bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–06–29
fifty-five papers selected by
Gavin McStay, Liverpool John Moores University
  1. Qishentaohong granules alleviate heart failure by modulating mitochondrial fission and mitophagy balance.
  2. Expression of Concern: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.
  3. Kaempferol improves mitochondrial homeostasis via mitochondrial dynamics and mitophagy in diabetic kidney disease.
  4. A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.
  5. Mitophagy as a therapeutic target for myocardial fibrosis: Mechanistic insights and potential pharmacological interventions.
  6. Chondroitin Sulfate as a Lysosomal Enhancer Attenuates Lipid-Driven Inflammation via Lipophagy and Mitophagy.
  7. ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion.
  8. METTL3-mediated m6A modification regulates D-galactose-induced skin fibroblast senescence through miR-208a-5p.
  9. [Advances of researches on acupuncture treatment of Parkinson's disease by regulating mitochondrial function].
  10. PINK1/Parkin Deficiency Enhances Vascular Remodeling and Aggravates Hypoxia-induced Pulmonary Hypertension.
  11. Redox-responsive dendritic copolymer-drug conjugates enhance therapeutic mitophagy through coordinated microtubule destabilization for synergistic triple-negative breast cancer therapy.
  12. CIRBP Enhances the Function of Yak Cumulus Cells by Activating AMPK/mTOR-Mediated Mitophagy.
  13. Oxidative Stress, Energy Metabolism Disorder, Mitochondrial Damage, and miR-144 Participated in Molecular Mechanisms of 4-Octylphenol-Caused Cardiac Autophagic Damage in Common Carps (Cyprinus carpio L.).
  14. Bone marrow microenvironment-responsive polymeric-drug/siRNA regulates leukemia stem cells assisting for prevention of AML relapse.
  15. Classical swine fever virus hijacks ESCRT-III and VPS4A to promote phagophore closure for accelerating mitophagy.
  16. