bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–08–10
fifty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. Peroxiredoxin Ⅲ mitigates mitochondrial H2O2-mediated damage and supports quality control in cardiomyocytes under hypoxia-reoxygenation stress.
  2. Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
  3. Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
  4. TRABD maintains mitochondrial homeostasis and protects against ischemia reperfusion-induced renal tubular injury.
  5. Tau Protein Disrupts Mitochondrial Homeostasis in a Yeast Model: Implications for Alzheimer's Disease.
  6. Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury.
  7. Kirenol attenuates pressure overload-induced heart failure by enhancing autophagy in macrophages.
  8. Mitophagy in the mechanisms of treatment resistance in solid tumors.
  9. Levosimendan alleviates myocardial ischemia-reperfusion injury by regulating mitochondrial autophagy through cGAS-STING signaling pathway.
  10. Calcium dysregulation disrupts mitochondrial homeostasis by interfering AMPK/Drp1 pathway to aggravate plaque progression and instability.
  11. Pioglitazone Ameliorates Mitochondrial Oxidative Stress and Inflammation via AMPK-Dependent Inhibition of Mitochondrial Fission in Leigh Syndrome.
  12. Cadmium-Induced Mitochondrial and MAMs Dysregulation in Rat Testis: The Protective Role of D-Aspartate.
  13. GLI2/Parkin-mediated mitophagy promotes pazopanib resistance in clear cell renal cell carcinoma.
  14. Cardiomyoprotective effect of Tanshinone IIA in diabetic cardiomyopathy achieved through enhancing PINK1-Parkin dependent mitophagy.
  15. The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux.
  16. Exploring the correlation between Drp1 protein and the neurotoxicity of propofol.
  17. ABCA4 regulates mitophagy in lung adenocarcinoma progression via AMPK pathway by modulating TMSB4X.
  18. MicroRNA-27b alleviates septic cardiomyopathy by targeting the Mff/MAVS axis.
  19. Transcription Factor MEOX1 Accelerates Pulmonary Fibrosis by Regulating Mitophagy and Senescence.
  20. Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.
  21. AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ.
  22. The role of mitochondrial dysfunction in diabetes-associated cognitive dysfunction: A bibliometric analysis.
  23. Mitochondrial dynamics imbalance and energy dyshomeostasis mediated developmental toxicity of ochratoxin a in zebrafish (Danio rerio).
  24. Hyperoside protects human osteoblasts from phthalate-induced mitochondrial dysfunction, oxidative stress, and apoptosis.
  25. Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
  26. Nanoparticle-induced excessive mitophagy combined with immune checkpoint blockade for enhanced cancer immunotherapy.
  27. New perspective on postmortem meat quality changes of Esox Lucius: The role of mitophagy-mediated ferroptosis pathway.
  28. Circulating mitochondrial components and metabolic and inflammatory markers in Charcot-Marie-Tooth type 2B.
  29. Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect.
  30. Excessive mitochondrial stress response triggers neuronal injury through the persistent eIF2α phosphorylation in mice exposed to manganese.
  31. Nanoparticle-Delivered siRNA Targeting NSUN4 Relieves Systemic Lupus Erythematosus through Declining Mitophagy-Mediated CD8+T Cell Exhaustion.
  32. Differential effects of β-blockers nebivolol and metoprolol on mitochondrial biogenesis and antioxidant defense in angiotensin II-induced pathology in H9c2 cardiomyoblasts.
  33. Urolithin A abolishes high anxiety and rescues the associated mitochondria-related transcriptomic signatures and synaptic function.
  34. The interplay involving oxidative stress and autophagy: Mechanisms, implications, and therapeutic opportunities.
  35. Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.
  36. Resveratrol alleviates lipopolysaccharide-induced acute lung injury through blocking the excessive autophagy/mitophagy via SIRT1/PGC-1α and TNF/NF-κB/JNK pathways.
  37. Effect of Regulating FUNDC1 Mitophagy-Mediated cGAS/STING Pathway in Oleic Acid-Induced Acute Lung Injury Model.
  38. PABPC1 SUMOylation enhances cell survival by promoting mitophagy through stabilizing U-rich mRNAs within stress granules.
  39. Mitochondrial dysfunction and defective quality control mechanisms in the kidney are not reversed by high-fat diet withdrawal in early obese mice.
  40. PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism.
  41. Pharmacological and genetic approaches to downregulate FIS1 mitigate neuropathic pain.
  42. OPTN deficiency through CRISPR/Cas9 downregulates autophagy and mitophagy in a SOD1-G93A-expressing transgenic cell line.
  43. Zearalenone Regulates Energy Metabolism and Proliferation of Goat Endometrial Epithelial Cells through Estrogen Receptor 1.
  44. Vinpocetine alleviates chemotherapy-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial biogenesis in mice.
  45. HIF1A/BNIP3 pathway affects ferroptosis in sepsis-induced cardiomyopathy through binding to BCL-2.
  46. Melatonin Alleviates Pulmonary Fibrosis Induced by Atrazine Targeting the Pulmonary Capillary Microenvironment.
  47. Piezo1 induces mitochondrial autophagy dysfunction leading to cartilage injury in knee osteoarthritis.
  48. SAP30BP aggravates mitochondrial-related ferroptosis in diabetic cardiomyopathy by regulating MFN2-ACSL4 axis.
  49. Arylsulfatase K attenuates airway epithelial cell senescence in COPD by regulating parkin-mediated mitophagy.
  50. An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial protein import.
  51. Ergothioneine supplementation improves pup phenotype and survival in a murine model of spinal muscular atrophy.
  52. Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
  53. A novel founder mutation in the MFN2 gene associated with variable Charcot-Marie-Tooth type 2 phenotype in two families from Southern Italy.
  54. Enteral nutrition intervention improves intestinal ischemia-reperfusion injury by modulating the SENP1/SIRT3 axis.
  1. Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00312-X. [Epub ahead of print]86 103799
    Peroxiredoxin Ⅲ mitigates mitochondrial H2O2-mediated damage and supports quality control in cardiomyocytes under hypoxia-reoxygenation stress.
    Ji Won Park, Seong Keun Sonn, Byung-Hoon Lee, Goo Taeg Oh, Tong-Shin Chang.
      Peroxiredoxin Ⅲ (PrxⅢ) is a mitochondria-localized peroxidase that plays a key role in detoxifying hydrogen peroxide (H2O2) and preserving organelle homeostasis. While its antioxidant function is well established under physiological conditions, the role of PrxⅢ in the context of cardiac hypoxia/reoxygenation (H/R) injury remains incompletely understood. In this study, we investigated the protective function of PrxⅢ in cardiomyocytes exposed to H/R stress, a widely used in vitro model to mimic ischemia/reperfusion injury. Using H9c2 cells and primary neonatal rat cardiomyocytes, we found that PrxⅢ knockdown significantly increased mitochondrial H2O2 accumulation, leading to excessive mitochondrial fragmentation, impaired mitophagy, and reduced cell survival following H/R. Western blot analysis revealed that mitophagy regulators Parkin and BNIP3 were upregulated under moderate oxidative stress but were markedly suppressed in PrxⅢ-deficient cells after H/R, indicating that mitophagy activation is sensitive to the degree of oxidative stress. These findings were confirmed in vivo using mt-Keima transgenic mice, which showed significantly reduced mitophagic flux in PrxⅢ knockout hearts subjected to ischemia/reperfusion. In addition, PrxⅢ loss impaired lysosomal acidification and proteolytic activity, further contributing to defective autophagic flux. Re-expression of PrxⅢ restored mitochondrial morphology, mitophagy activity, and lysosome function, highlighting its central role in maintaining mitochondrial quality control (MQC). Collectively, our results demonstrate that PrxⅢ mitigates mitochondrial oxidative damage and preserves MQC by coordinating mitochondrial dynamics, mitophagy, and lysosomal integrity. These findings suggest that PrxⅢ may serve as a promising therapeutic target for preventing cardiac injury induced by oxidative stress during ischemia/reperfusion.
    Keywords:  Cardiomyocyte injury; Hypoxia/reoxygenation injury; Mitochondrial oxidative stress; Mitophagy dysfunction; Peroxiredoxin Ⅲ
    DOI:  https://doi.org/10.1016/j.redox.2025.103799
  2. bioRxiv. 2025 Jul 21. pii: 2025.07.17.665416. [Epub ahead of print]
    Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
    Leena Kadam, Kaylee Chan, Ethan Tawater, Leslie Myatt.
       Introduction: The placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in both obese and GDM placentas of male and female fetuses. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria.
    Methods: We collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner.
    Results: Only placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1α and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), GDM placentas failed to mount this response.
    Discussion: Obesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.
    DOI:  https://doi.org/10.1101/2025.07.17.665416
  3. Res Sq. 2025 Jul 31. pii: rs.3.rs-7093535. [Epub ahead of print]
    Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
    Johan Auwerx, Xiaoxu Li, Weisha Li, Arwen Gao, YunYun Zhu, Elena Katsyuba, Katherine Overmyer, Terytty Yang Li, Ziwen Wang, Luc Legon, Lucie Plantade, Laurent Mouchiroud, Matteo Cornaglia, Hao Li, Riekelt Houtkooper, Joshua Coon.
      The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, highlighting its translational relevance. Overall, our dataset (https://lisp-lms.shinyapps.io/RIAILs_Dox/) serves as a unique resource to dissect lifespan and mitochondrial stress response modulators in a large genetic reference population.
    DOI:  https://doi.org/10.21203/rs.3.rs-7093535/v1
  4. Front Cell Dev Biol. 2025 ;13 1619339
    TRABD maintains mitochondrial homeostasis and protects against ischemia reperfusion-induced renal tubular injury.
    Wenqi Duan, Wenye Wu, Cui Yang, Mei Zhang, Xuemei Li, Wenmin Tian, Yang Chen, Xinjun Zhang.
      Mitochondria serve as hubs for many critical cellular processes, and their functions and dynamics are tightly controlled. TRABD is a Tiki/TraB family protein with unknown function. Here, we characterized TRABD as a novel outer mitochondrial membrane protein. Depletion of TRABD in cells severely impairs mitochondrial respiration and ATP production, inhibits cell growth, increases reactive oxygen species levels. Depletion of TRABD also affects mitochondrial dynamics and mitophagy, possibly through interactions with PGAM5. Knockout of TRABD in mice significantly exacerbates ischemia reperfusion-induced renal tubular injury by promoting mitochondrial fragmentation and damage. Our study identified a novel outer mitochondrial membrane protein and revealed the critical roles of TRABD in mitochondrial dynamics and ischemia reperfusion-induced renal tubular injury.
    Keywords:  PGAM5; TRABD; dynamics; ischemia reperfusion-induced renal tubular injury; mitochondrial membrane protein; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2025.1619339
  5. Mol Neurobiol. 2025 Aug 08.
    Tau Protein Disrupts Mitochondrial Homeostasis in a Yeast Model: Implications for Alzheimer's Disease.
    Yaisa Castillo-Casaña, Laura Kawasaki, Clorinda Arias, Hilario Ruelas-Ramírez, Soledad Funes, Norma Silvia Sánchez, María Guadalupe Códiz-Huerta, Laura Ongay-Larios, Roberto Coria.
      The microtubule-associated protein tau plays a central role in neurodegenerative diseases, called tauopathies, but the mechanism involved remains incompletely understood. Here, we used Saccharomyces cerevisiae as a model system to investigate the consequences of expressing the shortest human tau isoform 0N3R. After transfected, we detected widespread cellular distribution of tau and phosphorylation at key pathological residues involved in Alzheimer's disease (Ser199/202). We also found that a portion of tau localizes within the mitochondrial matrix. The mitochondrial uptake of tau required a chaperone machinery, including Hsp104 and the Ssa1/Ydj1 bichaperone complex. Functionally, tau expression caused marked mitochondrial fragmentation, reduced oxygen consumption, and a decrease in membrane potential during stationary phase, indicating impaired mitochondrial function. This dysfunction activated the yeast retrograde signaling pathway. Importantly, tau expression enhanced mitochondrial clearance through mitophagy, both under nitrogen starvation and during stationary phase, and this effect was dependent on the retrograde response. Together, these findings demonstrate that tau expression in yeast perturbs mitochondrial homeostasis, triggering both compensatory nuclear signaling and increased mitochondrial turnover, adding evidence on the potential mechanisms involved in tau neurotoxicity.
    Keywords:  0N3R-tau; Magic pathway; Mitophagy; Oxygen consumption; Retrograde response
    DOI:  https://doi.org/10.1007/s12035-025-05255-z
  6. Cell Mol Life Sci. 2025 Aug 08. 82(1): 305
    Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury.
    Shishi Zou, Yifan Zuo, Yukai Chen, Tianyu Zhang, Tinglv Fu, Guorui Li, Rui Xiong, Bohao Liu, Yong Hu, Zhaoyu Hu, Chunguang Miao, Xiaojing Wu, Ning Li, Qing Geng.
      The stimulator of interferon genes (STING) pathway serves as a crucial nexus in inflammatory responses and cell death. Despite its role in Mitochondria-Endoplasmic Reticulum Contact (MERC), the mechanistic contributions to inflammatory outcomes remain poorly understood. In clinical acute respiratory distress syndrome (ARDS) models of COVID-19 infection and animal models of LPS-induced acute lung injury (ALI), the STING pathway is closely associated with the pyroptosis pathway. The macrophage STING-N-GSDMD-mtDNA positive feedback loop, upon LPS challenge, induces inflammatory responses and pyroptosis. The GSDMD inhibitor disulfiram (DSF) specifically abrogates the N-terminal portion of GSDMD anchored to the mitochondrial membrane. Furthermore, macrophage STING mediates the direct interaction between Drp1 and N-GSDMD on mitochondrial membrane by regulating mitochondrial calcium, linking mitochondrial fission to the induction of inflammatory responses. Targeting STING-mediated mitochondrial homeostasis, both genetically and pharmacologically, may play a protective role in preventing and treating sepsis-induced acute lung injury. Overall, our study posits that STING deficiency mitigates the cooperative interaction between N-GSDMD and Drp1 in mediating mitochondrial permeabilization and rupture following LPS challenge, paving the way for further investigations into inflammation and pyroptosis.
    Keywords:  Endoplasmic Reticulum-Mitochondria contact; Mitochondrial calcium; Mitochondrial dynamics; MtDNA release; Pyroptosis
    DOI:  https://doi.org/10.1007/s00018-025-05774-x
  7. Int J Cardiol. 2025 Aug 04. pii: S0167-5273(25)00724-7. [Epub ahead of print]440 133681
    Kirenol attenuates pressure overload-induced heart failure by enhancing autophagy in macrophages.
    Zhenzhen Huang, Lei Pan, Zilong Xiao, Fang Rao, Wusiman Yakupu, Abudunaizier Rouzi, Kuan Cheng, Yang Pang, Yangang Su, Di Wu.
       BACKGROUND: Heart failure (HF) is characterized by chronic inflammation and pathological remodeling, with macrophage-mediated oxidative stress and inflammasome activation playing key roles in disease progression. Mitophagy regulates mitochondrial quality control and restrains inflammatory activation.
    METHODS: We investigated whether Kirenol, a flavonoid with antioxidant and autophagy-enhancing properties, ameliorates pressure overload-induced HF via mitophagy regulation in macrophages. A murine transverse aortic constriction (TAC) model was employed. Cardiac function, remodeling, and inflammation were assessed by echocardiography, histology, qPCR, immunoblotting, and flow cytometry. In vitro studies were conducted in Ang II-stimulated bone marrow-derived macrophages.
    RESULTS: Kirenol significantly improved cardiac function, reduced hypertrophy and fibrosis, and suppressed inflammatory responses in TAC mice. Mechanistically, Kirenol enhanced macrophage mitophagy, reduced mitochondrial ROS production, and inhibited NLRP3 inflammasome activation and IL-1β release. These protective effects were abrogated by mitophagy inhibition using cyclosporin A.
    CONCLUSIONS: Kirenol exerts cardioprotective effects in pressure overload-induced HF by promoting macrophage mitophagy and suppressing inflammasome-mediated inflammation. This identifies Kirenol as a potential therapeutic agent targeting immune-metabolic dysfunction in HF.
    Keywords:  Autophagy; Heart failure; Macrophage
    DOI:  https://doi.org/10.1016/j.ijcard.2025.133681
  8. Oncol Rev. 2025 ;19 1607983
    Mitophagy in the mechanisms of treatment resistance in solid tumors.
    Xiaoyi Yan, Hui Ding, Mengxiao Ren, Lei Zang.
      This review aims to explore the mechanisms by which mitophagy contributes to treatment resistance in solid tumors. As advancements in cancer therapies continue to evolve, treatment resistance emerges as a significant barrier to successful tumor management. Mitophagy, a specific form of cellular autophagy, has been implicated in the survival, proliferation, and drug resistance of tumor cells. This article will summarize the latest research findings and analyze how mitophagy impacts the biological characteristics of solid tumors, thereby revealing its potential implications in cancer treatment strategies. By understanding the role of mitophagy in the context of treatment resistance, we may uncover new therapeutic targets and strategies to enhance the efficacy of existing cancer treatments.
    Keywords:  cellular autophagy; mitophagy; solid tumors; treatment resistance; tumor biology
    DOI:  https://doi.org/10.3389/or.2025.1607983
  9. J Clin Biochem Nutr. 2025 Jul;77(1): 74-78
    Levosimendan alleviates myocardial ischemia-reperfusion injury by regulating mitochondrial autophagy through cGAS-STING signaling pathway.
    Feng Shi, Han Bao, Fanqing Meng, Yunting Pang.
      Levosimendan, a calcium sensitizer, has cardioprotective effects against myocardial ischemia-reperfusion injury (MIRI). Mitophagy plays an important role in MIRI, and the cGAS-STING signaling pathway can participate in mitophagy in a variety of ways. The purpose of this study was to explore the new molecular mechanism by which levosimendan exerts cardioprotective effects in order to provide a new experimental basis for the clinical application of levosimendan. In this study, an isolated MIRI rat model was established, and 48 rats were randomly divided into four groups (n = 12): continuous perfusion group (Group C), ischemia-reperfusion group (IR group), ischemia-reperfusion + levosimendan group (IR + L group), and ischemia-reperfusion + levosimendan + sting activator group (IR + LA group). The hemodynamic indices, myocardial infarction volume, expression of cGAS-STING signaling pathway proteins, and mitophagy-related proteins in isolated rat hearts of the four groups were compared. This study showed that levosimendan can reduce the level of myocardial mitophagy in ischemia-reperfusion rats by inhibiting the cGAS-STING signaling pathway, reducing myocardial injury, and playing a myocardial protective role.
    Keywords:  cGAS-STING signaling pathway; levosimendan; mitochondrial autophagy; myocardial ischemia-reperfusion injury
    DOI:  https://doi.org/10.3164/jcbn.25-8
  10. Theranostics. 2025 ;15(15): 7567-7583
    Calcium dysregulation disrupts mitochondrial homeostasis by interfering AMPK/Drp1 pathway to aggravate plaque progression and instability.
    Pingping Hu, Mengmeng Liu, Tongtong Wu, Yiping Zhang, Chenyuan Liu, Langtao Wang, Wanping Zhang, Yumei Que, Jiali You, Weimin Yu, Xiaoyong Tong.
      Rationale: Inactivation of Cys674 (C674) of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) disrupts intracellular calcium (Ca2+) homeostasis and SERCA2 dysfunction has been implicated in the pathogenesis of atherosclerosis and aortic aneurysms. However, the precise role of SERCA2 dysfunction in aortic smooth muscle cells (SMCs) and its contribution to atherosclerosis remains unclear. Methods: We Used heterozygous SERCA2 C674S knock-in (SKI) mice to mimic the partial irreversible oxidation inactivation of C674 thiol under pathological conditions. The whole aorta and aortic root were isolated for immunohistological analysis, RNA sequencing and proteomic analysis. The primary SMCs were collected for cell culture, protein expression and immunofluorescence analysis. Results: Compared with SMCs from WT mice, SKI SMCs demonstrated abnormally activated AMPK/Drp1 pathway adenosine 5'-monophosphate-activated protein kinase (AMPK)/dynamin related protein 1 (Drp1) pathway, and mitochondrial disorders, including increased cytosolic/mitochondrial Ca²⁺ level, oxidative stress, ATP depletion, decreased mitochondrial membrane potential (Δψm), and disrupted mitochondrial dynamics. In SKI SMCs, stimulation of AMPK by metformin or 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), or inhibition of Drp1 with mitochondrial division inhibitor 1 (Mdivi-1), restored mitochondrial homeostasis, mitigated excessive matrix metalloproteinase 2 and SMC apoptosis, thereby preserved SMC function. In vivo administration of metformin and Mdivi-1 both ameliorated atherosclerosis triggered by SERCA2 dysfunction and particularly enhanced plaque stability. Conclusions: SERCA2 dysfunction accelerates atherosclerotic plaques formation and increases plaque vulnerability by disrupting the AMPK/Drp1 pathway in aortic SMCs, leading to mitochondrial disorders and impairing SMCs function. Targeting of AMPK or Drp1 pharmacologically may offer promising therapeutic avenues for atherosclerosis, particularly in reducing atherosclerotic plaques vulnerability.
    Keywords:  AMPK; SERCA2; atherosclerosis; mitochondria; plaque stability
    DOI:  https://doi.org/10.7150/thno.112041
  11. Cell Prolif. 2025 Aug 06. e70109
    Pioglitazone Ameliorates Mitochondrial Oxidative Stress and Inflammation via AMPK-Dependent Inhibition of Mitochondrial Fission in Leigh Syndrome.
    Jie Luo, Ling Chen, Xiaoxian Zhang, Qiang Su, Xiaoya Zhou, Qizhou Lian.
      Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).
    DOI:  https://doi.org/10.1111/cpr.70109
  12. Environ Toxicol. 2025 Aug 04.
    Cadmium-Induced Mitochondrial and MAMs Dysregulation in Rat Testis: The Protective Role of D-Aspartate.
    Debora Latino, Sara Falvo, Massimo Venditti, Alessandra Santillo, Giulia Grillo, Gabriella Chieffi Baccari, Imed Messaoudi, Maria Maddalena Di Fiore.
      Cadmium (Cd), a heavy metal, disrupts the structure of seminiferous tubules and induces cell death at multiple stages of sperm development. Cd also impairs Leydig cells (LCs), resulting in reduced serum testosterone (T) levels. This study primarily examined the impact of Cd on the mitochondrial compartment and mitochondrial-associated endoplasmic reticulum membranes (MAMs) in rat testis. Additionally, the potential of D-aspartate (D-Asp) to mitigate Cd-induced effects on steroidogenesis and spermatogenesis was assessed by administering D-Asp simultaneously or preventively with Cd. The findings demonstrated that Cd exerts reprotoxicity by affecting the mitochondrial compartment and MAMs, evidenced by an imbalance in mitochondrial dynamics, impaired mitophagy pathway, and downregulated mitochondrial biogenesis. Cd exposure also reduced lipid transfer-related factor expression and increased ER stress. Moreover, elevated levels of Ca2+ transfer-related proteins, indicative of perturbed Ca2+ homeostasis, may be associated with enhanced oxidative stress and apoptosis, which are known effects of Cd. Immunofluorescent analysis revealed that the Cd-induced mitochondrial and MAMs damage was prominent in LCs, spermatocytes, and spermatids, confirming the metal's adverse effects on steroidogenesis and spermatogenesis. Conversely, co-administration or preventive administration of D-Asp with Cd preserved mitochondrial homeostasis and functional ER-mitochondria interactions. In conclusion, the study offers novel insights into the cellular mechanisms underlying Cd-induced reprotoxicity. Importantly, it highlights the efficacy of D-Asp in preventing or counteracting testicular damage caused by Cd by enhancing mitochondrial and MAMs functionality.
    Keywords:  D‐aspartate; MAMs; cadmium; mitochondria; testis
    DOI:  https://doi.org/10.1002/tox.24559
  13. Cell Signal. 2025 Aug 06. pii: S0898-6568(25)00469-3. [Epub ahead of print] 112054
    GLI2/Parkin-mediated mitophagy promotes pazopanib resistance in clear cell renal cell carcinoma.
    Yiwei Lin, Yuxiao Li, Zhixiang Qi, Xueyou Ma, Xinyang Niu, Dingheng Lu, Ben Liu.
      Advanced clear cell renal cell carcinoma (ccRCC) treatment primarily involves targeted therapy and immunotherapy; however, many patients exhibit resistance to these modalities. Understanding the mechanisms underlying this resistance is essential for improved outcomes. Herein, we created a pazopanib-resistant 786-O-PR cell line, revealing an active mitophagy pathway and increased Parkin expression in the resistant cells. Knocking down Parkin enhanced the sensitivity of resistant cells to pazopanib, while its overexpression in parental cells induced resistance, which was partially reversed by the mitophagy inhibitor 3-Methyladenine (3-MA). In xenograft models, Parkin knockdown and pazopanib administration inhibited tumorigenesis. We further identified GLI Family Zinc Finger 2 (GLI2) as a potential Parkin regulator, with high expression correlating with advanced tumor stages and poor prognosis. Knocking down GLI2 increased pazopanib sensitivity and diminished mitophagy level in resistant cells; however, its overexpression enhanced resistance and mitophagy, with partial rescue achieved using 3-MA. Furthermore, GLI2 knockdown reduced Parkin mRNA and protein levels. In pazopanib-resistant 786-O-PR cells, GLI2 knockdown and Parkin overexpression partially restored pazopanib resistance, while GLI2 overexpression and Parkin knockdown in parental cells partially restored sensitivity. GLI2's binding sites on the Parkin promoter were identified using JASPAR database analysis and confirmed using chromatin immunoprecipitation followed by quantitative polymerase chain reaction (CHIP-qPCR) and dual-luciferase assays, indicating GLI2's role in Parkin transcription. This study demonstrated that the GLI2-Parkin mitophagy pathway may be a therapeutic target for overcoming targeted therapy resistance in ccRCC.
    Keywords:  GLI2; Mitophagy; Parkin; Pazopanib resistance; ccRCC
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112054
  14. Histol Histopathol. 2025 Jul 29. 18973
    Cardiomyoprotective effect of Tanshinone IIA in diabetic cardiomyopathy achieved through enhancing PINK1-Parkin dependent mitophagy.
    Ke Wu, Chao Yu, Ping Li, Nannan Li.
      This study aimed to explore the beneficial effects and underlying protection mechanism of Tanshinone IIA (TSIIA) in diabetic cardiomyopathy (DCM) from the perspectives of mitophagy and mitochondrial integrity. Here, we found that TSIIA significantly increased STZ-induced body weight (L-TSIIA, 299.5 vs. 276.3; H-TSIIA, 308.3 vs. 276.3) and reduced blood glucose concentration (H-TSIIA, 16.1 vs. 21.5). Meanwhile, TSIIA effectively restored the function and morphology of myocardial tissue in diabetes mellitus (DM) rats. Further, TSIIA has been confirmed to have a protective effect on the ultrastructure and function of myocardial mitochondria, which was achieved through activation of mitophagy, as evidenced by enhanced co-localization of LC3 and COX IV (H-TSIIA, 88188.0 vs. 14829.0). Mechanistically, TSIIA alleviated DCM via activation of the PINK1/Parkin axis, increasing PINK1 (H-TSIIA, 0.5 vs. 0.2), Parkin (H-TSIIA, 0.6 vs. 0.3), Beclin-1 (H-TSIIA, 0.6 vs. 0.2) and LC3II/I (H-TSIIA, 0.5 vs. 0.3) expression, as well as decreasing p62 (H-TSIIA, 1.4 vs. 3.6) expression. This study provided a novel insight into the protective effect of TSIIA in DCM and revealed, for the first time, that TSIIA could noticeably improve STZ-induced DCM by enhancing PINK1-Parkin dependent mitophagy.
    DOI:  https://doi.org/10.14670/HH-18-973
  15. Nat Cell Biol. 2025 Aug 04.
    The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux.
    Mikhail Rudinskiy, Carmela Galli, Andrea Raimondi, Maurizio Molinari.
      Organellophagy receptors control the generation and delivery of portions of their homing organelle to acidic degradative compartments to recycle nutrients, remove toxic or aged macromolecules and remodel the organelle upon physiologic or pathologic cues. How they operate is not understood. Here we show that organellophagy receptors are composed of a membrane-tethering module that controls organellar and suborganellar distribution and by a cytoplasmic intrinsically disordered region (IDR) with net cumulative negative charge that controls organelle fragmentation and displays an LC3-interacting region (LIR). The LIR is required for lysosomal delivery but is dispensable for organelle fragmentation. Endoplasmic reticulum (ER)-phagy receptors' IDRs trigger DRP1-assisted mitochondrial fragmentation and mitophagy when transplanted at the outer mitochondrial membrane. Mitophagy receptors' IDRs trigger ER fragmentation and ER-phagy when transplanted at the ER membrane. This offers an interesting example of function conservation on sequence divergency. Our results imply the possibility to control the integrity and activity of intracellular organelles by surface expression of organelle-targeted chimeras composed of an organelle-targeting module and an IDR module with net cumulative negative charge that, if it contains a LIR, eventually tags the organelle portions for lysosomal clearance.
    DOI:  https://doi.org/10.1038/s41556-025-01728-4
  16. Front Neurosci. 2025 ;19 1614362
    Exploring the correlation between Drp1 protein and the neurotoxicity of propofol.
    Pu Guo, Jing Mei.
      Neurotoxicity is a common toxic reaction associated with the use of the anesthetic drug propofol. With the widespread use of propofol, the issue of neurotoxicity has garnered significant attention. Mitochondria are the energy metabolism centers of cells and play a crucial role in biological processes such as cell growth and development, invasion and metastasis, division and differentiation, and apoptosis. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission that can modulate the dynamic balance of mitochondria and plays an important role in maintaining mitochondrial morphology and function. The abnormal expression of Drp1 is closely related to the occurrence and development of various pathological conditions. Through a systematic review of multi-species animal and cellular studies, we elucidated the correlation between Drp1 and propofol-induced neurotoxicity. By analyzing Drp1-mediated mitochondrial fragmentation across different organ systems, this work provides crucial theoretical foundations for developing Drp1-targeted strategies in propofol neurotoxicity detection, prevention, and pharmacological intervention.
    Keywords:  Drp1; mitochondria; neuroprotection; neurotoxicity; propofol
    DOI:  https://doi.org/10.3389/fnins.2025.1614362
  17. Int Immunopharmacol. 2025 Aug 02. pii: S1567-5769(25)01296-2. [Epub ahead of print]163 115305
    ABCA4 regulates mitophagy in lung adenocarcinoma progression via AMPK pathway by modulating TMSB4X.
    Chan Zhang, Qi Li, Yujing Cheng, Xin Yang, Wanlu Chen, Kunhua He, Mingwei Chen.
       BACKGROUND: Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, has an unfavorable prognosis. ABCA4 has been identified as an oncogene in multiple malignancies, but its specific mechanisms in LUAD remain poorly understood. This study aims to explore the function of ABCA4 in LUAD with a focus on mitophagy.
    METHODS: ABCA4 expression in LUAD was evaluated using the TCGA database, western blotting, RT-qPCR, and immunohistochemistry. The effects of ABCA4 knockdown on LUAD progression were examined in vitro (CCK8, Muse® Cell Analyzer, Transwell), and in vivo through (xenogeneic tumor experiments). Mitophagy was assessed by JC-1, TMRE, and DCFH-DA staining, the Muse Oxidative Stress Kit, transmission electron microscopy, and western blotting. Chloroquine (CQ) and S7306 were applied in rescue experiment. RNA-seq identified differentially expressed genes (DEGs) after siABCA4 treatment, and the effects of ABCA4 on LUAD by modulating TMSB4X were explored.
    RESULTS: ABCA4 was up-regulated in the TCGA database, LUAD tissues, and cell lines. ABCA4 knockdown inhibited proliferation and tumor growth while promoting apoptosis and mitophagy. Mechanistically, siABCA4 increased AMPK phosphorylation levels. CQ or S7306 partially reversed these biological effects. Additionally, ABCA4 may interact with TMSB4X to regulate mitophagy via the AMPK pathway, thereby influencing LUAD progression.
    CONCLUSIONS: ABCA4 was overexpressed in LUAD, and its knockdown might promote mitophagy in LUAD progression via the AMPK pathway by modulating TMSB4X, suggesting that ABCA4 could serve as a therapeutic target for LUAD patients.
    Keywords:  ABCA4; AMPK pathway; Lung adenocarcinoma; Mitophagy; TMSB4X
    DOI:  https://doi.org/10.1016/j.intimp.2025.115305
  18. Front Cell Infect Microbiol. 2025 ;15 1588461
    MicroRNA-27b alleviates septic cardiomyopathy by targeting the Mff/MAVS axis.
    Xincai Wang, Long Huang, Jingqing Xu, Min Li, Hongxuan Zhang, Yuqing Yao, Yaqing Liu, Xingsheng Lin, Xiuling Shang.
       Objective: To investigate the protective role of microRNA-27b (miR-27b) in septic cardiomyopathy (SCM) and its regulatory mechanism on the mitochondrial fission factor (Mff)/mitochondrial antiviral signaling protein (MAVS) axis.
    Methods: Transcriptome data from septic patients' cardiac tissues (GSE79962) were analyzed. Serum miR-27b expression was measured in SCM patients (n=11), sepsis-only patients (n=22), and healthy controls (n=30). Mouse SCM model and HL-1 cardiomyocyte model were established by lipopolysaccharide (LPS) induction. The molecular mechanism was investigated using miR-27b agonist/antagonist and Mff intervention, combined with RT-qPCR, Western blot, immunofluorescence, and transmission electron microscopy.
    Results: Bioinformatics analysis revealed significant downregulation of miR-27b in SCM cardiac tissues (log2FC=-3.9, P<0.001). Clinical validation showed lower miR-27b expression in SCM patients' serum compared to sepsis-only patients and healthy controls (P<0.05). LPS-induced SCM model exhibited cardiac dysfunction, myocardial injury, mitochondrial abnormalities, decreased miR-27b expression, and increased Mff and MAVS levels. miR-27b targeted Mff to maintain mitochondrial homeostasis, thus attenuating LPS-induced cardiomyocyte inflammation and apoptosis, while Mff overexpression reversed this protective effect.
    Conclusion: miR-27b alleviates myocardial injury and inflammation in SCM by targeting the Mff/MAVS axis to maintain mitochondrial homeostasis, representing a potential novel therapeutic target for SCM.
    Keywords:  inflammation; microRNA-27b; mitochondrial antiviral signaling protein; mitochondrial fission factor; septic cardiomyopathy
    DOI:  https://doi.org/10.3389/fcimb.2025.1588461
  19. Eur J Pharmacol. 2025 Aug 06. pii: S0014-2999(25)00797-6. [Epub ahead of print] 178043
    Transcription Factor MEOX1 Accelerates Pulmonary Fibrosis by Regulating Mitophagy and Senescence.
    Lijun Fang, Linmao Lyu, Hongyu Zhong, Jiamao Lin, Pengtao Ren, Yu Wang, Yunhong Yin, Mengyu Zhang, Yiqing Qu.
      Idiopathic pulmonary fibrosis (IPF) is a kind of chronic and progressive interstitial lung disease of unclear aetiology. A key aspect of IPF is transforming growth factor-β1 (TGF-β1)-induced mitophagy dysfunction and senescence in lung fibroblasts. Mesenchyme homeobox 1 (MEOX1) is a critical transcription factor in the regulation of cell differentiation. However, the role of MEOX1 in the pathogenesis of lung fibrosis and mitophagy has not been clarified. In this study, RNA-sequencing analysis was employed to identify the differentially expressed genes in TGF-β1-treated lung fibroblasts and IPF lung tissue. In vivo, the mouse model of lung fibrosis was established by intratracheal injection of bleomycin (BLM), and fibroblast-specific knockdown of MEOX in mice was achieved by intratracheal injection of adeno-associated viruse-shMEOX1. And in vitro experiments were also carried out on human lung fibroblasts. Our results indicated that fibroblast-specific knockdown of MEOX1 protected mice from BLM-induced pulmonary fibrosis, connective tissue growth factor (CTGF) expression, and lung fibroblast activation, as well as mitophagy deficiency and senescence. In vitro, MEOX1 knockdown abolished TGF-β1-induced mitophagy deficiency by downregulating CTGF expression, thereby inhibiting senescence, over-activation and collagen production in lung fibroblasts. Furthermore, we also found that TGF-β1 upregulated the expression of MEOX1 through the NOX4-ROS-Smad pathway. In conclusion, MEOX1 knockdown may ameliorate pulmonary fibrosis by regulating mitophagy and senescence and may be a potential therapeutic target for IPF and other types of interstitial lung diseases.
    Keywords:  MEOX1; connective tissue growth factor (CTGF); idiopathic pulmonary fibrosis (IPF); mitophagy; senescence
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178043
  20. Cancer Res. 2025 Aug 07.
    Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.
    Mohamed Faisal Kassir, Han Gyul Lee, Natalia V Oleinik, Wyatt Wofford, Chase Walton, Firdevs Cansu Atilgan, Alhaji H Janneh, Paramita Chakraborty, Kubra Calisir, Elif Percin, Silvia G Vaena, Kalyani Sonawane, Ashish Deshmukh, Narayan R Bhat, Kumar Sambamurti, Onder Albayram, Ozgur Sahin, Shikhar Mehrotra, Besim Ogretmen.
      Alzheimer's disease (AD) patients have a decreased incidence of cancer., with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD compared to AD patients. Here, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress-mediated hyperactive mitophagy in aging T-cells, improving their anti-tumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice. Additionally, adoptive cell transfer (ACT)-based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage. Mechanistically, APP interaction with TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T-cells, preventing ceramide-dependent mitophagy. Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving anti-tumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T-cells, enhancing their anti-tumor activity to control tumor growth. Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched AD patients. Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance anti-tumor functions.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4740
  21. Mater Today Bio. 2025 Oct;34 102119
    AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ.
    Yingying Wang, Tianyi Ni, Qian Zhang, Zibo Xu, Zhechen Zhu, Jiaheng Xie, Min Yi, Liying Tu, Zexiong Cheng, Yiwen Gao, Haowen Xu, Wei Yan, Jingping Shi.
      Delayed healing of diabetic foot ulcers (DFUs) is driven by chronic inflammation and mitochondrial dysfunction. We identify the aryl hydrocarbon receptor (AhR) as a key regulator of immune and mitochondrial homeostasis in diabetic wounds. AhR expression was elevated in macrophages from human and murine DFUs. In AhR knockout mice, loss of AhR impaired M2 macrophage polarization and enhanced NLRP3 inflammasome activation via the cGAS-STING pathway. Mechanistically, AhR deficiency suppressed mitophagy, causing mitochondrial DNA leakage and sustained inflammatory signaling. To target this axis, we developed a FICZ-loaded GelMA hydrogel (GelMA-FICZ). Local application of GelMA-FICZ restored mitochondrial function, inhibited inflammasome activation, and significantly improved wound healing in diabetic mice. This study reveals a critical AhR-mitochondria-inflammasome pathway in DFUs and suggests a novel biomaterial-based immunomodulatory therapy for diabetic wound repair.
    Keywords:  Aryl hydrocarbon receptor (AhR); GelMA hydrogel; Macrophage polarization; Mitophagy
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102119
  22. J Alzheimers Dis. 2025 Aug 06. 13872877251364845
    The role of mitochondrial dysfunction in diabetes-associated cognitive dysfunction: A bibliometric analysis.
    Chen Wang, Siyi He, Lingling Wang, Yushuang Yin, Wenqi Zhang, Guanwen Lin, Duozhi Wu, Qin Zhou, Zhihua Wang.
      BackgroundDiabetes, a prevalent chronic disorder, is frequently complicated by diabetes-associated cognitive dysfunction (DACD). The impact of diabetes on specific cerebral regions accelerates the progression from mild cognitive impairment to Alzheimer's disease. Research has indicated that mitochondrial dysfunction is a pivotal factor in DACD, yet its underlying mechanisms remain elusive.ObjectiveOur research aims to elucidate the research trends in this field over the past fifteen years by employing bibliometric analysis.MethodsA systematic search and aggregation of literatures related to mitochondrial dysfunction in DACD published within the Web of Science Core Collection from 2010 to 2024 were performed. Subsequently, a bibliometric analysis was conducted employing four bibliometric software: HistCite, R-bibliometrix, VOSviewer, and CiteSpace.ResultsA total of 309 papers were identified for analysis. The most prolific country, institution, and authors were China, University of Coimbra, Moreira PI, and Li YS, respectively. The USA, Texas Tech University, and Reddy PH were the key country, institution, and author, respectively. Among references to articles in this field, Diabetes has the most cumulative citations. According to the analysis of co-citations, oxidative stress was the largest cluster. The primary keywords were "Alzheimer's disease" and "oxidative stress". In recent years, the keyword "mitophagy" has received a lot of attention.ConclusionsOxidative stress represents a principal research topic within this field. Mitophagy offers a potential therapeutic avenue for DACD and may emerge as a novel focus of future investigations.
    Keywords:  Alzheimer's disease; bibliometric analysis; diabetes-associated cognitive dysfunction; mitochondrial dysfunction; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1177/13872877251364845
  23. Food Chem Toxicol. 2025 Aug 04. pii: S0278-6915(25)00447-8. [Epub ahead of print]204 115679
    Mitochondrial dynamics imbalance and energy dyshomeostasis mediated developmental toxicity of ochratoxin a in zebrafish (Danio rerio).
    Meng Li, Mengai He, Zhenfeng Liao, Chenxi Li, Yingqiu Mi, Ningning Pan, Xinyi Xie, Zhiyu Liu, Jiayin Hou, Xueli Yu, Liezhong Chen.
      Ochratoxin A (OTA) has been increasingly detected in foodstuffs and human samples. However, the molecular mechanisms of developmental toxicity induced by OTA remain poorly explored. Our results demonstrated that oxidative stress induced by OTA caused mitochondrial dysfunction in larvae, characterized by malformed mitochondria, and decreased mitochondrial membrane potential and complex II, IV and V activities. Central carbon metabolism analysis indicated that exposure to OTA induced energy metabolism disturbance by decreasing ATP contents and altering energy-relevant metabolite contents. Energy metabolism disturbance was further confirmed by transcriptomics analysis, with differentially expressed genes significantly enriching in glycolysis and TCA cycle. Additionally, molecular docking simulations and surface plasmon resonance analysis demonstrated that OTA interacted with mfn1 and mfn2, verifying its interference effects on mitochondrial dynamics. The insufficient energy supply induced by OTA activated AMP-activated protein kinase signal pathways, which accelerated catabolic processes, accompanied by decreases in yolk sac size and yolk lipid. Finally, insufficient energy supply caused developmental retardation of zebrafish larvae. Collectively, this study systematically elucidated the roles of mitochondrial dynamics imbalance and energy dyshomeostasis in the developmental toxicity induced by OTA, providing critical insights for refining food safety standards and therapeutic interventions.
    Keywords:  Developmental toxicity; Energy metabolism; Mitochondrial dynamics; Ochratoxin A; Zebrafish
    DOI:  https://doi.org/10.1016/j.fct.2025.115679
  24. Toxicol Appl Pharmacol. 2025 Aug 05. pii: S0041-008X(25)00267-4. [Epub ahead of print]503 117491
    Hyperoside protects human osteoblasts from phthalate-induced mitochondrial dysfunction, oxidative stress, and apoptosis.
    Ekramy M Elmorsy, Huda A Al Doghaither, Ayat B Al-Ghafari, Neven A Ebrahim, Mohamed E Mohamed, Samah F Ibrahim, Farouk S Elgendy, Ahmed Abdeen.
      Butyl cyclohexyl phthalate (BCP), an emerging environmental contaminant, impairs osteoblast function via oxidative stress, mitochondrial dysfunction, and apoptosis. This study evaluated hyperoside (HYP), a flavonoid, for its protective effects against BCP-induced toxicity in human osteoblasts. Molecular docking showed strong binding of BCP and HYP to oxidative stress- and apoptosis-related proteins. In vitro assays revealed BCP's dose-dependent cytotoxicity, marked by decreased ATP production, mitochondrial membrane potential, mitochondrial complexes I and III activities, and suppressed mitophagy (PINK1/PARKIN downregulation), elevated oxidative stress biomarkers, and activated apoptosis (Cas-3/-8/-9, Bax/Bcl2 imbalance). HYP co-treatment restored osteoblast viability, secretory function, and mitophagy while reducing oxidative stress via Nrf2/HO-1 activation. HYP also inhibited caspases and normalized Bax/Bcl2 ratios, preventing apoptosis. These findings demonstrate HYP's dual cytoprotective role: enhancing mitochondrial quality control and mitigating BCP-induced oxidative/apoptotic damage. The study unveils BCP's osteotoxic mechanisms and positions HYP as a promising therapeutic to counteract environmental bone toxicity by targeting mitophagy, redox balance, and apoptotic pathways, highlighting the potential of flavonoid-based interventions in osteotoxicity management.
    Keywords:  Antioxidants; Bone health; Butyl cyclohexyl phthalate (BCP); Nrf2/HO-1 signaling; Osteoblast cytotoxicity; Oxidative stress
    DOI:  https://doi.org/10.1016/j.taap.2025.117491
  25. Nat Commun. 2025 Aug 04. 16(1): 7174
    Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
    Ioannis Segos, Jens Van Eeckhoven, Simon Berger, Nikhil Mishra, Eric J Lambie, Barbara Conradt.
      The unequal segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial dynamics. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide in vivo evidence that the unequal segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division in a developing animal.
    DOI:  https://doi.org/10.1038/s41467-025-62484-5
  26. Acta Biomater. 2025 Aug 05. pii: S1742-7061(25)00583-5. [Epub ahead of print]
    Nanoparticle-induced excessive mitophagy combined with immune checkpoint blockade for enhanced cancer immunotherapy.
    Yuan Cao, Rui Xu, Junyue Fang, Zixuan Zhao, Guo Wu, Yuxuan Zhang, Rong Li, Yanan Lu, Xiaoding Xu.
      Tumor microenvironment (TME) is the major obstacle in cancer immunotherapy due to its adverse effects on tumor-infiltrating immune cells. Emerging evidences have revealed that mitophagy plays an important role in regulating cell fate and immune microenvironment. Targeted regulation of mitophagy could be a promising strategy for enhanced cancer immunotherapy, which however remains unexploited due to the absence of robust therapeutic platform. We herein developed a mitophagy-induced RNA interfering (RNAi) nanoplatform composed of a hydrophilic polyethylene glycol (PEG) shell and an endosomal pH-responsive hydrophobic core encapsulating the complexes of mitophagy-inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and small interfering RNA (siRNA) for enhanced breast cancer (BCa) immunotherapy. Using the orthotopic and metastatic BCa tumor models, we demonstrate that this nanoplatform could effectively induce excessive mitophagy in BCa cells to suppress their proliferation and silence PD-L1 expression to block its immunosuppressive effect on CD8+ T cells. More importantly, excessive mitophagy could inhibit C-C motif chemokine ligand 2 (CCL2) secretion from BCa cells and thus alleviate the immunosuppressive effect on CD8+ T cells via impairing the tumor infiltration of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), which could ultimately combine with the PD-L1 silencing to synergistically enhance the antitumor immunity and inhibit BCa tumor growth. STATEMENT OF SIGNIFICANCE: Amplification of mitophagy in tumor cells has been considered as a promising strategy for effective cancer therapy due to its important role in regulating cell fate and TME. We herein developed a mitophagy-induced RNAi nanoplatform, which could effectively induce BCa cell death via amplifying mitophagy and enhance the tumoricidal ability of CD8+ T cells via silencing PD-L1 expression. More importantly, this nanoplatform-induced excessive mitophagy could inhibit tumor-derived CCL2 secretion and thus remodel the immunosuppressive TME via impairing the tumor infiltration of TAMs, Tregs, and MDSCs, leading to enhanced antitumor immunity and significant inhibition of BCa tumor growth. The nanoplatform developed herein could be used as an effective tool for enhanced cancer immunotherapy.
    Keywords:  Mitophagy; RNA interfering (RNAi); cancer immunotherapy; nanoplatform; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.actbio.2025.08.001
  27. Food Chem. 2025 Aug 05. pii: S0308-8146(25)03048-1. [Epub ahead of print]493(Pt 2): 145797
    New perspective on postmortem meat quality changes of Esox Lucius: The role of mitophagy-mediated ferroptosis pathway.
    Wenbo Yan, Hui Li, Xinyao Yu, Xin Chen, Lingzhen Ma, Xiaorong Deng, Jian Zhang.
      This study investigated the occurrence of mitophagy and ferroptosis, and the potential connection between meat quality and mitophagy-mediated ferroptosis in postmortem Esox Lucius during 4 °C storage. Results showed that water holding capacity (WHC) and shear force decreased during the storage period from 0 to 96 h (P < 0.05). With decreasing membrane potential and increasing permeability, mitochondria suffered damage, which activated the PINK1/Parkin-mediated mitophagy pathway. Additionally, mitophagy induced ferroptosis through the release of ferrous ions (Fe2+), manifested by ROS accumulation, glutathione (GSH) depletion, and downregulation of glutathione peroxidase 4 (GPX4) expression. Furthermore, significant accumulation of malondialdehyde (MDA) (P < 0.05) and disruption of mitochondrial structure further confirmed the occurrence of ferroptosis. These results demonstrated that mitophagy and ferroptosis occurred during postmortem storage and correlated with meat quality change. Based on these findings, we propose a new perspective that the mitophagy-mediated ferroptosis pathway affects postmortem fish quality change.
