agent to prevent tubular injury in DKD.
    Keywords:  Caffeic acid phenethyl ester; Diabetic kidney disease; Ferroptosis; Mitophagy; Tubular epithelial cells
    DOI:  https://doi.org/10.1186/s10020-025-01318-y
  25. J Ethnopharmacol. 2025 Jul 21. pii: S0378-8741(25)00989-4. [Epub ahead of print] 120297
    Corrigendum to "Qishentaohong granules alleviate heart failure by modulating mitochondrial fission and mitophagy balance" [J. Ethnopharmacol. 352 (2025) 120190].
    Jialin Jin, Yuxuan Li, Sinai Li, Dong Li, Jing Liu, Jinjin Lu, Qiaozhi Dong, Qian Wu, Yan Li, Qian Lin.
      
    DOI:  https://doi.org/10.1016/j.jep.2025.120297
  26. Life Sci. 2025 Jul 18. pii: S0024-3205(25)00495-3. [Epub ahead of print] 123860
    PTEN-L dephosphorylates Parkin and Ub Ser65 to aggravate mitophagy dysfunction in prion disease cell models.
    Xueyuan Li, Jie Li, Fengting Gou, Yuexin Dai, Mengyang Zhao, Dongdong Wang, Zhixin Sun, Pei Wen, Jingjing Wang, Qing Fan, Tianying Ma, Xiaoyu Wang, Deming Zhao, Lifeng Yang.
      PINK1-Parkin-dependent mitophagy dysfunction is a critical contributor to the accumulation of damaged mitochondria in prion disease, leading to impaired autophagy and neurons apoptosis. However, the specific molecular mechanisms underlying mitophagy dysfunction in prion disease remain unclear. Phosphorylation of Parkin at Ser65 (pSer65-Parkin) is a key determinant for the initiation of PINK1-Parkin-mediated mitophagy. In the prion disease cell model, we observed a significant reduction in pSer65-Parkin and pSer65-Ub expression. PTEN-L, an isoform of the PTEN family, has been implicated in the regulation of PINK1-Parkin-mediated mitophagy. Here, we demonstrate that PTEN-L acts as a phosphatase for Parkin and Ub, exerting a regulatory role in mitophagy in prion disease. We found that PTEN-L expression and mitochondrial translocation were elevated in PrP106-126-treated SH-SY5Y cells. Increased PTEN-L dephosphorylates pSer65-Parkin pSer65-Ub, leading to reduced pSer65-Parkin and pSer65-Ub, then impaired mitophagy initiation. Overexpression of PTEN-L in SH-SY5Y cells mimicked the effects of PrP106-126 treatment, reducing Parkin mitochondrial translocation and pSer65-Parkin levels. PTEN-L knockout alleviates these deficits, restoring Parkin and ubiquitin recruitment to mitochondria and increasing Ser65 phosphorylation in prion disease cell models. Furthermore, PTEN-L deficiency mitigated mitophagy dysfunction and apoptosis in neurons exposed by PrP106-126. These findings suggest that PrP106-126 upregulates PTEN-L, enhancing dephosphorylation of pSer65-Parkin and pSer65-Ub, thereby impairing mitophagy initiation. Targeting PTEN-L expression or activity may represent a novel therapeutic strategy for prion disease.
    Keywords:  Mitophagy; PTEN-L; Parkin; Prion disease; Ubiquitin
    DOI:  https://doi.org/10.1016/j.lfs.2025.123860
  27. Ageing Res Rev. 2025 Jul 21. pii: S1568-1637(25)00184-9. [Epub ahead of print] 102838
    The Evolution of Alzheimer's Disease: From Mitochondria to Microglia.
    Feng-Ge Yang, Yu-Lin Liang, Xu Wang, Jun-Ting Wang, Wei Gao, Qiu-Yan Ye, Xue-Yuan Li, Yu Yang, Hong-Lin Li.
      Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These impairments modulate microglial activation states, precipitating exacerbated neuroinflammation, altered phagocytic capacity, and increased cellular apoptosis, collectively contributing to microglial dysfunction. This paper presents a narrative review on the relationship between mitochondrial dysfunction and AD, elucidating the impact of mitochondrial impairment on microglia. It summarizes therapeutic strategies that target mitochondria to modulate microglial function, aiming to prevent and treat AD. The goal is to provide new perspectives and insights for AD research and treatment, contributing to improving patients' quality of life and prognosis.
    Keywords:  Alzheimer's disease; Microglial cell polarization; Mitochondrial dysfunction; Mitophagy; Neuroinflammation; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.arr.2025.102838
  28. Am J Pathol. 2025 Jul 18. pii: S0002-9440(25)00240-8. [Epub ahead of print]
    AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.
    Liang Shao, Ji Zhang, Fan Hu, Wen Chai, Yuxuan Zhou, Pengtao Zou, Ping Zhang.
      Parkinson's disease (PD) is a commonly diagnosed neurodegenerative disease with rising prevalence globally. However, the pathology of PD remains largely undefined. The aim of this study is to get better understanding of microglial mitophagy in PD. 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescent (IF) showed that autophagy was enhanced in MPTP-induced PD mice. IF, qRT-PCR, western blot and co-immunoprecipitation (co-IP) also revealed that silencing of Hsp90α protected against mitophagy in PD mice. In microglia/DA neurons co-culture system, ELISA assay, Transmission Electron Microscopy (TEM), JC-1 staining, measurement of ATP content and Annexin V/PI staining showed that lack of Hsp90α in MPTP-treated microglia attenuated DA neuronal death via suppressing mitophagy. IF staining and co-IP confirmed that Hsp90α formed a complex with AHSA1, and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. Hsp90α inhibitor geldanamycin (GA) and AHSA1 knockdown further revealed that AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.
    Keywords:  AHSA1; Hsp90α; Parkinson's disease; TOMM70; microglial mitophagy
    DOI:  https://doi.org/10.1016/j.ajpath.2025.06.007
  29. Front Pharmacol. 2025 ;16 1590458
    Novel mitophagy inducer TJ0113 alleviates pulmonary inflammation during acute lung injury.
    Zhengyuan Liu, Danruo Fang, Kaijun Chen, Lingling Dong, Huaqiong Huang, Zhihua Chen.
       Introduction: Acute lung injury (ALI) is a severe respiratory disease with limited effective therapeutic options. Recent studies have highlighted mitochondrial damage as a crucial factor in the progression of ALI. Mitophagy, which facilitates the removal of damaged mitochondria, has been shown to reduce inflammation. Our collaborators constructed a small molecule mitophagy inducer, TJ0113. TJ0113 has received clinical approval for Alport syndrome from both the China National Medical Products Administration and the U.S. Food and Drug Administration. Therefore, we explored the potential of TJ0113 as a novel therapeutic for ALI.
    Methods: The mitophagy-inducing potential of TJ0113 was assessed in HEK293T cells. The anti-inflammatory effects of TJ0113 were further evaluated in vivo using a mouse model of lipopolysaccharide (LPS)-induced ALI and in vitro using LPS-stimulated bone-marrow-derived macrophages (BMDMs).
    Results: TJ0113 selectively induced mitophagy in damaged mitochondria. Furthermore, the PINK1-Parkin pathway was identified as a specific mitophagy pathway induced by TJ0113. In LPS-induced ALI mouse model, intraperitoneal injection of TJ0113 significantly reduced lung inflammation and mortality. In vitro, TJ0113 significantly inhibited the expression of LPS-induced inflammatory cytokines in BMDMs. Finally, we found that TJ0113 inhibited LPS-induced inflammation by inducing mitophagy and inhibiting nuclear factor κB (NF-κB) and inflammasome activation.
    Conclusion: TJ0113 alleviates LPS-induced inflammation by inducing mitophagy and inhibiting NF-κB and inflammasome activation. Its selective action on damaged mitochondria suggests minimal side effects, positioning TJ0113 as a promising therapeutic candidate for ALI.
    Keywords:  NF-κB; NLRP3 inflammasome; TJ0113; acute lung injury; mitophagy inducer
    DOI:  https://doi.org/10.3389/fphar.2025.1590458
  30. Res Sq. 2025 Jul 15. pii: rs.3.rs-7042684. [Epub ahead of print]
    Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
    Tim Heden, Melina Mancini, Cameron McCall, Robert Noland, Wagner Dontas.
      Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.
    DOI:  https://doi.org/10.21203/rs.3.rs-7042684/v1
  31. Zhongguo Zhong Yao Za Zhi. 2025 Jun;50(12): 3346-3355
    [Mechanism of Jiming Powder in improving mitophagy for treatment of myocardial infarction based on PINK1-Parkin pathway].
    Xin-Yi Fan, Xiao-Qi Wei, Wang-Jing Chai, Kuo Gao, Fang-He Li, Xue Yu, Shu-Zhen Guo.
      In the present study, a mouse model of coronary artery ligation was employed to evaluate the effects of Jiming Powder on mitophagy in the mouse model of myocardial infarction and elucidate its underlying mechanisms. A mouse model of myocardial infarction post heart failure was constructed by ligating the left anterior descending branch of the coronary artery. The therapeutic efficacy of Jiming Powder was assessed from multiple perspectives, including ultrasonographic imaging, hematoxylin-eosin(HE) staining, Masson staining, and serum cardiac enzyme profiling. Dihydroethidium(DHE) staining was employed to evaluate the oxidative stress levels in the hearts of mice from each group. Mitophagy levels were assessed by scanning electron microscopy and immunofluorescence co-localization. Western blot was employed to determine the levels of key proteins involved in mitophagy, including Bcl-2-interacting protein beclin 1(BECN1), sequestosome 1(SQSTM1), microtubule-associated protein 1 light chain 3 beta(LC3B), PTEN-induced putative kinase 1(PINK1), phospho-Parkinson disease protein(p-Parkin), and Parkinson disease protein(Parkin). The results demonstrated that compared with the model group, high and low doses of Jiming Powder significantly reduced the left ventricular internal diameter in systole(LVIDs) and left ventricular internal diameter in diastole(LVIDd) and markedly improved the left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), effectively improving the cardiac function in post-myocardial infarction mice. Jiming Powder effectively reduced the levels of myocardial injury markers such as creatine kinase(CK), creatine kinase isoenzyme(CK-MB), and lactate dehydrogenase(LDH), thereby protecting ischemic myocardium. HE staining revealed that Jiming Powder attenuated inflammatory cell infiltration after myocardial infarction. Masson staining indicated that Jiming Powder effectively inhibited ventricular remodeling. Western blot results showed that Jiming Powder activated the PINK1-Parkin pathway, up-regulated the protein level of BECN1, down-regulated the protein level of SQSTM1, and increased the LC3Ⅱ/LC3Ⅰ ratio to promote mitophagy. In conclusion, Jiming Powder exerts therapeutic effects on myocardial infarction by inhibiting ventricular remodeling. The findings pave the way for subsequent pharmacological studies on the active components of Jiming Powder.
    Keywords:  Jiming Powder; PINK1-Parkin pathway; heart failure; mitophagy; myocardial infarction
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250303.401
  32. Cell Biochem Funct. 2025 Jul;43(7): e70105
    Role of Mitochondria-Associated ER in Apoptosis.
    Mudan Sang, Xindong Li, Mi Chen, Xiaoli Ren, Sheng Kang, Zhenyu Chang, Qingxia Wu.
      Apoptosis represents a critical noninflammatory mechanism for cell clearance in both physiological and pathological contexts, precisely regulated through the balance between proapoptotic and antiapoptotic signaling. Three well-characterized apoptotic pathways have been identified: (1) the intrinsic (mitochondria-mediated) pathway, (2) the extrinsic (death receptor-mediated) pathway, and (3) the endoplasmic reticulum (ER)-stress pathway. These processes are coordinated through the mitochondria-associated ER membrane (MAMs), which serves as a vital coupling platform between mitochondria and the ER. MAMs play pivotal roles in maintaining Ca²⁺ homeostasis and regulating apoptosis through dynamic alterations in architecture (e.g., gap width, contact number) that influence Ca²⁺ trafficking and tethering protein expression. Key protein complexes localized at MAMs (including the IP3Rs-Grp75-VDAC1 complex, Mfn1/Mfn2 complex, and PTPIP51-containing complex) regulate apoptosis through three primary mechanisms: Ca²⁺ homeostasis maintenance, lipid synthesis and transport, and mitochondrial morphology and dynamics. Furthermore, MAMs-mediated mitochondrial dynamics, particularly mitochondrial fission and cristae remodeling, contribute to apoptosis by facilitating Bax/Drp1 dimerization. This review systematically examines: how MAMs' structural dynamics influence Ca²⁺ signaling and tethering protein expression, the roles of MAMs-tethered proteins and their regulators in Ca²⁺ homeostasis, lipid metabolism, and mitochondrial dynamics, and the impact of mitochondrial dynamics on Bax/Drp1 dimerization during apoptosis.
    Keywords:  Bcl‐2 family proteins; apoptosis; mitochondrial dynamics; mitochondria‐associated ER; tether proteins
    DOI:  https://doi.org/10.1002/cbf.70105
  33. Adv Sci (Weinh). 2025 Jul 20. e05592
    Mortalin and PINK1/Parkin-Mediated Mitophagy Represent Ovarian Cancer-Selective Targets for Drug Development.
    Vishal Chandra, Justin Garland, Rajani Rai, Donghua Zhao, Charuksha Walgama, Sadagopan Krishnan, Andrew T Long, Tongzu Liu, Laura Adhikari, Doris M Benbrook.
      Mortalin is an essential chaperone for the import of nuclear-encoded proteins into mitochondria and is elevated in ovarian cancer in association with poor patient prognosis. The investigational new drug, SHetA2, interacts with mortalin releasing its client proteins. In this study, interactions of SHetA2 moieties and mortalin substrate binding domain (SBD) amino acids are demonstrated by surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) to occur at low micromolar SHetA2 concentrations that selectively kill cancer cells over noncancerous cells. In both ovarian cancer and noncancerous cells SHetA2 reduces: mitochondria import of mortalin, degradation of mortalin's mitochondrial localization sequence (MLS), mortalin/inositol 1,4,5-trisphosphate receptors complexes and oxidative phosphorylation. In cancer cells only, SHetA2 reduces calcium levels, mitochondrial length and fusion proteins, while inducing autophagy and PTEN-induced kinase 1 (PINK1)/PARKIN-mediated mitophagy. Noncancerous cells exhibit increased mitochondrial branch length in response to SHetA2 and a low level of inducible autophagy that is resistant to SHetA2. Inhibition of autophagosome-lysosome fusion reduces, or increases, SHetA2 cytotoxicity in ovarian cancer or noncancerous cells, respectively. SHetA2 inhibits mortalin and growth, and induces mitophagy in ovarian cancer xenografts and increases survival post-surgical tumor removal. In conclusion, SHetA2 binds directly to mortalin's SBD and causes distinct responses in ovarian cancer and noncancerous cells.
    Keywords:  PINK1; SHetA2; autophagy; mitochondrial networking; mitophagy
    DOI:  https://doi.org/10.1002/advs.202505592
  34. J Transl Med. 2025 Jul 24. 23(1): 821
    EphrinB2 alleviates tubulointerstitial fibrosis in diabetic kidney disease.
    Lihua Ni, Qiuyuan Zhou, Xueyun Gao, Feng Chen, Ayinigaer Yusufu, Jin-Hu Chen, Cheng Yuan, Xiaoyan Wu.
       BACKGROUND: Diabetic kidney disease (DKD) is characterized by progressive fibrosis, oxidative stress, and mitochondrial dysfunction, contributing to renal dysfunction. EphrinB2, a cell surface protein, has been implicated in tissue repair and fibrosis, but its role in DKD remains poorly understood. This study investigates the impact of EphrinB2 expression on renal fibrosis, mitochondrial dynamics, and cellular signaling pathways in DKD.
    METHODS: EphrinB2 expression and function were investigated in renal tissues from DKD patients, STZ-induced diabetic mice, and HG-treated HK-2 cells. EphrinB2 overexpression was achieved using AAV in vivo and lentiviral vectors in vitro. Functional assessments included histological and biochemical evaluations, while mechanistic studies utilized siRNA knockdown, pathway-specific inhibitors and activators, and co-immunoprecipitation to explore the role of the Epac1-Rap1 signaling pathway in EphrinB2-mediated antifibrotic and mitochondrial protective effects.
    RESULTS: EphrinB2 expression was significantly downregulated in the kidneys of DKD patients and STZ-induced diabetic mice, correlating with increased fibrosis and tubular injury. Overexpression of EphrinB2 (EphrinB2-OE) in diabetic mice restored renal function, reduced fibrosis, alleviated oxidative stress, and preserved mitochondrial structure. In HK-2 cells, EphrinB2-OE mitigated HG-induced fibrosis, reduced ROS levels, and restored MMP and ATP production. Mechanistically, EphrinB2-OE enhanced the Epac1-Rap1 pathway, stabilizing Epac1 protein and promoting mitochondrial biogenesis via PGC-1α. Additionally, EphrinB2-OE modulated the E-cadherin/β-catenin complex and preventing β-catenin nuclear translocation, and preserving epithelial integrity and epithelial-to-mesenchymal transition (EMT).
    CONCLUSIONS: EphrinB2 exerts protective effects against renal fibrosis and dysfunction in diabetic conditions by regulating fibrosis pathways, mitochondrial dynamics, and epithelial stability. Targeting EphrinB2 signaling presents a promising therapeutic strategy for diabetic kidney disease.
    Keywords:  Diabetic kidney disease (DKD); Epac1-Rap1 signaling; EphrinB2; Mitochondrial dynamics; Oxidative stress; Renal fibrosis; β-catenin
    DOI:  https://doi.org/10.1186/s12967-025-06852-1
  35. Nat Commun. 2025 Jul 19. 16(1): 6651
    PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning.
    Xuetao Ji, Xu Zhang, Tong Zhang, Yao Xue, Mengping He, Chaopu Li, Yun Huang, Haoyu Wang, Jing Ju, Li'e Cai, Yuzhu Wang, Ning Wang, Lijuan Fan, Hui Tong, Heng Fan, Qinsheng Chen, Qinwei Lu, Cong Li, Huiru Tang, Yongsheng Chang, Xingxing Kong, Hanming Shen, Aihua Gu, Hui Liang, Hongwen Zhou, Qian Wang, John Zhong Li.
      PINK1/Parkin-mediated ubiquitin-dependent mitophagy is a critical negative regulatory machinery for browning in the inguinal white adipose tissue (iWAT). However, the precise regulatory mechanism underlying PINK1/Parkin-mediated mitophagy during browning of iWAT remains largely unknown. Here we report that PNPLA7, an Endoplasmic Reticulum and mitochondria-associated membrane (MAM) protein, inhibits browning of iWAT by promoting PINK1/Parkin-mediated mitophagy upon cold challenge or β3-adrenergic receptor agonist treatment. With genetic manipulation in mice, we show that adipose tissue overexpressing PNPLA7 induces mitophagy, abolishes iWAT browning and interrupts adaptive thermogenesis. Conversely, conditional ablation of PNPLA7 in adipose tissue promotes browning of iWAT, resulting in enhanced adaptive thermogenesis. Mechanistically, PNPLA7 interacts with Parkin to promote mitochondrial recruitment of Parkin for mitophagy activation and mitochondria degradation by disrupting PKA-induced phosphorylation of Parkin under cold challenge. Taken together, our findings suggest that PNPLA7 is a critical regulator of mitophagy that resists cold-induced browning of iWAT, thus providing a direct mechanistic link between mitophagy and browning of iWAT.
    DOI:  https://doi.org/10.1038/s41467-025-61904-w
  36. Pharmacol Res. 2025 Jul 23. pii: S1043-6618(25)00267-1. [Epub ahead of print] 107842
    Retraction notice to "Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease" [Pharmacol. Res., Vol. 174 (2021) 105973].
    Sudhir Kshirsagar, Neha Sawant, Hallie Morton, Arubala P Reddy, P Hemachandra Reddy.
      
    DOI:  https://doi.org/10.1016/j.phrs.2025.107842
  37. Comput Struct Biotechnol J. 2025 ;27 3045-3065
    Inhibiting MARCH5/Mfn2 signaling as an alternative strategy to protect cardiomyocytes from hypoxia-induced mitochondrial dysfunction.
    Faten Habrat Zoabi, Mulate Zerihun, Roy Lizarovich, Chiara Dalla Torre, Liron Davis, Offir Ertracht, Michal Barsheshet, Shaul Atar, Deborah E Shalev, Marta De Zotti, Hanoch Senderowitz, Nir Qvit.
      The mitochondrial E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5) and the GTPase Mitofusin 2 (Mfn2) both play crucial roles in regulating mitochondrial dynamics, which are essential for cellular homeostasis. Dysregulation of the MARCH5/Mfn2 signaling has been implicated in mitochondrial dysfunction, a key factor in cardiovascular diseases (CVDs). To investigate the therapeutic potential of targeting this interaction, we developed a novel peptide, CVP-220, designed to specifically disrupt the MARCH5/Mfn2 protein interaction. Using a hypoxia-reoxygenation (H/R) injury model in rat cardiomyocyte cell lines, CVP-220 demonstrated significant cardioprotective effects. Treatment with CVP-220 enhanced cell viability by 30 % compared to untreated controls and reduced reactive oxygen species (ROS) production by 45 %, suggesting improved mitochondrial function. Notably, CVP-220 selectively modulated MARCH5-mediated ubiquitination of Mfn2 without affecting other MARCH5 interactions, thereby preserving mitochondrial fusion and preventing fragmentation under stress conditions. A plausible binding mode of CVP-220 on Mfn2 was suggested through a combination of molecular docking and molecular dynamics simulations and was experimentally validated by mutational analysis. These findings highlight CVP-220 as a promising tool for modulating mitochondrial dynamics and mitigating mitochondrial damage in cardiac cells, with potential implications for therapeutic strategies targeting mitochondrial dysfunction in CVDs. Further investigation into the role of MARCH5/Mfn2 signaling in cardiac pathology could pave the way for novel peptide-based treatments.
    Keywords:  Cardiovascular diseases; Docking; Fission; Fusion; MARCH5; Mfn2; Mitochondria; Mitophagy; Molecular dynamics simulations; Peptide; Peptidomimetic; Protein-Protein Interaction
    DOI:  https://doi.org/10.1016/j.csbj.2025.07.001
  38. Mol Neurobiol. 2025 Jul 22.
    Mammalian Sterile 20-Like Kinase 2 Knockdown Alleviates Neuropathic Pain in Rats by Mitochondrial Protection.
    Qing Zeng, Bei-Xu Huang, Chang Liu, Nen Liang, Jian Yu, Song-Jie Liao.
      Neuropathic pain (NP) is a common chronic pain that lacks durable, mechanism-based therapies, making it a global health concern. Mitochondrial protection is essential to alleviate oxidative stress and maintain normal energy metabolism, playing a critical role in the treatment of NP. Mammalian ste20-like kinase 2 (Mst2) is a key protein in the Hippo pathway and plays a pivotal role in regulating mitochondrial function. Sirt1 mediates autophagy and BNIP3-related mitophagy, and is modulated by the phosphorylation of the Hippo pathway. Utilizing a sciatic nerve constriction injury (CCI) model on male rats to simulate traumatic NP, we further administered Mst2-siRNA to the injured sciatic nerve. Behavioral tests revealed that Mst2 knockdown significantly alleviated CCI-induced NP. Morphological analysis and western blot showed that the observed effects of Mst2 knockdown were attributed to the promotion of autophagy and the activation of BNIP3-mediated mitophagy. These processes contributed to the protection of mitochondria, myelin and axons within the sciatic nerve. In vitro studies in Schwann cell line and SH‑SY5Y‑derived neuroblastoma cells confirmed that Mst2 knockdown promotes autophagic flux and induces BNIP3‑mediated mitophagy, safeguarding mitochondrial function. Mechanistically, our study further showed that Mst2 downregulation reduces Sirt1 phosphorylation and elevates FOXO3‑driven BNIP3 transcription, establishing the significant role of Mst2 in Sirt1/FOXO3/BNIP3 regulation. These findings position Mst2 as a critical modulator in nerve injury-induced NP, highlighting autophagy and mitophagy regulation as potential targets for novel NP therapies.
    Keywords:  Autophagic flux; BNIP3; Mitophagy; Mst2; Neuropathic pain; Sirt1
    DOI:  https://doi.org/10.1007/s12035-025-05202-y
  39. Exp Cell Res. 2025 Jul 21. pii: S0014-4827(25)00282-4. [Epub ahead of print] 114682
    DNAJC6 in Acute Kidney Injury: A Novel Target for Protecting Renal Tubular Epithelial Cells Through PGC-1α-Mediated Mitochondrial Homeostasis.
    Liyun Ma, Jialiang Hui, Guangting He, Zaisheng Qin.
       BACKGROUND: Acute kidney injury (AKI) is a severe clinical syndrome that critically threatens patients' lives and health. It is characterized by complex pathogenesis and lacks effective therapeutic strategies. Mitochondrial homeostasis disruption plays a pivotal role in AKI progression, yet its precise molecular mechanisms remain unclear. This study aimed to investigate the role of DNAJC6 in AKI and its molecular mechanism of mitochondrial homeostasis regulation.
    METHODS: Utilizing cisplatin-induced mouse AKI models and human proximal tubular epithelial cell line HK-2, we employed multiple experimental approaches including bioinformatics analysis, cell transfection, immunohistochemical staining, immunofluorescence, TUNEL assay, and mitochondrial function detection to explore the role and molecular mechanisms of DNAJC6 in AKI.
    RESULTS: In cisplatin-induced AKI models, renal DNAJC6 expression decreased. DNAJC6 overexpression markedly alleviated kidney injury, reduced cell apoptosis, and attenuated inflammatory responses. Mechanistic investigations revealed that DNAJC6 regulated mitochondrial homeostasis by promoting PGC-1α nuclear translocation. Specifically, DNAJC6 improved mitochondrial respiratory function and reduced mitochondrial oxidative stress levels. Moreover, DNAJC6 enhanced mitochondrial biogenesis and suppressed inflammatory factor expression. Upon PGC-1α knockdown, DNAJC6's protective effects were almost completely abolished, confirming that PGC-1α was a critical molecular mediator.
    CONCLUSION: This study elucidated the molecular mechanism by which DNAJC6 protected renal tubular epithelial cells through PGC-1α-mediated mitochondrial homeostasis in AKI. These findings not only provide a novel perspective on AKI pathogenesis but also offer a crucial theoretical foundation for developing potential therapeutic strategies. DNAJC6 emerges as a promising molecular target for AKI treatment.
    Keywords:  AKI; DNAJC6; Mitochondrial Homeostasis; PGC-1α; Renal Tubular Epithelial Cells
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114682
  40. Adv Sci (Weinh). 2025 Jul 20. e08503
    NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.
    Shuoting Zhou, Xi Xiong, Jialong Hou, Qi Duan, Yi Zheng, Tao Jiang, Jiani Huang, Haijun He, Jiaxue Xu, Keke Chen, Wenwen Wang, Jinlai Cai, Jingjing Qian, Huijun Chen, Weihong Song, XinShi Wang, Chenglong Xie.
      Serving as a pivotal hub for cellular metabolism and intracellular signaling, the mitochondrion has emerged as a crucial organelle whose dysfunction is linked to many human diseases, including neurodegenerative disorders, particularly Parkinson's disease (PD). However, whether mitochondrial quality control (MQC) can be targeted for therapeutic interventions remains uncertain. This study uses clinical samples, molecular biology techniques, pharmacological interventions, and genetic approaches to investigate the significance of NAD+ levels in cross-species models of PD. These results reveal that treatment of rotenone-incubated cells with NAD+ boosters (such as NMN, siCD38, and NAT) increases UPRmt/mitophagy-related MQC, reduces pro-inflammatory cytokine expression, inhibits apoptosis, and strengthen redox reactions. In vivo, NMN supplementation inhibits motor deficit and forestalls the neuropathological phenotypes of MPTP-induced PD mice, which are required for the atf4-related mitochondrial UPR pathway. Notably, bulk omics signatures and metabolomic profiling analyses of the striatum reveal NMN-induced transcriptional changes in genes and proteins involved in mitochondrial homeostasis. Thus, these findings demonstrate that the accelerated pathology in PD models is probably mediated by impaired MQC and that bolstering cellular NAD+ levels alleviates mitochondrial proteotoxic stress and mitigate PD phenotypes.
    Keywords:  NAD+‐boosters; Parkinson's disease; mitochondria quality control; mitochondrial unfolded protein response; nicotinamide mononucleotide
    DOI:  https://doi.org/10.1002/advs.202408503
  41. J Cardiovasc Transl Res. 2025 Jul 25.
    Single-Cell Sequencing Identifies the Crucial Role of Mitochondrial Fission-Fusion Imbalance in Heart Failure Progression.
    Tao He, Jianmei Sha, Yuxin Hu, Caihong Shao, Yi Zhou, Lu Chen, Jianhua Yao, Junli Gao.
      The heart grows in response to both pathological and physiological stimuli. Pathological hypertrophy often leads to cardiomyocyte loss and heart failure (HF), whereas physiological hypertrophy paradoxically protects the heart. Comparing these two types of hypertrophy can elucidate the differences and connections in their molecular mechanisms, which is pivotal for unraveling the pathogenesis of HF. This study compares pathological (TAC-induced) and physiological (exercise-induced) cardiac hypertrophy using single-cell and bulk transcriptomics. Mitochondrial fusion/fission imbalance emerged as a key dysregulated pathway in both models. An early increase in the fusion/fission ratio (2 weeks post-TAC) resembled exercise-induced remodeling, while a progressive decline at 5-8 weeks marked transition to pathological hypertrophy. By 11 weeks, suppressed fusion and increased fission led to heart failure. Downregulation of fusion genes (Mfn1, Mfn2, Opa1) and upregulation of fission genes (Fis1, Dnm1l) highlight mitochondrial dynamics as critical drivers of disease progression.
    Keywords:  Heart failure; Mitochondrial fission; Mitochondrial fusion; Pathological hypertrophy; Physiological hypertrophy; Single-cell transcriptomics
    DOI:  https://doi.org/10.1007/s12265-025-10662-7
  42. Clin Immunol. 2025 Jul 21. pii: S1521-6616(25)00146-9. [Epub ahead of print]280 110571
    Mitochondrial bioenergetic failure in SLE immunocytes: Targeting fitness for therapy.
    Anjali S Yennemadi, Natasha Jordan, Sophie Diong, Mark Little, Joseph Keane, Gina Leisching.
       BACKGROUND: Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses linked to immunometabolic perturbations. While mitochondrial dysfunction has been implicated in SLE, its cell-type-specific impact on immune subsets remains underexplored.
    METHODS: We repurposed existing RNA-seq data from SLE patient peripheral blood mononuclear cells, with a focus on nuclear-encoded mitochondrial (NEmt) genes, as well as mitochondrial genes themselves, to identify differentially expressed genes compared to healthy controls. Mitochondrial stress tests were performed on freshly isolated CD4+ T cells, CD8+ T cells, B cells, and monocytes from SLE patients and healthy donors to assess bioenergetic function.
    RESULTS: RNA-seq revealed that both NEmt genes and mitochondrial genes were downregulated in the PBMC population of SLE patients. In situ mitochondrial stress tests revealed significant reductions in oxygen consumption rate (OCR), indicating impaired oxidative phosphorylation (OXPHOS) across all immune subsets, while extracellular acidification rate (ECAR), a marker of glycolysis, remained unchanged. These findings highlight immune-cell-specific mitochondrial bioenergetic failure in SLE, without compensatory glycolytic adaptation.
    CONCLUSION: Our results position mitochondrial fitness as a novel therapeutic target in SLE. We propose leveraging high-throughput screening of mitochondria-targeted compounds, including FDA-approved agents, to enhance OXPHOS, regulate mitophagy, or mitigate oxidative stress. This precision-based approach offers a paradigm shift from conventional immunosuppression to metabolic recalibration, with the potential to restore immune homeostasis in SLE. Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses linked to immunometabolic perturbations. While mitochondrial dysfunction has been implicated in SLE, its cell-type-specific impact on immune subsets remains underexplored.Using existing RNA-seq data we focused on nuclear-encoded mitochondrial (NEmt) genes, as well as mitochondrial genes themselves. Mitochondrial stress tests were performed on freshly isolated CD4+ T cells, CD8+ T cells, B cells, and monocytes from SLE patients and healthy donors to assess bioenergetic function.RNA-seq revealed that both NEmt genes and mitochondrial genes were downregulated in the PBMC population of SLE patients. In situ mitochondrial stress tests revealed significant reductions in oxygen consumption rate, indicating impaired oxidative phosphorylation across all immune subsets, while glycolysis remained unchanged. These findings highlight immune-cell-specific bioenergetic failure in SLE and propose mitochondrial fitness as a novel therapeutic target in SLE. This precision-based approach offers a paradigm shift from conventional immunosuppression to metabolic recalibration.
    Keywords:  B cells; CD4+ T cells; CD8+ T cells; Metabolic therapy; Mitochondrial dysfunction; Oxidative phosphorylation; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.clim.2025.110571
  43. iScience. 2025 Jul 18. 28(7): 112913
    Engineering a cell-based orthogonal ubiquitin transfer cascade for profiling the substrates of RBR E3 Parkin.
    Shuai Fang, Li Zhou, Geng Chen, Jing Zhang, Xiaoyu Wang, In Ho Jeong, Savannah E Jacobs, Bradley R Kossmann, Wei Wei, Shu Liu, Geon H Jeong, Yayun Xie, Duc Duong, Nicholas T Seyfried, Ivaylo Ivanov, Angela M Mabb, Hiroaki Kiyokawa, Bo Zhao, Jun Yin.
      The E3 ubiquitin (UB) ligase Parkin utilizes a Ring-Between-Ring (RBR) domain to mediate UB transfer to substrate proteins, and mutations affecting Parkin catalysis promote cancer and are associated with Parkinson's disease. An essential role of Parkin is to initiate mitophagy by ubiquitinating mitochondrial proteins. Still, it is unclear how Parkin carries out other cellular functions, such as the regulation of the cell cycle, metabolism, and the neuronal synapse. Here, we used phage display to engineer the RBR domain of Parkin and assembled an orthogonal ubiquitin transfer (OUT) cascade to profile Parkin substrates in living cells. Guided by the substrate profile from the OUT screen, we verified a panel of Rab GTPases and CDK5 as Parkin substrates. We also showed mitophagy stimulation enhanced Parkin-mediated ubiquitination of Rab proteins. Our work demonstrates that the OUT cascade can be an empowering tool for identifying Parkin substrates to elucidate its multifaceted cellular functions.
    Keywords:  Biochemistry; Biomolecular engineering; Methodology in biological sciences; Protein; Structural biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112913
  44. Vet Res. 2025 Jul 21. 56(1): 156
    Increased ROS levels activate AMPK-ULK1-mediated mitophagy to promote pseudorabies virus replication.
    Yuan Zhao, Xiaoyi Qi, Zhenbang Zhu, Wenqiang Wang, Wei Wen, Xiangdong Li.
      Increasing evidence has confirmed that oxidative stress plays a nonnegligible role in the viral pathogenic process. In this study, we investigated the role of reactive oxygen species (ROS) in the replication of pseudorabies virus (PRV). Our data showed that PRV infection initially enhanced the contact between the endoplasmic reticulum (ER) and mitochondria, leading to an upsurge of mitochondrial Ca2+ (mtCa2+) concentration, which resulted in the loss of mitochondrial membrane potential (MMP) and excessive ROS production. Instead of translocating it to the nucleus, PRV infection concurrently sequestered Nrf2 in cytoplasm impeding the efficient scavenging of intracellular ROS. The excessive ROS production and failure in ROS clearance contributed to the persistently high ROS levels during PRV infection. Furthermore, elevated ROS levels elicited activation of the AMPK-ULK1 axis, initiating PINK1-Parkin-dependent mitophagy that selectively degraded damaged mitochondria along with mitochondrial-localized mitochondrial antiviral signaling protein (MAVS). This process suppressed MAVS-mediated type I interferon responses by eliminating both dysfunctional mitochondria and their associated antiviral signaling platforms, thereby creating a cellular environment permissive to viral replication. Overall, our findings elucidated the mechanism by which ROS enables the virus to resist the host interferon immune response and provided a theoretical basis for ROS-based antiviral strategies.
    Keywords:  AMPK; Nrf2; Pseudorabies virus; mitochondria Ca2+ ; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.1186/s13567-025-01595-9
  45. Metabolites. 2025 Jul 16. pii: 481. [Epub ahead of print]15(7):
    Enhanced Mitochondrial Dynamics and Reactive Oxygen Species Levels with Reduced Antioxidant Defenses in Human Epicardial Adipose Tissue.
    Ana Burgeiro, Diana Santos, Ana Catarina R G Fonseca, Inês Baldeiras, Ermelindo C Leal, João Moura, João Costa-Nunes, Patrícia Monteiro Seraphim, Aryane Oliveira, António Canotilho, Gonçalo Coutinho, David Prieto, Pedro Antunes, Manuel Antunes, Eugenia Carvalho.
      Background/Objectives: Epicardial adipose tissue (EAT) is metabolically active and is in dynamic crosstalk with the surrounding cardiomyocytes, modulating their function and metabolism. Oxidative stress is a key contributor to cell death and cardiac remodeling, is a hallmark of diabetes (DM) and cardiovascular disease, such as coronary artery disease (CAD). However, little is known about these processes in EAT from patients undergoing cardiac surgery. This study investigates changes in mitochondrial dynamics, reactive oxygen species (ROS) production, and antioxidant defense levels in EAT compared to subcutaneous adipose tissue (SAT) in patients undergoing cardiac surgery, with a focus on the impact of DM and CAD. Methods: Adipose tissue biopsies were collected from 128 patients undergoing surgical cardiac intervention. Mitochondrial dynamics and oxidative stress markers were analyzed. Results: EAT exhibited increased expression of mitochondrial fusion markers [mitofusin 1 (p ≤ 0.001), mitofusin 2 (p = 0.038), and optic atrophy 1 (p ≤ 0.001)], as well as fission markers [fission 1 (p ≤ 0.001) and dynamin-related protein 1 (p ≤ 0.001)] relative to SAT. Additionally, ROS levels (dihydroethidium, p = 0.004) were elevated, while lipid peroxidation (malondialdehyde, p ≤ 0.001) was reduced in EAT compared to SAT. Reduced glutathione (GSH) levels (p ≤ 0.001) and the redox buffer ratio between reduced and oxidized glutathione (GSH/GSSG, p ≤ 0.001) were significantly increased in EAT. Interestingly, glutathione peroxidase activity (p ≤ 0.001) and the antioxidant defense markers catalase (p ≤ 0.001) and superoxide dismutase 2 (p = 0.001) were significantly reduced in EAT compared to SAT. Conclusions: The findings provide a unique molecular insight into the mitochondrial dynamics and oxidative stress profiles of EAT, highlighting potential avenues for a novel diagnostic method and therapeutic strategies for cardiac disease.
    Keywords:  antioxidant defense; coronary artery disease; diabetes mellitus; epicardial adipose tissue; mitochondrial dynamics; oxidative stress; subcutaneous adipose tissue
    DOI:  https://doi.org/10.3390/metabo15070481
  46. Mol Aspects Med. 2025 Jul 20. pii: S0098-2997(25)00049-4. [Epub ahead of print]105 101385
    Mitophagy: A key regulator of radiotherapy resistance in the tumor immune microenvironment.
    Jing Xia, Jing Jin, Shuang Dai, HaoHan Fan, KeLiang Chen, JianMei Li, Feng Luo, Xingchen Peng.
      Cancer remains a leading global cause of mortality, with radiation therapy (RT) as a cornerstone of treatment despite frequent radioresistance. Emerging evidence indicates that mitophagy activation contributes to adaptive radioresistance of cancer cells within the tumor microenvironment (TME). In this review, we highlight the dual role of mitophagy in modulating RT resistance and shaping the immune landscape of the TME. Mitophagy enhances cancer cell resilience by clearing radiation-damaged mitochondria, preserving metabolic homeostasis and reducing oxidative stress, while simultaneously altering the balance between immune activation and suppression within the TME. To provide mechanistic insight, we summarize key mitophagy-regulating pathways-including the PINK1/Parkin axis, BNIP3/NIX, and FUNDC1-mediated mechanisms-that respond to RT-induced mitochondrial stress and represent potential therapeutic targets. Furthermore, we explore how the interplay between mitophagy, metabolic reprogramming, and immune modulation shapes resistance not only to RT but also to immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T (CAR-T) cell therapy. Additionally, we examine how Type 2 diabetes(T2DM) mellitus impacts this process, as its associated metabolic disturbances exacerbate mitochondrial vulnerability to radiation and create an immunosuppressive milieu that compromises the tumor immune landscape. Understanding these interactions may support development of personalized therapeutic strategies for diabetic cancer patients.
    Keywords:  Diabetes; Immune modulation; Mitophagy; Radiotherapy resistance; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.mam.2025.101385
  47. Environ Pollut. 2025 Jul 22. pii: S0269-7491(25)01250-3. [Epub ahead of print] 126877
    Reversal of neurodevelopmental toxicity induced by combined exposure to the neonicotinoid insecticides acetamiprid and imidacloprid in zebrafish through targeting DRP-1: insights into mitophagy and apoptosis mechanisms.
    Yuzhi Zhao, Shaozhuo Wang, Siyue Tan, Gaoyuan Wang, Haojie Zhou, Chengyu Geng, Chunjin Li, Yuewen He, Yifan Shi, Zhongxiu Deng, Siyu Chen, Qitong Yuan, Sirui Wang, Yuxi Yang, Xinyan Jiang, Wenqing He, Shou-Lin Wang, Huibin Dong, Chao Wang.
      Neonicotinoid pesticides, including acetamiprid (ACE) and imidacloprid (IMI), are widely used due to their high efficacy and broad-spectrum activity. Despite IMI prohibition in certain countries by 2023, its residual effects, particularly in conjunction with ACE, which is frequently detected at elevated concentrations in rivers and surface waters, remain inadequately explored. In this study, the combined neurodevelopmental toxicity of ACE and IMI in zebrafish was investigated, with emphasis on mitochondrial dynamics and potential intervention strategies. We developed a 120-h acute exposure model using zebrafish embryos and a long-term chronic exposure model involving six months of environmentally relevant doses in adult zebrafish. Various parameters were systematically assessed using these models, including general toxicity, larval behavioral characteristics, outcomes of the novel tank diving test and light-dark test in adults, neurodevelopmental status, associated gene expression levels, and mitochondrial function. Furthermore, exposure experiments were conducted using transgenic zebrafish larvae Tg (huc:eGFP) and Tg (hb9:eGFP) to elucidate specific effects on the nervous system. Human neuroblastoma SK-N-SH cells were used to evaluate apoptosis, oxidative stress, ATP levels, mitochondrial membrane potential, and calcium ion concentrations. Protein markers associated with apoptosis (Bax, BCL-2, and Cleaved Caspase-3) and mitophagy (LC3A/B, P62, Parkin, and Pink-1) were analyzed. Additionally, DRP-1, Bax, and CytC levels were quantified in both mitochondrial and cytoplasmic fractions. The DRP-1 inhibitor Mdivi-1 was used to substantiate the role of mitochondrial dynamics. The results revealed a synergistic neurotoxic effect resulting from the combined exposure to ACE and IMI, which was characterized by impaired neural development, behavioral abnormalities, and mitochondrial dysfunction. Treatment with Mdivi-1 ameliorated these effects, reducing neurotoxicity in zebrafish. This study elucidates the synergistic neurodevelopmental toxicity of ACE and IMI, underscores the pivotal role of mitochondrial pathways, and provides insights into potential mitigation strategies for neonicotinoid-induced neurotoxicity.
    Keywords:  combined exposure; mitochondrial dynamics; neonicotinoid pesticides; neurodevelopmental toxicity; zebrafish
    DOI:  https://doi.org/10.1016/j.envpol.2025.126877
  48. Mutat Res Rev Mutat Res. 2025 Jul 17. pii: S1383-5742(25)00024-9. [Epub ahead of print]796 108553
    Rett syndrome: Pathogenicity and regulation of MECP2 (human) and Mecp2 (mouse) genes and their protein products through various molecular mechanisms.
    Bashir Ahmad, John Sieh Dumbuya, Ji-Xin Tang, Wen Li, Xiuling Chen, Jun Lu.
      Rett syndrome was first described over 50 years ago as an unusual clinical entity. Mutations in the X-linked MECP2 gene are the primary causes of Rett syndrome. The unstructured MeCP2 protein adopts various functional conformations, complicating its study. Researchers have investigated the pathogenicity and regulation of MECP2 through mechanisms such as apoptosis, mitophagy, the PI3K/AKT/mTOR pathway, BMP signaling, NF-kB, STAT3, and the Wnt/β-catenin pathway. These mechanisms have not been reviewed in such detail before. Summarizing these pathways is essential for facilitating further exploration by researchers; therefore, we have comprehensively summarized these pathways.
    Keywords:  MECP2; Mitophagy; Pathogenicity; Rett syndrome
    DOI:  https://doi.org/10.1016/j.mrrev.2025.108553
  49. Zhongguo Zhong Yao Za Zhi. 2025 May;50(10): 2711-2718
    [Alleviation of hypoxia/reoxygenation injury in HL-1 cells by ginsenoside Rg_1 via regulating mitochondrial fusion based on Notch1 signaling pathway].
    Hui-Yu Zhang, Xiao-Shan Cui, Yuan-Yuan Chen, Gao-Jie Xin, Ce Cao, Zi-Xin Liu, Shu-Juan Xu, Jia-Ming Gao, Hao Guo, Jian-Hua Fu.
      This paper explored the specific mechanism of ginsenoside Rg_1 in regulating mitochondrial fusion through the neurogenic gene Notch homologous protein 1(Notch1) pathway to alleviate hypoxia/reoxygenation(H/R) injury in HL-1 cells. The relative viability of HL-1 cells after six hours of hypoxia and two hours of reoxygenation was detected by cell counting kit-8(CCK-8). The lactate dehydrogenase(LDH) activity in the cell supernatant was detected by the lactate substrate method. The content of adenosine triphosphate(ATP) was detected by the luciferin method. Fluorescence probes were used to detect intracellular reactive oxygen species(Cyto-ROS) levels and mitochondrial membrane potential(ΔΨ_m). Mito-Tracker and Actin were co-imaged to detect the number of mitochondria in cells. Fluorescence quantitative polymerase chain reaction and Western blot were used to detect the mRNA and protein expression levels of Notch1, mitochondrial fusion protein 2(Mfn2), and mitochondrial fusion protein 1(Mfn1). The results showed that compared with that of the control group, the cell activity of the model group decreased, and the LDH released into the cell culture supernatant increased. The level of Cyto-ROS increased, and the content of ATP decreased. Compared with that of the model group, the cell activity of the ginsenoside Rg_1 group increased, and the LDH released into the cell culture supernatant decreased. The level of Cyto-ROS decreased, and the ATP content increased. Ginsenoside Rg_1 elevated ΔΨ_m and increased mitochondrial quantity in HL-1 cells with H/R injury and had good protection for mitochondria. After H/R injury, the mRNA and protein expression levels of Notch1 and Mfn1 decreased, while the mRNA and protein expression levels of Mfn2 increased. Ginsenoside Rg_1 increased the mRNA and protein levels of Notch1 and Mfn1, and decreased the mRNA and protein levels of Mfn2. Silencing Notch1 inhibited the action of ginsenoside Rg_1, decreased the mRNA and protein levels of Notch1 and Mfn1, and increased the mRNA and protein levels of Mfn2. In summary, ginsenoside Rg_1 regulated mitochondrial fusion through the Notch1 pathway to alleviate H/R injury in HL-1 cells.
    Keywords:  Mfn1; Mfn2; Notch1; ginsenoside Rg_1; mitochondrial fusion; myocardial ischemia-reperfusion injury(MIRI)
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20241219.403
  50. J Inflamm Res. 2025 ;18 9537-9555
    IL-1β-Mediated Immunometabolic Adaptation in Corneal Epithelial Cells.
    Jose Marcos Sanches, Rajalakshmy Ayilam Ramachandran, Natalia Mussi, Hamid Reza Baniasadi, Danielle M Robertson.
       Purpose: As an external mucosal surface, the corneal epithelium is subject to a barrage of stressors that are known to trigger inflammation. IL-1β, a master regulator of inflammation, is secreted into the preocular tear film by ocular surface epithelial cells and infiltrating immune cells. While increased levels of IL-1β have been associated with corneal disease, the effects of IL-1β on mitochondrial function in corneal epithelial cells (CECs) is unknown.
    Methods: To investigate the effects of IL-1β on mitochondrial function, telomerase immortalized human CECs were cultured in either 50 ng/mL or 100 ng/mL IL-1β for short term (24 hours) or prolonged (72 hours) time periods. Cells were assessed for ROS, inflammatory cytokine production, mitochondrial polarization and ultrastructure, mitophagy, and changes in the metabolite composition. Lipid drops were examined using light and fluorescent microscopy.
    Results: Short term exposure to IL-1β triggered an increase in IL-8 and ROS levels that corresponded to a reduction in mitochondrial membrane potential. Long term exposure also showed increased levels of IL-8 and IL-6 and further increased ROS. After long term exposure however, there was a paradoxical increase in mitochondrial membrane potential that was associated an increase in spare respiratory capacity and mitochondrial hyperfusion. Metabolomics confirmed an upregulation of the pentose phosphate pathway and the TCA cycle. Fumarate was also increased, suggesting an increase in flux through complex II. Changes in lipid metabolism included an upregulation in cardiolipin and de novo triacylglyceride biosynthesis, along with increasing numbers of lipid droplets.
    Conclusion: Prolonged exposure to IL-1β induces metabolic rewiring in CECs that results in an increase in spare respiratory capacity. These findings suggest that the corneal epithelium is able to adapt to certain levels of chronic inflammation and may have important implications in our understanding of immune tone and cellular stress responses in ocular surface epithelia.
    Keywords:  IL-1β; cornea; epithelial cells; inflammation; metabolites; metabolome; mitochondria; mitophagy
    DOI:  https://doi.org/10.2147/JIR.S495323
  51. Phytomedicine. 2025 Jul 07. pii: S0944-7113(25)00698-1. [Epub ahead of print]145 157059
    Magnolin Promotes PINK1-Parkin-mediated Mitophagy in Diffuse Large B-cell Lymphoma Cells via PPAR-γ Pathway.
    Xiaoli Zhou, Qianqian Guo, Qiqi Qiao, Xiaosheng Fang, Yujie Jiang, Xin Wang, Shunfeng Hu.
       BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is both genetically and phenotypically heterogeneous, yet precise treatment strategies are insufficient. Magnolin, a natural compound derived from the Magnolia plant, has been clinically used for its anti-allergic, anti-inflammatory, antihypertensive, and antibacterial effects. Recent studies have shown its promising therapeutic effects in tumor treatment. However, the anti-tumor effects of Magnolin in DLBCL remain unverified.
    PURPOSE: This study aimed to elucidate the effects of Magnolin in DLBCL and reveal the underlying molecular mechanisms in vitro.
    METHODS: DLBCL cell lines, including LY1 and LY10, were used in the study. The drug library screening (n = 1746) was used to screen effective anti-lymphoma drugs and its synergetic anti-tumor drugs. The intricate molecular mechanism of Magnolin was explored using network pharmacology and molecular docking analyses. Using the drug affinity responsive target stability (DARTS) assay, the potential of Magnolin to target peroxisome proliferator-activated receptor gamma (PPAR-γ) was explored. Mitochondrial membrane potential (MMP), superoxide and the colocalization of mitochondria and lysosomes were evaluated by confocal microscopy. Co-immunoprecipitation (CO-IP) and immunofluorescence were performed to verify the PPAR-γ interactive proteins.
    RESULTS: Through the drug library screening (n = 1746), Magnolin was identified as an effective anti-tumor drug for DLBCL, which effectively inhibited the progression of DLBCL through inhibiting cell viability, proliferation, and inducing cell cycle arrest (LY1, IC50=53 μM, LY10, IC50=42 μM). Besides, Magnolin treatment resulted in a decrease in mitochondrial membrane potential and an increase in MitoSOX in DLBCL. The colocalization of mitochondria with autophagosomes and lysosomes was increased after Magnolin treatment, indicating the activation of mitophagy pathway. The mitophagy inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) enhanced the anti-tumor effect of Magnolin. Moreover, Magnolin was found to exert synergetic anti-tumor effects with Venetoclax in DLBCL based on the drug library screening and cell viability assays. Mechanistically, we identified PPAR-γ as a downstream molecule of Magnolin through network pharmacology and molecular docking analyses. Using DARTS, CO-IP and immunofluorescent assays, Magnolin was found to exert anti-lymphoma effects by directly binding to PPAR-γ, thereby increasing expression of PPAR-γ and promoting its transfer from nuclei to cytoplasm. In addition, PPAR-γ could interact with PINK1 in DLBCL, and then promoted mitophagy by activating PINK1-Parkin pathway.
    CONCLUSIONS: In summary, our findings firstly identified the anti-tumor effects of Magnolin in DLBCL cells and highlighted that Magnolin promoted mitophagy in DLBCL cells through activating PPAR-γ/PINK1-Parkin pathway, which proposed a novel therapeutic strategy for DLBCL treatment.
    Keywords:  Diffuse large B-cell Lymphoma; Intracellular localization; Magnolin; Mitophagy; PPAR-γ
    DOI:  https://doi.org/10.1016/j.phymed.2025.157059
  52. Phytother Res. 2025 Jul 22.
    Natural Products in Regulating Mitophagy for the Intervention of Atherosclerosis and Its Risk Factors: Mechanisms and Therapeutic Potential.
    Yu-Han Li, Hao Ma, Ying-Rui Wang, Si-Xiang Zhang, You-Min Zhao, Zheng Liu.
      Atherosclerosis (AS) is a chronic systemic disease that poses a significant and escalating global challenge. The pathological process of AS involves multiple aspects. In addition to lipid-lowering therapy, therapeutic strategies such as anti-inflammatory and immunotherapy have been proposed, and attention has been paid to the intervention of its risk factors. However, the available drugs are still limited. Therefore, there is an urgent need to discover new pharmacological targets and drugs. Mitophagy is closely associated with AS and its risk factors, and it represents an important breakthrough in the intervention of AS and its risk factors. Natural products (NPs), with multiple pharmacological activities and lower toxicity, have caught attention as the new force in the treatment of AS and its risk factors. This review discusses the mechanisms and therapeutic potential of NPs in regulating mitophagy to alleviate AS and intervene in its risk factors. It also introduces the application prospects of the NPs, with the expectation of contributing to the treatment of AS and the development of innovative drugs.
    Keywords:  atherosclerosis; mitophagy; natural products; risk factors; treatment
    DOI:  https://doi.org/10.1002/ptr.70041
  53. J Vis Exp. 2025 Jul 03.
    Determination of Mitochondrial Morphology in Live Cells Using Confocal Microscopy.
    Manna Lin, Jiakang Wang, Zihong Xian, Chunyuan Zeng, Jiangping Xu.
      The dynamic balance of mitochondrial fusion and fission directly contributes to mitochondrial homeostasis, which influences numerous cellular functions in addition to adenosine triphosphate (ATP) homeostasis. Therefore, assessing mitochondrial morphology under stress conditions is essential for mechanistic research. This study describes a detailed protocol for analyzing mitochondrial morphology, encompassing the preparation of a MitoTracker solution, staining of mitochondria, optimization of imaging parameters, and detection of morphological features. MitoTrackers are commonly used, cost-effective mitochondrion-specific dyes. However, some changes in mitochondrial morphology may occur owing to inappropriate handling, which can be unperceivable and fail to reflect the true state of mitochondria. Therefore, it is necessary to understand how to analyze changes in mitochondrial morphology using MitoTrackers. The protocol utilized SH-SY5Y cells stimulated with 1-methyl-4-phenylpyridinium iodide (MPP+) to illustrate the protocol of mitochondrial morphological analysis. Compared with control cells, MPP+-stimulated cells exhibited smaller and more fragmented mitochondria, with morphological parameters indicating decreased mitochondrial footprint. These results suggest that MitoTracker staining is an effective and feasible method for mitochondrial morphological analysis that (with minor modifications) can be applied to study various conditions.
    DOI:  https://doi.org/10.3791/68167
  54. Zhonghua Zhong Liu Za Zhi. 2025 Jul 23. 47(7): 645-656
    [MiR-1-3p inhibits mitophagy in esophageal squamous cell carcinoma by targeting SLC7A11].
    S M Zhen, H R Zhang, J X Si, J Q Wang, Y Zhao, Y L Jia, L H Liu.
      Objective: To investigate the effect of miR-1-3p on mitophagy in human esophageal squamous cell carcinoma (ESCC) cells and the related mechanisms. Methods: The differentially expressed miRNAs in ESCC were screened using the GEO database. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure miR-1-3p expression in normal esophageal epithelial cells (HET-1A) and ESCC cell lines (TE1, KYSE30, KYSE150, KYSE410, Eca109). Bioinformatics tools were utilized to predict target genes of miR-1-3p, subcellular localization was confirmed by fluorescence in situ hybridization. The targeting relationship between miR-1-3p and SLC7A11 was validated using dual-luciferase reporter assay. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Furthermore, experimental validation demonstrated that overexpression of SLC7A11 rescued the presence of the miR-1-3p/SLC7A11 axis. Confocal microscopy was used to detect changes in mitochondrial autophagic lysosomes, while transmission electron microscopy was employed to observe mitophagy and morphological alterations. Western blot was conducted to evaluate the expression of autophagy-related proteins LC3 and P62. Flow cytometry was used to measure mitochondrial membrane potential and reactive oxygen species (ROS). Immunohistochemistry was applied to assess SLC7A11 expression in 133 ESCC patient tissues and 115 normal esophageal epithelial tissues. The correlation between SLC7A11 expression level and clinicopathological features was analyzed. Survival analysis was performed using the Kaplan-Meier method, and Cox proportional hazard regression models were used for multivariate analysis. Results: The expression of miR-1-3p in ESCC cells was significantly lower than that in HET-1A cells (P＜0.05). SLC7A11 was a target gene of miR-1-3p. Transfection of miR-1-3p mimic inhibited the proliferation of ESCC cells. CCK-8 assay results showed that the proliferative capacity of KYSE30 and KYSE410 cells in the miR-1-3p mimic group (absorbance values: 2.88±0.24 and 2.88±0.18, respectively) was significantly lower than that in the miRNA mimic negative control (NC) group (3.94±0.27, P＜0.001; 4.20±0.21, P＜0.001). Meanwhile, the proliferative capacity of KYSE30 and KYSE410 cells in the miR-1-3p mimic+SLC7A11-overexpression (OE) group (absorbance values: 3.57±0.15 and 3.60±0.13, respectively) was significantly higher than that in the miR-1-3p mimic +empty vector (EV) group (2.54±0.10, P＜0.001, 2.36±0.16, P＜0.001). Additionally, transfection of miR-1-3p mimic promoted apoptosis. Flow cytometry results demonstrated that the apoptosis rates of KYSE30 and KYSE410 cells in the miR-1-3p mimic group [(9.22±0.05)% and (6.55±0.37)%, respectively] were significantly higher than those in the miRNA mimic NC group [(0.81±0.17)%,P＜0.001); (1.04±0.12)%, P＜0.001]. Conversely, the apoptosis rates of KYSE30 and KYSE410 cells in the miR-1-3p mimic + SLC7A11-OE group [(0.73±0.04)% and (1.19±0.05)%, respectively] were significantly lower than those in the miR-1-3p mimic+EV group [(9.83±0.41)%, P＜0.001); (6.09±0.17)%, P＜0.00)]. MiR-1-3p mimic downregulated SLC7A11 protein expression and the LC3Ⅱ/LC3I ratio (P＜0.05), upregulated P62 protein expression (P＜0.05), this phenomenon can be rescued by overexpressing SLC7A11 (P＜0.05). Additionally, miR-1-3p mimic increased ROS levels and decreased mitochondrial membrane potential (JC-1 aggregate/monomer ratio), this phenomenon can be rescued by overexpressing SLC7A11 (P＜0.05). SLC7A11 expression was higher in ESCC tissues compared to normal esophageal epithelial tissues (P＜0.001), and SLC7A11 serves as an independent prognostic factor in ESCC (HR=2.15, 95% CI: 1.27-3.65, P=0.004). Conclusion: miR-1-3p inhibits mitophagy in esophageal squamous cell carcinoma by targeting SLC7A11.
    DOI:  https://doi.org/10.3760/cma.j.cn112152-20240219-00078
  55. Free Radic Biol Med. 2025 Jul 16. pii: S0891-5849(25)00840-8. [Epub ahead of print]239 27-42
    MITF promotes MFN2-dependent mitochondrial fusion to protect retinal pigment epithelial cells from mitochondrial damage.
    Ying-Ao Chen, Wan-Ni Lu, Pingping Li, Tianyin Nie, Yan Li, Rui Zeng, Sen Lin, Meiling Gao, J Fielding Hejtmancik, Ling Hou, Xiaoyin Ma.
      There is growing indication that protecting the retinal pigment epithelium (RPE) against mitochondrial damage is crucial for preventing RPE cell dysfunction and retinal degeneration. However, the molecular mechanisms remain largely unknown. Here, we show that microphthalmia-associated transcription factor (MITF), a potent antioxidant inducer in RPE, promotes mitochondrial fusion in RPE cells and protects them from mitochondrial uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced mitochondrial damage in ARPE-19 or mouse primary RPE cells ex vivo and Mitf heterozygous mice (Mitf-/+), Mitf-overexpressing transgenic mice (Dct-Mitf) or AAV mediated MITF overexpression mice in vivo. Mechanistically, MITF directly binds to the promoter of Mitofusin 2 (MFN2), a mitochondrial membrane protein that participates in mitochondrial fusion, and activates its transcription. Conversely, the knockdown of MFN2 neutralized the effects of MITF on mitochondrial fusion and mitochondrial damage protection. Intravitreal injection of mitochondria-targeted SkQ-1 nanoparticles effectively protects RPE cells from CCCP-induced damage in the Mitf-/+ mice in vivo. These findings suggest that MITF has an important role in regulating mitochondrial fusion in RPE cells and provides new insights into understanding the mechanisms of MITF deficiency induced RPE abnormalities and retinal degeneration.
    Keywords:  MITF; Mitochondria; Mitochondrial fusion; RPE; Retinal degeneration
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.025
  56. Kidney Int. 2025 Aug;pii: S0085-2538(25)00399-0. [Epub ahead of print]108(2): 329
    Critique of "Repression of PGC-1α leads to loss of mitochondrial homeostasis, contributing to maladaptive kidney repair".
    Javeria Kashaf Zain, Iftikhar Khan, Sozen Rehman, Aisha Nayab Babar.
      
    DOI:  https://doi.org/10.1016/j.kint.2025.04.020
  57. Phytomedicine. 2025 Jul 12. pii: S0944-7113(25)00687-7. [Epub ahead of print]145 157048
    Alpha-Heredin targets CAMKⅡ/DRP1-Mediated mitochondrial fission to trigger ferroptosis in pancreatic ductal adenocarcinoma.
    Xin Li, Waimei Si, Yuan Zhang, Peiwen Yang, Linjie Ruan, He Ba, Zhen Chen.
       PURPOSE: This study investigates the anti-tumor mechanisms of the natural triterpenoid Alpha-Heredin in pancreatic ductal adenocarcinoma, focusing on its dual effects on mitochondrial dynamics (via CAMKⅡ/DRP1 signaling) and ferroptosis induction.
    METHODS: In vitro assays including CCK-8, EdU, colony formation, and flow cytometry were employed to assess Alpha-Heredin's effects on proliferation, migration, and cell cycle arrest. Functional studies utilized FerroOrange staining, MDA/GSH/SOD quantification, transmission electron microscopy (TEM), and MitoSOX/JC-1 assay to evaluate ferroptosis markers and mitochondrial function. Bioinformatics analysis integrated PDAC patient RNA-seq data (GSE85916) with GSVA and WGCNA to link mitochondrial dysfunction with ferroptosis pathways. Subcutaneous PDAC xenograft models treated with Alpha-Heredin (5/10 mg/kg) were analyzed for tumor growth, Ki-67/GPX4/xCT expression, and CAMKⅡ/DRP1 signaling in vivo.
    KEY RESULTS: Alpha-Heredin dose-dependently suppressed PDAC proliferation and induced G0/G1 arrest. It inhibited CAMKⅡ/DRP1 phosphorylation, causing mitochondrial elongation, ROS accumulation, and cristae disruption. Ferroptosis induction was confirmed by iron overload, GSH/SOD depletion, and GPX4/xCT downregulation, reversible by Ferrostatin-1. In vivo, Alpha-Heredin (10 mg/kg) reduced tumor growth without systemic toxicity, while suppressing CAMKⅡ/DRP1 signaling and activating ferroptosis.
    CONCLUSION: Alpha-Heredin suppresses PDAC progression by dual targeting of mitochondrial fission and ferroptosis activation, offering a novel therapeutic strategy against pancreatic cancer.
    Keywords:  Alpha-Heredin; CAMKⅡ/DRP1 signaling; Ferroptosis; Mitochondrial fission; Oxidative stress; Pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.phymed.2025.157048
  58. Cancer Cell Int. 2025 Jul 19. 25(1): 272
    The DRP1 receptor FIS1 is critical to the expansion of triple-negative breast cancer tumor-initiating cells.
    Tetiana Katrii, Tanya Freywald, Malkon G Estrada, Amr El Zawily, Behzad Toosi, Frederick S Vizeacoumar, Franco J Vizeacoumar, Andrew Freywald, Scot C Leary.
       PURPOSE: To investigate whether individually targeting the outer mitochondrial membrane fission receptors FIS1 and MFF rather than the universally essential fission GTPase DRP1 is sufficient to suppress tumor initiating cells (TICs) without causing general mitochondrial dysfunction.
    METHODS: FIS1 or MFF were silenced or knocked out in triple-negative breast cancer (TNBC) cells to investigate their essentiality for maintaining TICs in cell culture and xenograft models. We further investigate the impact of FIS1 deficiency on several functional properties of mitochondria including morphology, membrane potential and ROS production.
    RESULTS: We demonstrate that FIS1 absence consistently suppressed TIC populations in cultured TNBC cells, and reduced tumor initiating activity in TNBC xenografts. Remarkably, we found that this phenotypic effect occurred in the absence of significant changes in ROS production, mitochondrial membrane potential and oxidative phosphorylation complex abundance even though FIS1-deficient TICs harbored a more reticular mitochondrial network. Finally, our in silico analyses established that all four DRP1 receptors (FIS1, MFF, MID49 and MID51) are ubiquitously expressed in healthy human tissues, and FIS1 is the most highly expressed DRP1 receptor in mammary gland.
    CONCLUSION: Our data collectively suggest that FIS1 targeting should allow for the suppression of TICs in TNBC tumors without compromising mitochondrial functionality or causing major, systemic toxicity. We believe our findings have the potential to facilitate the development of TIC suppressing therapies for TNBC patients, which is of considerable clinical relevance given that this malignancy has very limited targeted treatment options and is associated with a high mortality rate.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Breast cancer; FIS1 therapeutic targeting; Fission; Mitochondria; Tumor initiating cells
    DOI:  https://doi.org/10.1186/s12935-025-03909-5
  59. FASEB J. 2025 Jul 31. 39(14): e70863
    SARS-CoV-2-Induced Phosphorylation of HSPA9 at Ser627: Potential Implications for Mitochondrial Function, Cell Cycle Regulation, and Immune Evasion.