    Keywords:  Esox Lucius; Ferroptosis; Mitophagy; Postmortem; Quality
    DOI:  https://doi.org/10.1016/j.foodchem.2025.145797
  28. Neurobiol Dis. 2025 Aug 05. pii: S0969-9961(25)00267-0. [Epub ahead of print] 107051
    Circulating mitochondrial components and metabolic and inflammatory markers in Charcot-Marie-Tooth type 2B.
    Giulia Girolimetti, Federico Marini, Riccardo Calvani, Hélio José Coelho-Júnior, Jacopo Gervasoni, Lavinia Santucci, Stefano Tozza, Fiore Manganelli, Paola Saveri, Davide Pareyson, Emanuele Marzetti, Cecilia Bucci, Anna Picca, Flora Guerra.
      Charcot-Marie-Tooth type 2B (CMT2B) is a rare inherited neuropathy caused by mutations in the RAB7A gene. Altered mitochondrial dynamics and late endosome trafficking contribute to CMT2B pathophysiology. In this case-control study, we quantified levels of circulating cell-free mtDNA (ccf-mtDNA), mitochondrial proteins secreted within mitochondria-derived vesicles (MDVs), and metabolic and inflammatory markers in biofluids of individuals with CMT2B (n = 5) and healthy controls (n = 4). ccf-mtDNA was quantified in serum by droplet digital PCR. MDVs were purified by immunoprecipitation and analyzed by Western blotting. A panel of 27 inflammatory markers was assayed in serum by multiplex immunoassay. Forty-four amino acids and derivatives were quantified in serum and urine by ultraperformance liquid chromatography/mass spectrometry (UPLC/MS). Fourteen long-chain fatty acids and asymmetric dimethyl arginine (ADMA) were measured in serum by UPLC/MS. Analysis of variance - simultaneous component analysis models were built to explore differences in metabolic and inflammatory markers between cases and controls. Mann-Whitney U test was used to compare ccf-mtDNA levels between groups. CMT2B participants had higher levels of ADMA as well as of interleukin (IL)-1b, IL-8, IL-9, IL-13, eotaxin, and most fatty acids than controls. Spearman's correlation analysis was applied to explore the relationship between markers of inflammation, endothelial dysfunction, and fatty acid metabolism. Serum levels of 1- and 3-methylhistidine, alfa- and beta-aminobutyric acid, asparagine, glycine, threonine, and fibroblast growth factor were lower in CMT2B samples than in controls. No significant differences were observed for ccf-mtDNA levels between groups, while differences in MDV content were identified between participants with CMT2B and controls. Among the metabolic markers, ADMA was the most discriminant biomolecule distinguishing CMT2B participants from controls and showed a positive correlation with some fatty acids. Collectively, these findings suggest that CMT2B may be associated with altered endosomal trafficking and mitochondrial and endothelial dysfunction.
    Keywords:  Biomarker; Cytokine; Damage-associated molecular patterns; Inflammation; Mitochondrial quality; Mitophagy; Multi-marker
    DOI:  https://doi.org/10.1016/j.nbd.2025.107051
  29. Res Sq. 2025 Jul 29. pii: rs.3.rs-7077811. [Epub ahead of print]
    Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect.
    Bhupesh Kumar Prusty, Claudia Hollmann, Eun Chan Park, Zheng Liu, Faye Nourollahi, Georgy Nikolayshvili, Jonathan Dietz, Emils Bašēns, Mehul Vora, Trushnal Waghmare, Tongbin Li, Fabian Imdahl, Christopher Rongo.
      Multiple mechanisms of immunity must be coordinated to defend against a comprehensive range of pathogens; however, the mechanisms by which broad-spectrum antipathogens act remain largely elusive. Here, we employed systems biology approaches to understand the organization of human immune cells at the single-cell level, as well as their reorganization in response to K21, a silane derivative effective against viral, bacterial, and fungal infections. K21 induced pro-inflammatory pathways in M1 and M2c macrophages without altering cytokine secretion, decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, and improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of mechanism. Our work demonstrates that a drug that remodels mitochondria and metabolism can shape the immune cell repertoire, which could aid the development of more effective antimicrobials and prevent the emergence of drug-resistant pathogens.
    DOI:  https://doi.org/10.21203/rs.3.rs-7077811/v1
  30. J Hazard Mater. 2025 Jul 30. pii: S0304-3894(25)02323-4. [Epub ahead of print]496 139407
    Excessive mitochondrial stress response triggers neuronal injury through the persistent eIF2α phosphorylation in mice exposed to manganese.
    Yunfei Jia, Bin He, Keyu Chen, Kuan Liu, Changjiang Yu, Bo Sun, Zhuo Ma, Bin Xu.
      Manganese (Mn) overexposure-induced neurocognitive abnormalities are intensively linked to hippocampal neuronal injury, but the neurotoxic mechanisms involved are ambiguous. Under various mitochondrial stress, mitochondrial stress response (MSR) is activated and plays a dual role in cells, promoting adaptive survival while also contributing to detrimental damage, depending on the severity of mitochondrial dysfunction. Excessive MSR can lead to inevitable cell death and organ damage, ultimately driving the onset and progression of numerous disorders. Yet, whether excessive MSR is implicated in Mn-induced neuronal injury remains unclear. In this study, Mn poisoning models were established in C57BL/6 mice and hippocampal primary neurons to investigate the role of excessive MSR in mitochondria-mediated neuronal apoptosis following Mn exposure. Specifically, excessive MSR triggered hippocampal neuronal mitochondrial damage and neurocognitive abnormalities, which was primarily driven by the persistent phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Furthermore, excessive acetylation of growth arrest and DNA damage-inducible protein 34 (GADD34) impaired the dephosphorylation of phospho-eIF2α by disrupting the protein phosphatase 1α/GADD34 complex in primary neurons following Mn exposure. Finally, Sirtuin 1-mediated GADD34 deacetylation facilitated the dephosphorylation of phospho-eIF2α, thus mitigating excessive MSR-triggered neuronal apoptosis and mitochondrial dysfunction. These findings underscore the critical role and complexity of excessive MSR in Mn-induced neuronal injury.
    Keywords:  EIF2α phosphorylation; Manganese; Mitochondrial stress response; Neurons
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.139407
  31. MedComm (2020). 2025 Aug;6(8): e70311
    Nanoparticle-Delivered siRNA Targeting NSUN4 Relieves Systemic Lupus Erythematosus through Declining Mitophagy-Mediated CD8+T Cell Exhaustion.
    Bincheng Ren, Kaini He, Ning Wei, Shanshan Liu, Xiaoguang Cui, Xin Yang, Xiaojing Cheng, Tian Tian, Ru Gu, Xueyi Li.
      5-Methylcytosine modification (m5C) is an important posttranscriptional regulatory mechanism of gene expression. Exhausted CD8+T cells contribute to the development of many major diseases; however, their exact role and relationship to m5C in systemic lupus erythematosus (SLE) remain unknown. In this study, we identified a CD7highCD74high CD8+T subgroup that were robustly expanded in SLE patients through single-cell transcriptome sequencing (scRNA-seq). CD7highCD74high CD8+T cells displayed exhausted features and exhibited a superior diagnostic value in SLE. Then, we explored the m5C landscape of SLE patients by performing m5C epitranscriptome sequencing (m5C-seq). ScRNA-seq and m5C-seq were conjointly analyzed to screen m5C-related therapeutic targets for SLE, and NOP2/Sun RNA methyltransferase 4 (NSUN4) was identified as a key regulator of SLE pathogenesis. Knockdown of NSUN4 downregulated CD74 expression via reduction of m5C and suppressed CD8+T cell exhaustion by declining CD44/mTOR (mechanistic target of rapamycin kinase)-mediated mitophagy. Finally, we verified that nanoparticle-delivered siRNA against Nusn4 decreased autoimmune reaction kidney damage in both spontaneous and pristane-induced SLE mouse models. In conclusion, we identify an exhausted CD7highCD74high CD8+T cell subset and propose the crucial role of NSUN4/CD74-induced dysregulation of mitophagy in SLE pathogenesis, and targeting NSUN4 is a promising treatment strategy for SLE patients.
    Keywords:  CD8+T cell mitophagy and exhaustion; NSUN4; nanoparticle‐delivered siRNA; single‐cell RNA sequencing and m5C sequencing; systemic lupus erythematosus
    DOI:  https://doi.org/10.1002/mco2.70311
  32. BMC Pharmacol Toxicol. 2025 Aug 04. 26(1): 142
    Differential effects of β-blockers nebivolol and metoprolol on mitochondrial biogenesis and antioxidant defense in angiotensin II-induced pathology in H9c2 cardiomyoblasts.
    Rukhsana Gul, Arwa Bazighifan, Shahid Nawaz, Assim A Alfadda.
       BACKGROUND: Mitochondrial dysfunction and oxidative stress induced by overactivation of angiotensin II (Ang II) are major contributors to the progression of cardiovascular diseases (CVD). This study investigates the comparative effects of nebivolol, a third-generation β1-adrenergic blocker, and metoprolol, a second-generation β1-adrenergic blocker, on Ang II-induced mitochondrial impairment in H9c2 cardiomyoblasts.
    METHODS: Nebivolol and metoprolol mediated protective effects were demonstrated against Ang II-induced mitochondrial dysfunction in H9c2 cells. Intracellular reactive oxygen species (ROS) production was assessed by detecting 2',7'-dichlorofluorescein (DCF) fluorescence. Western blotting and Real-time PCR were used to quantify protein and mRNA levels, respectively.
    RESULTS: Our results showed that both nebivolol and metoprolol significantly attenuated Ang II-induced ROS generation and the expression of apoptotic and proinflammatory genes. However, nebivolol demonstrated higher efficacy than metoprolol in suppressing the expression of the proapoptotic marker BNIP3, while upregulating the antioxidant defense system and anti-apoptotic BCL2 expression. Additionally, nebivolol enhanced the mitochondrial biogenesis and fusion related gene expression.
    CONCLUSION: In conclusion, both nebivolol and metoprolol effectively reduce oxidative stress and expression of proinflammatory genes in response to Ang II. However, nebivolol provides increased protection by restoring the antioxidant defense system and mitochondrial functions, highlighting its potential therapeutic advantage in Ang II-induced cardiac pathology.
    Keywords:  Ang II; Mitochondrial dysfunction; Oxidative stress; β-blockers
    DOI:  https://doi.org/10.1186/s40360-025-00970-8
  33. Biol Psychiatry. 2025 Jul 31. pii: S0006-3223(25)01378-2. [Epub ahead of print]
    Urolithin A abolishes high anxiety and rescues the associated mitochondria-related transcriptomic signatures and synaptic function.
    David Mallet, Doğukan Hazar Ülgen, Jocelyn Grosse, Olivia Zanoletti, Isabelle Guillot de Suduiraut, Anna S Monzel, Davide D'Amico, Chris Rinsch, Martin Picard, Simone Astori, Carmen Sandi.
       BACKGROUND: Chronic anxiety is common, disabling, and often refractory to current therapies. Mounting evidence implicates mitochondrial abnormalities in anxiety-related phenotypes. Urolithin A (UA), a gut microbiota-derived metabolite known to enhance mitochondrial health, has shown neuroprotective effects. However, its potential to alleviate anxiety remains unexplored.
    METHODS: UA was administered chronically to two validated rodent models of high anxiety: outbred animals displaying natural variation in trait anxiety and rats selectively bred for high stress-reactivity, while low-anxiety animals served as controls. Anxiety-like behaviors were assessed across multiple tasks. Molecular profiling of nucleus accumbens (NAc) medium spiny neurons (MSNs) was performed using single-nucleus RNA sequencing, with MitoPathway analysis to evaluate mitochondria-related transcriptomic signatures. Electrophysiological, immunohistochemical, and morphological approaches were used to assess synaptic and structural correlates.
    RESULTS: UA produced a robust anxiolytic effect in both high-anxiety models, in both sexes, without altering behavior in low-anxiety animals. High-anxiety MSNs displayed coupled dysregulation of mitochondrial and synaptic gene pathways that UA normalized to low-anxiety levels across MSN subtypes. These changes were accompanied by structural and functional rescue of MSN dendritic architecture, spine density, and excitatory synaptic transmission. Notably, UA also restored expression of mitofusin-2 (Mfn2), a mitochondrial protein causally involved in the regulation of anxiety-related behavior and circuit dysfunction in the NAc, further supporting a mechanistic link between mitochondrial remodeling and UA's anxiolytic efficacy.
    CONCLUSIONS: These findings position UA as a mechanistically informed intervention in preclinical models of heightened anxiety and provide systems-level insights into how mitochondrial pathways interface with synaptic function and circuit regulation in anxiety states.