    Zi-Xiang Guo, Can Xie, Xian-Xin Lai, Yu-Qing Zhang, Yi Gao, Ruo-Chen Wang, Ze-Cong Zeng, Zhong-Wei Zhou.
      Heat shock proteins (HSPs), particularly those in the HSP70 family, play essential roles in maintaining cellular homeostasis and orchestrating stress responses, including those triggered by viral infections. Based on data mining of published datasets and experimental characterization, this study identified HSPA9 phosphorylation at serine 627 (S627) as a potential regulatory site associated with SARS-CoV-2 infection. Our findings demonstrate that phospho-S627 HSPA9 enhances mitochondrial function and mass, potentially meeting the elevated energy demands of viral replication. Concurrently, phosphorylation at S627 suppresses host cell proliferation, potentially delaying immune activation and facilitating viral spread. Moreover, phosphorylation at both the S627 and S378 sites markedly reduces the expression of the proinflammatory cytokines IL-6 and IL-8, which may further weaken the immune response during SARS-CoV-2 infection. These data suggest that SARS-CoV-2 may exploit HSPA9 phosphorylation to bolster its replication and evade host defenses. Notably, MAPKAPK2 has emerged as a latent kinase that regulates this phosphorylation, making it a promising therapeutic target for the treatment of these conditions. Overall, our results shed light on a novel mechanism of SARS-CoV-2 pathogenesis, suggesting that HSPA9 phosphorylation may be a potential therapeutic target.
    Keywords:  HSPA9; SARS‐CoV‐2; cell cycle; immune evasion; mitochondrial dynamics; phosphorylation
    DOI:  https://doi.org/10.1096/fj.202501244R
  60. Metabolites. 2025 Jul 11. pii: 472. [Epub ahead of print]15(7):
    Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control.
    Danlin Zhu, Lian Wang, Haoyang Gao, Ze Wang, Ke Li, Xiaotong Ma, Linlin Zhao, Weihua Xiao.
      Background: Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of life and capacity for independent living. Accumulating evidence indicates that moderate-intensity aerobic exercise is an effective strategy for promoting overall health in older adults and exerts a beneficial effect that mitigates age-related sarcopenia. However, the underlying molecular mechanisms through which exercise confers these protective effects remain incompletely understood. Methods: In this study, we established a naturally aging mouse model to investigate the effects of a 16-week treadmill-based aerobic exercise regimen on skeletal muscle physiology. Results: Results showed that aerobic exercise mitigated age-related declines in muscle mass and function, enhanced markers associated with protein synthesis, reduced oxidative stress, and modulated the expression of genes and proteins implicated in mitochondrial quality control. Notably, a single session of aerobic exercise acutely elevated circulating levels of β-hydroxybutyrate (β-HB) and upregulated the expression of BDH1, HCAR2, and PPARG in the skeletal muscle, suggesting a possible role of β-HB-related signaling in exercise-induced muscle adaptations. However, although these findings support the beneficial effects of aerobic exercise on skeletal muscle aging, further investigation is warranted to elucidate the causal relationships and to characterize the chronic signaling mechanisms involved. Conclusions: This study offers preliminary insights into how aerobic exercise may modulate mitochondrial quality control and β-HB-associated signaling pathways during aging.
    Keywords:  Sarcopenia; aerobic exercise; mitochondrial quality control; skeletal muscle
    DOI:  https://doi.org/10.3390/metabo15070472
  61. PLoS Biol. 2025 Jul 21. 23(7): e3003298
    A protein-specific priority code in presequences determines the efficiency of mitochondrial protein import.
    Saskia Rödl, Yasmin Hoffman, Felix Jung, Annika Egeler, Annika Nutz, Oliver Šimončík, Martin Jung, Markus Räschle, Petr Muller, Zuzana Storchova, Timo Mühlhaus, Johannes M Herrmann.
      The biogenesis of mitochondria relies on the import of hundreds of different precursor proteins from the cytosol. Most of these proteins are synthesized with N-terminal presequences which serve as mitochondrial targeting signals. Presequences consistently form amphipathic helices, but they considerably differ with respect to their primary structure and length. Here we show that presequences can be classified into seven different groups based on their specific features. Using a test set of different presequences, we observed that group A presequences endow precursor proteins with improved in vitro import characteristics. We developed IQ-Compete (for Import and de-Quenching Competition assay), a novel assay based on fluorescence de-quenching, to monitor the import efficiencies of mitochondrial precursors in vivo. With this assay, we confirmed the increased import competence of group A presequences. Using mass spectrometry, we found that the presequence of the group A protein Oxa1 specifically recruits the tetratricopeptide repeat (TPR)-containing protein TOMM34 to the cytosolic precursor protein. TOMM34, and the structurally related yeast co-chaperone Cns1, apparently serve as a presequence-specific targeting factor which increases the import efficiency of a specific subset of mitochondrial precursor proteins. Our results suggest that presequences contain a protein-specific priority code that encrypts the targeting mechanism of individual mitochondrial precursor proteins.
    DOI:  https://doi.org/10.1371/journal.pbio.3003298
  62. Nat Metab. 2025 Jul 21.
    LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
    Jin Li, Yamei Deng, Marie Gasser, Jie Zhu, Emily M Walker, Vaibhav Sidarala, Emma C Reck, Dre L Hubers, Mabelle B Pasmooij, Chun-Shik Shin, Khushdeep Bandesh, Eftyhmios Motakis, Siddhi Nargund, Romy Kursawe, Venkatesha Basrur, Alexey I Nesvizhskii, Michael L Stitzel, David C Chan, Guy A Rutter, Scott A Soleimanpour.
      Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.
    DOI:  https://doi.org/10.1038/s42255-025-01333-7
  63. Clin Ophthalmol. 2025 ;19 2343-2362
    TRAP1 Improves Diabetic Retinopathy by Preserving Mitochondrial Function.
    Yuchen Li, Weida Xu, Guiyang Zhao, Yuchen Guo, Liyuan Wang, Qianming Du, Yuxiang Fei, Xueteng Hu, Haoshen Hu, Lixun Chen, Yidan Xu.
       Background: Recent studies have demonstrated that mitochondrial dysfunction is pivotal in early diabetic retinopathy (DR). Tumor necrosis factor-associated protein 1 (TRAP1), a mitochondrial chaperone regulating stress responses, remains unexplored in DR pathogenesis.
    Methods: We established in vivo and in vitro models of DR. Hematoxylin and eosin (H&E) staining was utilized to evaluate retinal lesions in rats. Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence staining were employed to assess TRAP1 expression in the retina. Cell viability, reactive oxygen species (ROS), mitochondrial damage, and TRAP1 expression levels were measured in ARPE-19 cells. RNA sequencing (RNA-seq) identified gene expression and pathway changes in shTRAP1 cells. The role of TRAP1 in ferroptosis in ARPE-19 cells was evaluated with or without ferrostatin-1 (Fer-1) and erastin. Potential ferroptosis-related proteins interacting with TRAP1 were validated using co-immunoprecipitation (CO-IP) techniques. This study confirmed TRAP1's critical role in the pathogenesis of DR.
    Results: Our findings elucidate a significant reduction in TRAP1 expression in diabetic rat retinas, particularly in the pigment epithelium. High glucose levels correspondingly diminished TRAP1 expression in ARPE-19 cells, causing decreased cellular viability, increased ROS generation, and mitochondrial dysfunction. Notably, the overexpression of TRAP1 effectively preserved mitochondrial homeostasis under stress, mitigated mitochondrial impairment, and enhanced cellular viability. Importantly, TRAP1 may alleviate hyperglycemia-induced mitochondrial damage by reducing ferroptosis through its interactions with ferroptosis-related proteins, including acyl-CoA synthetase long-chain family member 1 (ACSL1), acyl-CoA synthetase long-chain family member 4 (ACSL4), and cytochrome b5 reductase 1 (CYB5R1).
    Conclusion: TRAP1 exerts a protective influence on mitochondrial function in ARPE-19 cells. Reduced levels of TRAP1 may play a crucial role as an early contributor to mitochondrial dysfunction in diabetic retinopathy. Furthermore, the association of TRAP1 with ferroptosis improves cellular viability by enhancing mitochondrial resilience against high glucose-induced stressors and preventing cellular ferroptosis.
    Keywords:  TRAP1; diabetic retinopathy; ferroptosis; mitochondria; oxidative stress
    DOI:  https://doi.org/10.2147/OPTH.S521660
  64. J Cell Sci. 2025 Jul 24. pii: jcs.263736. [Epub ahead of print]
    The mammalian protein MTCH1 can function as an insertase.
    Anna Roza Dimogkioka, Anni Elias, Doron Rapaport.
      The outer mitochondrial membrane (OMM) hosts a variety of proteins such as import machineries, enzymes, fission/fusion factors, and pore proteins. In Saccharomyces cerevisiae, the MIM complex, consisting of Mim1 and Mim2, mediates the insertion of α-helical proteins into the OMM. Until recently, it was unclear which proteins serve this function in higher eukaryotes. Recent studies identified MTCH2 as the insertase of α-helical proteins into the OMM in mammals. MTCH1 is a paralogue of MTCH2 but its general function and contribution to the biogenesis process are not clear. To better characterize MTCH1, we explored whether MTCH1 or MTCH2 could functionally replace Mim1/Mim2 in yeast. Expression of MTCH1 and MTCH2 in yeast cells lacking Mim1, Mim2, or both revealed that MTCH1, but not MTCH2, could compensate the growth defects upon deleting the MIM complex. Furthermore, MTCH1 could restore the biogenesis of MIM substrates, TOM complex stability, and morphology of mitochondria. These findings indicate that MTCH1 by itself has insertase activity and is a functional homologue of the MIM complex, despite the absence of any evolutionary relation between the mammalian and yeast insertases.
    Keywords:  Insertase; MIM; MTCH1; MTCH2; Mitochondria; Outer membrane
    DOI:  https://doi.org/10.1242/jcs.263736
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