    Keywords:  Mitochondria; anxiety; mitophagy; nucleus accumbens; patch-clamp; snRNAseq
    DOI:  https://doi.org/10.1016/j.biopsych.2025.07.020
  34. Exp Mol Pathol. 2025 Aug 01. pii: S0014-4800(25)00039-5. [Epub ahead of print]143 104989
    The interplay involving oxidative stress and autophagy: Mechanisms, implications, and therapeutic opportunities.
    Noha A Gouda, Assem Zhakupova, Ahmed M Abdelaal, Firdos Ahmad, Ahmed Elkamhawy.
      Reactive oxygen species (ROS) are extremely reactive molecules produced during cellular metabolism, which play important roles in signaling and immune responses. Excessive ROS accumulation results in oxidative stress and cellular damage. As a result, autophagy (a cellular recycling process) is induced to overcome oxidative stress conditions by eliminating impaired cellular components. By selectively targeting and degrading dysfunctional mitochondria and peroxisomes through mitophagy and pexophagy, respectively, cells can effectively reduce ROS accumulation. Conversely, oxidative stress can disrupt autophagy, impairing protein aggregate clearance and thereby exacerbating ROS accumulation. In this review, we discuss the complex correlation between oxidative stress and autophagy, highlighting the mechanisms of regulation and their pathological implications. Additionally, we discuss the latest advances and challenges in developing autophagy-modulating therapies.
    Keywords:  Autophagy; Mitophagy; Oxidative stress; Pexophagy; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.yexmp.2025.104989
  35. Metabolism. 2025 Aug 07. pii: S0026-0495(25)00230-6. [Epub ahead of print]172 156361
    Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.
    Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden.
      Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.
    Keywords:  Ceramides; High-intensity interval training; Insulin resistance; Mitochondrial quality control; Sphingomyelinases; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.metabol.2025.156361
  36. Int J Biol Macromol. 2025 Aug 04. pii: S0141-8130(25)07057-6. [Epub ahead of print]321(Pt 3): 146500
    Resveratrol alleviates lipopolysaccharide-induced acute lung injury through blocking the excessive autophagy/mitophagy via SIRT1/PGC-1α and TNF/NF-κB/JNK pathways.
    Huari Li, Xueyi Wang, Yian Deng, Mingze Liu, Wenjie Li, Junjie Wang, Cuiping Zeng, Hanchuan Dai.
      Acute lung injury (ALI) is a hypoxic respiratory insufficiency disease characterized by oxidative damage, inflammatory response, and autophagic cell death. Resveratrol (Res) modulates the autophagy activation and excessive autophagy inhibition to counteract oxidative stress, yet the latter mechanism has been vague. Herein, effects and regulatory mechanisms of Res on lung injury, inflammation, and autophagy/mitophagy were explored in lipopolysaccharide (LPS)-stimulated rats and RAW264.7 cells. Transcriptome data exhibited that, Res influenced oxidative stress, inflammation, apoptosis, necroptosis, proliferation, and migration probably through TNF/NF-kB-mediated phagosome and lysosome formations in ALI rats. In subsequent assays, Res significantly reversed the LPS-induced lung injury and mitochondrial dysfunction via activating the SIRT1/PGC-1α pathway. Also, Res reduced LPS-triggered inflammatory cytokines through restraining the TNF/NF-κB/JNK pathway. Importantly, Res attenuated excessive LC3/ATG5/p62-mediated autophagy and PINK1/Parkin-adjusted mitophagy, decreasing the autophagic flux by inactivating the NF-κB pathway. Thus, Res augmented anti-oxidative and anti-inflammatory effects most likely through ameliorating the excessive autophagy/mitophagy via two converging pathways (SIRT1/PGC-1α and TNF/NF-κB/JNK). Notably, Res down-regulated the DNMT2/TRDMT1 expression and probably adopted a similar binding pattern with plant flavonoids to block this enzyme. Altogether, these findings will provide a novel mechanism and therapeutic strategy for ALI or related lung diseases by Res-modulated autophagy/mitophagy inactivation and DNMT2/TRDMT1 inhibition.
    Keywords:  Acute lung injury; DNMT2/TRDMT1; Excessive autophagy/mitophagy; Resveratrol; TNF/NF-κB/JNK pathway
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146500
  37. Pulm Circ. 2025 Jul;15(3): e70137
    Effect of Regulating FUNDC1 Mitophagy-Mediated cGAS/STING Pathway in Oleic Acid-Induced Acute Lung Injury Model.
    Liangyu Mi, Yuankai Zhou, Wenyan Ding, Xiangyu Chen, Yingying Yang, Qianlin Wang, Lu Wang, Longxiang Su, Yun Long.
      Acute lung injury (ALI) involves inflammatory cytokines and chemokines, resulting in lung and multiple organ injuries. This study explored the mechanism of mitophagy and cGAS/STING pathway in oleic acid (OA)-induced ALI. Mice and pulmonary microvascular endothelial cells were divided into four groups: control group (Con), ALI group, FUNDC1 -/- control group (F-Con), and FUNDC1 -/- ALI group (F-ALI). After 24 h of modeling, proceed with tissue collection. Lung tissues were stained using hematoxylin eosin. Autophagosomes were observed by electron microscope and mtDNA was detected by qPCR. Western blot was used to analyze protein expression of pathways cGAS, STING, pTBK1, pIRF3, and pNF-κB. Serum IFN-β expression was detected by ELISA. Cellular morphological changes were observed using microscopy. LDH level, cGAS, and STING in endothelial cells were observed. Compared with control group, pathological changes in ALI group were significantly aggravated. Expressions of serum IFN-β, cGAS, STING, pTBK1, pIRF3, and pNF-κB in lung tissues of ALI mice were significantly higher than control group. After OA, the morphology of lung microvascular endothelial cells changed and LDH expression increased. After FUNDC1 gene was knocked out to inhibit mitophagy, autophagosomes were significantly reduced and mtDNA increased. Expressions of pathway proteins in lung tissues and cells of FUNDC1 -/- ALI group were higher than those of wild-type ALI group. Serum IFN-β expression also increased. Silencing FUNDC1 inhibits mitophagy. Subsequently, accumulated mtDNA activates cGAS/STING pathway, aggravating ALI pathological damage and inflammation, suggesting that mitophagy may provide protection in OA-induced ALI through cGAS/STING pathway.
    Keywords:  FUNDC1; STING; acute lung injury; cGAS; mitophagy
    DOI:  https://doi.org/10.1002/pul2.70137
  38. Nat Commun. 2025 Aug 07. 16(1): 7308
    PABPC1 SUMOylation enhances cell survival by promoting mitophagy through stabilizing U-rich mRNAs within stress granules.
    Caihu Huang, Jiayi Huang, Runhui Lu, Ari Jiazhuo Yu, Arno Shengzhuo Yu, Yingting Cao, Lian Li, Junya Li, Hongyan Li, Zihan Zhou, Yixin Zhang, Anan Xu, Ran Chen, Yanli Wang, Xian Zhao, Jian Huang, Yujie Fu, Ming Xu, Hailong Zhang, Jianxiu Yu.
      Stress granules (SGs) are cytoplasmic, membraneless organelles that modulate mRNA metabolism and cellular adaptation under stress, yet the mechanisms by which they regulate cancer cell survival remain unclear. Here, we identify Poly(A)-Binding Protein Cytoplasmic 1 (PABPC1), a core SG component, as stress-inducible SUMOylation target. Upon various stress conditions, SUMOylated PABPC1 promotes SG assembly and enhances cancer cell survival. Transcriptome-wide analysis reveals that SUMOylated PABPC1 selectively stabilizes mRNAs enriched in conserved U-rich elements. Mechanistically, SUMOylated PABPC1 interacts with RNA-binding protein TIA1 to form PABPC1-SUMO-TIA1 complex that recruits U-rich mRNAs into SGs, protecting them from degradation. This process facilitates the expression of U-rich genes, such as mitophagy-related genes FUNDC1, BNIP3L, thereby maintaining cellular homeostasis and promoting cell survival under adverse conditions. Our findings reveal that PABPC1 SUMOylation connects stress granule assembly with selective U-rich mRNA stabilization and mitophagy, promoting cancer cell stress adaptation.
    DOI:  https://doi.org/10.1038/s41467-025-62619-8
  39. Mol Cell Endocrinol. 2025 Aug 05. pii: S0303-7207(25)00186-8. [Epub ahead of print] 112635
    Mitochondrial dysfunction and defective quality control mechanisms in the kidney are not reversed by high-fat diet withdrawal in early obese mice.
    Patrícia C Braga, Rui Vitorino, Rita Ferreira, Mariana Marques, Pedro F Oliveira, Anabela S Rodrigues, Marco G Alves.
      High fat diet (HFD) induces glomerulopathy and proximal tubule injury. The precise pathophysiological mechanisms triggering obesity-related kidney impairment remain elusive, especially after dietary correction. Male C57BL6/J mice (n=15) were divided in: control group (CTR) fed with standard chow; a group fed with HFD for 200 days (28-29 weeks); and a group fed with HFD for 60 days (8-9 weeks) and then with standard chow (HFDt)(∼21 weeks). Biometric data and whole-body metabolism were assessed. Expression of genes associated with mitochondrial dynamics, mitochondrial complexes and antioxidant defenses were analyzed. Kidney homogenates enriched in mitochondria were prepared and characterized by mass spectrometry-based proteomics. Kidney tissue of mice fed HFD exhibited reduced PGC-1α expression, an imbalance between fusion (increased MFN1 and decreased OPA1) and fission (decreased FIS1 and DRP1) processes. The activity of mitochondrial CI was increased, while activity of CII was decreased in the kidney after HFD and HFDt. Antioxidant defense Manganese Superoxide dismutase (MnSOD) was decreased in the kidney of HFD, while Glutathione reductase (GR) increased, with both activities being restored upon dietary reversion. Proteomic analysis showed alterations in proteins associated with glutathione and glycine metabolism, fatty acid oxidation (FAO), and peroxisomal function. HFD negatively impacted kidney glutathione related proteins (Gsta3 and Gsr) however dietary correction reverted this condition. Acsm3 protein was downregulated in kidney after HFD and upregulated after dietary correction. Some machinery is shared by mitochondria and peroxisomes, with their network being crucial particularly under stress conditions. A HFD impaired kidney FAO in peroxisomes, as evidenced by downregulation of Pecr after HFD and HFDt. Dietary correction after early-obesity mitigates the systemic metabolic dysfunction and can attenuate mitochondria dysfunction but is unable to completely restore mitochondria dynamics and bioenergetics. The results highlight the integrity of mitochondrial network as a main point for targeted therapeutic strategies aimed at preventing the progression of kidney disease.
    Keywords:  Diabetic kidney disease; Diet reversion; Fatty acid metabolism; Mitochondria dynamics and Obesity
    DOI:  https://doi.org/10.1016/j.mce.2025.112635
  40. Dev Cell. 2025 Aug 07. pii: S1534-5807(25)00475-7. [Epub ahead of print]
    PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism.
    Changfeng Li, Ying Zhang, Xing Cheng, Hua Yuan, Shan Zhu, Jiao Liu, Qirong Wen, Yangchun Xie, Jinbao Liu, Guido Kroemer, Daniel J Klionsky, Michael T Lotze, Herbert J Zeh, Rui Kang, Daolin Tang.
      
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.018
  41. J Neurosci. 2025 Aug 06. pii: e0523252025. [Epub ahead of print]
    Pharmacological and genetic approaches to downregulate FIS1 mitigate neuropathic pain.
    Chang-Lei Zhu, Shu-Jiao Li, Zhi-Peng Lin, Zi-Wei Ni, Ke Tian, Yu-Lu Xia, Jing-Jing Tie, Xue-Yin Pu, Yun-Qiang Huang, Fei-Fei Wu, Hui Liu, Kun-Long Zhang, Shuai Zhang, You-Sheng Wu, Fei Tian, Nan-Nan Liu, Cai-Lian Ruan, Yan-Ling Yang, Ya-Yun Wang.
      Despite the established link between neuropathic pain and abnormal mitochondrial fission in neurons, the specific role of mitochondrial fission protein 1 (FIS1) in this process remains to be fully elucidated. In this study, the subjects we investigated were 6-8-week-old male mice. Comprehensive behavioral tests and immunostaining, along with Western blot analysis, revealed that neuropathic pain induced by spared nerve injury (SNI) upregulated FIS1 expression in the spinal cord dorsal horn (SC-DH). Furthermore, artificially upregulated FIS1 in SC-DH caused hyperalgesia behaviors in normal mice, while downregulation alleviated neuropathic pain. Using GAD2-MITO and vGluT2-MITO transgenic mice, we found that mitochondria network of both excitatory and inhibitory neurons in the SC-DH were disrupted. Selective downregulation of FIS1 in excitatory neurons via vGluT2-Cre mice reversed mitochondrial impairments and alleviated neuropathic pain. Network pharmacological prediction analysis combined with pharmacological tests indicated that compounds capable of downregulating FIS1 expression, such as epigallocatechin gallate (EGCG), the primary bioactive component of tea polyphenols, may possess analgesic properties. In contrast, cinnamic acid (CA), an organic acid derived from cinnamon bark, did not exhibit the capability to downregulate FIS1 expression and consequently lacked analgesic efficacy. Our research findings suggest that FIS1 may represent a novel molecular target for the treatment of neuropathic pain.Significance Statement Neuropathic pain is closely related to abnormal mitochondrial fission, but the mechanism remains unclear. This study shows that SNI-induced neuropathic pain leads to increased expression of FIS1 in the spinal cord dorsal horn (SC-DH). Upregulation of FIS1 in the SC-DH causes hyperalgesia, while downregulation alleviates neuropathic pain. In the pain state, mitochondrial network in both excitatory and inhibitory neurons in the SC-DH are disrupted. Downregulation of FIS1 in excitatory neurons of the SC-DH can improve mitochondrial dysfunction and thereby alleviate neuropathic pain. Network pharmacology combined with pain-related behaviors suggest that the epigallocatechin gallate (EGCG) can relieve neuropathic pain by inhibiting FIS1 in the SC-DH. In conclusion, FIS1 may be a novel molecular target for the treatment of neuropathic pain.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0523-25.2025
  42. IBRO Neurosci Rep. 2025 Dec;19 307-316
    OPTN deficiency through CRISPR/Cas9 downregulates autophagy and mitophagy in a SOD1-G93A-expressing transgenic cell line.
    Di Wen, Qiusheng Li, Yuanyuan Li, Wenyu Yan, Yanyan Wang, Yakun Liu.
      Amyotrophic lateral sclerosis (ALS) is characterized by the loss of upper and lower motor neurons (MNs) and is the most common adult paralysis neurodegenerative disease. Dysregulated autophagy, which has been reported in the pathogenesis of familial ALS, has been found in superoxide dismutase 1 (SOD1) transgenic mice and cell lines. Optineurin (OPTN) is a signal regulator that coordinates many crucial cellular processes, including autophagy, mitophagy and aggrephagy. Recent studies have shown that OPTN gene mutations are correlated with ALS, glaucoma and Paget's disease of the bone. Indeed, defects in autophagosome-lysosome fusion have been reported in patients with ALS-associated OPTN mutations. However, the exact function of OPTN in the pathology of ALS remains unknown. To determine the function of OPTN, we generated OPTN-knockdown cell lines from SOD1-G93A-expressing NSC34 cells with the clustered regularly interspaced short palindromic repeats/associated system 9 (CRISPR/Cas9) approach. In our research, we observed that the loss of OPTN resulted in the impairment of autophagy and mitophagy pathways. Moreover, the mitochondrial transmembrane potential was depolarized by LV-sgRNA-OPTN. On the basis of observations of live cells, the production of reactive oxygen species (ROS) was increased, the autophagic flux decreased, and the autophagic flux merged with that of mitochondria according to confocal live-cell imaging. A decreased LC3-II and an increased p62 levels indicated that autophagy pathway activation was decreased. The protein levels of VDAC1 and TBK1 decreased after OPTN knockdown, suggesting that mitophagy was blocked. Our results suggest that OPTN plays a pivotal role in regulating autophagy and mitophagy.
    Keywords:  Amyotrophic lateral sclerosis; Autophagy; CRISPR/Cas9; Mitophagy; OPTN; SOD1-G93A transgenic cell line
    DOI:  https://doi.org/10.1016/j.ibneur.2025.07.011
  43. J Agric Food Chem. 2025 Aug 05.
    Zearalenone Regulates Energy Metabolism and Proliferation of Goat Endometrial Epithelial Cells through Estrogen Receptor 1.
    Qi Zhang, Rongxin Xia, Junhui Shao, Rumeng Ren, Yuji Sun, Yanli Zhang, Feng Wang, Guomin Zhang.
      Zearalenone (ZEN), an estrogenic mycotoxin inducing reproductive toxicity, disrupts endometrial cell function and contributes to pregnancy failure, although its endometrial toxicity mechanisms remain unclear. This study reveals that ZEN inhibits goat endometrial epithelial cells (EECs) proliferation through estrogen receptor 1 (ESR1) homodimers. ESR1 knockout reversed ZEN-induced mitochondrial structural/functional damage via the ESR1-OMA1 zinc metallopeptidase (OMA1) axis. Furthermore, ZEN suppresses glycolysis and mitochondrial pyruvate transport in goat EECs through the ESR1-pyruvate kinase isoenzyme type M2 (PKM2) pathway. Pyruvate level alterations critically influence mitochondrial function and cell proliferation, with the expression of OMA1 mediating this regulatory process. Collectively, ZEN impairs mitochondrial dynamics in goat EECs through ESR1-OMA1 signaling and disrupts energy metabolism via the ESR1-PKM2 pathway, ultimately arresting cell proliferation. These mechanistic insights into ZEN's reproductive toxicity may guide protective strategies for human and animal health.
    Keywords:  cell proliferation; goat endometrial epithelial cells; mitochondria; pyruvate; zearalenone
    DOI:  https://doi.org/10.1021/acs.jafc.5c05264
  44. Biomed Pharmacother. 2025 Aug 06. pii: S0753-3322(25)00628-6. [Epub ahead of print]190 118434
    Vinpocetine alleviates chemotherapy-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial biogenesis in mice.
    Guanghai Nan, Lin Lin, Leejeong Kim, Kyeongmin Kim, Nari Kang, Hee Young Kim, Myeounghoon Cha, Bae Hwan Lee.
      Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of cancer treatment and is primarily driven by oxidative stress and mitochondrial dysfunction. Despite its clinical relevance, effective mechanism-based therapies remain limited. Vinpocetine, a neuroprotective compound, has shown antioxidant, anti-inflammatory, and mitochondrial function-preserving effects; however, its efficacy in CIPN remains unknown. This study aimed to evaluate the efficacy and underlying mechanisms of vinpocetine in a paclitaxel-induced CIPN mouse model. In behavioral tests, acute administration of vinpocetine alleviated mechanical hypersensitivity, whereas repeated treatment provided sustained relief from mechanical, thermal, and cold hypersensitivity. Mechanistically, vinpocetine reduced mitochondrial reactive oxygen species (ROS), restored SOD2 levels, and activated mitochondrial biogenesis via the PGC-1α-NRF1-TFAM pathway, as shown by Western blot analysis. In oxidative stress-induced pain models, vinpocetine also attenuated mechanical hypersensitivity, reinforcing its antioxidant properties. Voltage-sensitive dye imaging revealed reduced spinal neuronal hyperexcitability. Immunohistochemistry analysis further demonstrated reduced expression of AMPA and PKC-α in NeuN-positive neurons. This preclinical study is the first to demonstrate that vinpocetine alleviates CIPN by enhancing mitochondrial biogenesis, reducing oxidative stress, and suppressing neuronal excitability in the spinal cord. These results provide mechanistic insights into its effects on CIPN and support further translational research in this indication.
    Keywords:  Central sensitization; Chemotherapy-induced peripheral neuropathy; Mitochondrial biogenesis; Neuronal hyperexcitability; Oxidative stress; Vinpocetine
    DOI:  https://doi.org/10.1016/j.biopha.2025.118434
  45. Redox Rep. 2025 Dec;30(1): 2544412
    HIF1A/BNIP3 pathway affects ferroptosis in sepsis-induced cardiomyopathy through binding to BCL-2.
    Xiaoyue Wang, Jinze Li, Yixin Zhang, Ming Huang, Pengqiang Yang, Tianwen Huang, Qinghong Cheng.
       BACKGROUND: Sepsis-induced cardiomyopathy (SIC) involves ferroptosis, an iron-dependent cell death. Hypoxia-inducible factor-1α (HIF-1α) regulates autophagy and apoptosis, but its role in ferroptosis remains unclear. This study investigates the interaction between the HIF1A/BNIP3 signaling pathway and the ferroptosis axis, SLC7A11/GPX4, in septic myocardial injury.
    METHODS: A rat model of septic myocardial injury was created via cecal ligation and puncture (CLP), with an in vitro model using lipopolysaccharide (LPS)-treated H9c2 cardiomyocytes. Groups: sham, CLP, CLP + solvent, CLP + HIF1A inhibitor (LW6), CLP + ferroptosis inhibitor (Fer-1), and CLP + LW6 + Fer-1. Cardiac function, histopathological changes, and biomarkers (myocardial injury/inflammation/ferroptosis) were measured. In vitro, H9c2 cells were treated with LPS, LW6, or fenbendazole (FZ) and transfected with BNIP3 shRNA. Various assays were used to evaluate cell viability, ROS levels, and protein interactions.
    RESULTS: (1) HIF1A/BNIP3 activation aggravated septic myocardial injury and ferroptosis; inhibition reversed this. (2) BNIP3 knockdown alleviated LPS-induced injury and ferroptosis in H9c2 cells. (3) BNIP3 and BECN1 competed for BCL-2 binding, modulating ferroptosis-related signaling.
    CONCLUSION: BCL-2 links the HIF1A/BNIP3 and BECN1/SLC7A11/GPX4 pathways, offering insights into septic myocardial injury mechanisms and potential therapeutic targets.
    Keywords:  BCL-2; BECN1/SLC7A11/GPX4; HIF-1α/BNIP3; Sepsis-induced cardiomyopathy; apoptosis; autophagy; ferroptosis; myocardial injury
    DOI:  https://doi.org/10.1080/13510002.2025.2544412
  46. J Agric Food Chem. 2025 Aug 06.
    Melatonin Alleviates Pulmonary Fibrosis Induced by Atrazine Targeting the Pulmonary Capillary Microenvironment.
    Wei-Hong Lu, Xin Yao, Wen-Ting Qiao, Yu-Qian Zhang, Tian-Ning Yang, Kanwar Kumar Malhi, Jin-Long Li.
      Atrazine (ATZ), a common herbicide, accumulates in water sources, raising concerns about lung hazards from excessive tap water residues. Pulmonary capillary endothelial cells (PCECs) are primary targets of bloodborne toxins. Melatonin (MLT), an endogenous neuroendocrine hormone, shows promise in mitigating lung disease. This study developed a mouse model for studying the pulmonary effects of ATZ through drinking water and the protective effect of MLT. The results indicate that ATZ-induced pulmonary injury primarily alters PCECs, upregulating the Notch ligand Jag1 via a β-catenin-dependent manner, recruiting Notch1-expressing perivascular M2 macrophages, and promoting fibrosis. MLT attenuated lung injury and collagen deposition by restoring autophagy and inhibiting the Wnt1/β-catenin pathway, thereby reducing Jag1 expression and M2 macrophage activation. MLT also mitigated ATZ-induced lung necrosis and apoptosis. In conclusion, this study highlights MLT's potential in treating ATZ-induced lung injury by blocking Jag1-mediated macrophage phenotypic switching.
    Keywords:  Atrazine; Melatonin; mitophagy; pulmonary fibrosis; β-catenin-Jag1-Notch1 pathway
    DOI:  https://doi.org/10.1021/acs.jafc.5c00603
  47. Mol Med. 2025 Aug 02. 31(1): 272
    Piezo1 induces mitochondrial autophagy dysfunction leading to cartilage injury in knee osteoarthritis.
    Likai Yu, Zishan Su, Di Tian, Shangqi Liu, Li Zhang, Zeen Wang, Shaobo Guo, Wenhui Zhu, Peimin Wang, Nongshan Zhang.
       BACKGROUND: External mechanical stress plays a pivotal role in the pathogenesis of knee osteoarthritis. Piezo1 can sense mechanical stress changes on the surface of various cell types and convert them into bioelectrical signals to regulate cellular functions. Therefore, our study aimed to investigate the role of Piezo1 in mechanically induced KOA and elucidate its underlying mechanisms.
    METHODS: In this study, we employed various techniques to assess the effects of mechanical stress on knee joint cartilage in vivo and in vitro experiments. In vivo, we performed Micro-CT scanning, H&E staining, and ELISA analysis on the knee joints to evaluate the degree of cartilage damage and the expression of pro-inflammatory factors. In vitro, we utilized a cell stretcher to apply mechanical stress specifically to chondrocytes. Subsequently, we investigated the expression levels of Piezo1, pro-inflammatory factors, Collagen II, and other relevant markers within the chondrocytes. This approach aimed to shed light on the potential impact of Piezo1 on chondrocytes when subjected to mechanical stress.
    RESULTS: Elevated expression of Piezo1 was observed in the cartilage of mice post-treadmill exercise intervention, with noticeable damage to the cartilage tissue and reduced surface smoothness. External mechanical stress significantly lowered the synthesis of the extracellular matrix in chondrocytes, potentially through the inhibition of mitochondrial autophagy levels, leading to increased mitochondrial dysfunction and the induction of pro-apoptotic proteins and pro-inflammatory cytokines.
    CONCLUSIONS: Mechanical stress induces extracellular matrix degradation and promotes KOA progression through Piezo1-mediated chondrocyte autophagy dysfunction and apoptotic injury.
    Keywords:  Autophagy; Cartilage; Knee osteoarthritis; Mitochondria; Piezo1
    DOI:  https://doi.org/10.1186/s10020-025-01335-x
  48. Eur J Pharmacol. 2025 Aug 05. pii: S0014-2999(25)00800-3. [Epub ahead of print] 178046
    SAP30BP aggravates mitochondrial-related ferroptosis in diabetic cardiomyopathy by regulating MFN2-ACSL4 axis.
    Tong Zhao, Chen Chen, Wenjie Zhao, Jingjing Han, M O H A M M A D Omar Jan, Han Lou, Zhouxiu Chen, Xin Liu, Shenhong Jing.
      Ferroptosis is characterized by iron overload and uncontrolled lipid peroxidation, which plays a substantial role in the development of diabetic cardiomyopathy (DCM). However, the exact factor responsible for inducing ferroptosis in DCM has not been fully elucidated. SAP30 binding protein (SAP30BP), a member of the HCNGP family, functions as a transcription regulator. Our research reveals a significant increase in SAP30BP expression in the hearts of DCM mice and cardiomyocytes treated with high glucose (HG). Knockdown of SAP30BP ameliorated cardiac dysfunction and inhibited ferroptosis and mitochondrial damage in DCM hearts. At the cellular levels, transfection of si-SAP30BP suppressed ferroptosis, as evidenced by the reduced oxidative stress, iron overload and lipid peroxidation. RNA-seq and GEO database analysis suggested that mitochondrial dynamics contributed to SAP30BP induced ferroptosis. Mechanistically, SAP30BP inhibited the transcription of MFN2 through HDAC1-mediated histone deacetylation, leading to mitochondrial dynamic disruption and dysfunction. This process ultimately hindered the mitochondrial translocation of ACSL4 and mitochondria-associated ferroptosis. Collectively, our findings demonstrate the therapeutic benefits of SAP30BP knockdown in DCM by effectively suppressing mitochondria-associated ferroptosis through the MFN2-ACSL4 pathway. These results provide new mechanistic insights and a basis for developing mitochondria and ferroptosis targeting therapies for DCM.
    Keywords:  Diabetic cardiomyopathy; HDAC1; MFN2; SAP30BP; ferroptosis
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178046
  49. Redox Biol. 2025 Jul 31. pii: S2213-2317(25)00306-4. [Epub ahead of print]86 103793
    Arylsulfatase K attenuates airway epithelial cell senescence in COPD by regulating parkin-mediated mitophagy.
    Ruonan Yang, Yuan Zhan, Zhesong Deng, Jiaheng Zhang, Shanshan Chen, Yating Zhang, Hao Fu, Xiangling Meng, Jixing Wu, Yiya Gu, Qian Huang, Congyi Wang, Jungang Xie.
      Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by irreversible airflow limitation, primarily due to cigarette smoke (CS) exposure. Emerging research underscores the pivotal role of cellular senescence in the pathogenesis of COPD. The arylsulfatase family, known for its involvement in various age-related diseases, has yet to be investigated in the context of COPD. This study investigated the role of the arylsulfatase family, particularly ARSK, in COPD pathogenesis. Bioinformatics analysis and clinical validation revealed significantly reduced ARSK expression in COPD patients' lungs, especially in airway epithelium. ARSK overexpression alleviated CS-induced epithelial cellular senescence and improved mitophagy and mitochondrial function, while ARSK knockdown had an opposite effect. In vivo, Arsk-AAV administration relieved lung senescence and impaired lung function upon CS exposure, whereas airway-specific Arsk knockout aggravated these effects. Mechanistically, ARSK interacted with Parkin (PRKN) to regulate the phosphorylation of PRKN at serine 65 and subsequent mitophagy, thus attenuating cellular senescence. Additionally, the androgen receptor (AR) was identified as a transcription factor binding to the ARSK promoter, modulating its expression. These findings highlight the protective role of ARSK against epithelial cellular senescence, offering a potential therapeutic target for COPD.
    Keywords:  Airway epithelial cell senescence; Arylsulfatase K; Chronic obstructive pulmonary disease; Cigarette smoke; Mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2025.103793
  50. bioRxiv. 2025 Jul 23. pii: 2025.07.19.665690. [Epub ahead of print]
    An allosteric network governs Tom70 conformational dynamics to coordinate mitochondrial protein import.
    Max J Bachochin, Kelly L McGuire, Brian D Cook, Qiaozhen Ye, Steve Silletti, Kevin D Corbett, Elizabeth A Komives, Mark A Herzik.
      Tom70 mediates mitochondrial protein import by coordinating the transfer of cytosolic preproteins from Hsp70/Hsp90 to the translocase of the outer membrane (TOM) complex. In humans, the cytosolic domain of Tom70 ( Hs Tom70c) is entirely α -helical and comprises modular TPR motifs divided into an N-terminal chaperone-binding domain (NTD) and a C-terminal preprotein-binding domain (CTD). However, the mechanisms linking these functional regions remain poorly understood. Here, we present the 2.04 Å crystal structure of unliganded Hs Tom70c, revealing two distinct conformations - open and closed - within the asymmetric unit. These states are stabilized in part by interdomain crystal contacts and are supported in solution by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Principal component and dynamical network analyses reveal a continuum of motion linking the NTD and CTD via key structural elements, notably residues in helices α 7, α 8, and α 25. Engagement of the CTD by the viral protein Orf9b interrupts this network, stabilizing a partially-closed intermediate conformation and dampening dynamics at distal NTD sites. Collectively, our findings lay the groundwork for understanding Tom70 allostery and provide a framework for dissecting its mechanistic roles in chaperone engagement, mitochondrial import, and viral subversion.
    DOI:  https://doi.org/10.1101/2025.07.19.665690
  51. FEBS Lett. 2025 Aug 06.
    Ergothioneine supplementation improves pup phenotype and survival in a murine model of spinal muscular atrophy.
    Francesca Cadile, Daniela Ratto, Giorgia Rastelli, Ottavia Eleonora Ferraro, Caterina Temporini, Sunil Kumar, Simona Boncompagni, Paola Rossi, Monica Canepari.
      Spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of spinal motor neurons. The conventional therapy does not always lead to a full restoration of the clinical symptoms, partially due to the need for early treatment. Accumulating evidence describes the crucial role of mitochondrial dysfunction and oxidative stress in skeletal muscle of SMA patients. We aimed to investigate the effects of prenatal supplementation with the antioxidant molecule ergothioneine (ERGO) on an SMNΔ7 mouse model of SMA containing a knockout of survival motor neuron protein (SMN1) and two transgenes, one with a single normal copy of human SMN2 and the second with a human SMN2 promoter and a human SMN2 cDNA lacking exon 7. ERGO had a significant positive effect on the survival and locomotor abilities of SMA pups. In isolated diaphragm muscle, ERGO was found to stimulate mitophagy. The results of the current study highlight the need for further research into ERGO as an adjuvant therapy for SMA. Impact statement Our finding that ergothioneine supplementation improves survival in a murine model of spinal muscular atrophy may aid research into a novel potential adjuvant to alleviate the symptoms of this serious neuromuscular disease in humans.
    Keywords:  antioxidant; diaphragm muscle; ergothioneine; mitophagy; spinal muscular atrophy
    DOI:  https://doi.org/10.1002/1873-3468.70136
  52. bioRxiv. 2025 Jul 24. pii: 2025.07.23.666395. [Epub ahead of print]
    Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
    Mariella Quispe-Carbajal, Lauren Todd, Steven E Glynn.
      Yme1 is a conserved ATP-dependent protease that maintains mitochondrial function by degrading proteins in the intermembrane space. However, how Yme1 selects substrates within the crowded mitochondrial environment is poorly understood. An established substrate of Yme1 in yeast is the Tim10 subunit of the small Tim9-Tim10 protein chaperone complex, which is degraded following disruption of the subunit's internal disulfide bonds. Here, we use biochemical and biophysical approaches to examine initial substrate binding and degradation of small Tim proteins by Yme1 and shed light on the molecular mechanism of substrate selection. We show that Yme1 preferentially binds Tim10 over other small Tim proteins by forming a high-affinity interaction with the subunit irrespective of the presence of its disulfide bonds. This interaction is primarily mediated by Tim10's flexible N-terminal 'tentacle', though substrate unfolding exposes additional contact sites that enhance engagement. Notably, the human ortholog TIMM13 is also recognized by yeast Yme1, suggesting conservation of recognition strategy across species. Yme1 also binds to the assembled Tim9-Tim10 chaperone but independently of the Tim10 N-terminal tentacle. These findings suggest that Yme1 surveils the folding state of Tim10 throughout its functional lifecycle - both as a folded monomer and as a subunit of the functional chaperone complex - but only commits to degradation after disruption of its disulfide bonds.
    DOI:  https://doi.org/10.1101/2025.07.23.666395
  53. BMJ Case Rep. 2025 Aug 08. pii: bcr0820080652. [Epub ahead of print]2009
    A novel founder mutation in the MFN2 gene associated with variable Charcot-Marie-Tooth type 2 phenotype in two families from Southern Italy.
    Maria Muglia, Giovanni Vazza, Alessandra Patitucci, Micaela Milani, Davide Pareyson, Franco Taroni, Aldo Quattrone, Maria Luisa Mostacciuolo.
      Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy. CMT falls into two main forms: the demyelinating CMT type 1 with decreased nerve conduction velocities and the axonal CMT type 2. CMT2 is further subtyped by linkage analysis into >10 loci, with eight genes identified.Recently, mutations in the mitochondrial fusion protein 2 (MFN2) gene were reported in families with CMT2A1 and additional mutations have been detected in other studies, bringing to 42 the total number of different MFN2 mutations described thus far.2-4In the current study, we report a novel MFN2 mutation shared by two apparently unrelated CMT2 families originating from the same area in Southern Italy.
    DOI:  https://doi.org/10.1136/bcr.08.2008.0652
  54. J Clin Biochem Nutr. 2025 Jul;77(1): 55-63
    Enteral nutrition intervention improves intestinal ischemia-reperfusion injury by modulating the SENP1/SIRT3 axis.
    Shizhuang Wei, Zhenhua Li, Bo Wen, Wei Wang, Daolai Huang, Chao Zhang, Xianghua Wu.
      Intestinal ischemia-reperfusion (II/R) injury is a significant clinical concern with high mortality rates. Mitochondria play a crucial role in this process, and maintaining mitochondrial homeostasis is a potential treatment target. SENP1 is a de-SUMOylated hydrolase that may regulate SIRT3, a major mitochondrial deacetylase. However, the role of SENP1 and SIRT3 in II/R remains unclear. Employing a combination of in vitro cell culture experiments utilizing Caco-2 cells and in vivo II/R models with SD rats, along with an array of molecular biology techniques such as gene silencing, protein detection methods, immunoprecipitation, histological analysis, and functional assays, this study delved into the role of SENP1 and SIRT3 in intestinal ischemia-reperfusion injury. Statistical analysis was meticulously conducted to evaluate the significance of the obtained results. SENP1 and SIRT3 are co-expressed and interact in Caco-2 cells. In models of II/R, the expression of SENP1 increased while that of SIRT3 decreased. Reducing SENP1 expression by siRNA or enteral nutrition intervention with bupropion alleviated intestinal II/R injury, reduced mitochondrial damage and oxidative stress, and improved the number and function of mitochondria. Our study demonstrates the importance of SENP1 and SIRT3 in intestinal ischemia-reperfusion injury. Reducing SENP1 expression through siRNA or enteral nutrition intervention shows promise as a potential therapeutic approach. This research provides new insights into the mechanism of II/R injury and paves the way for further investigations.
    Keywords:  SENP1; SIRT3; enteral nutrition; intestinal ischemia-reperfusion injury; mitochondrial homeostasis
    DOI:  https://doi.org/10.3164/jcbn.25-31
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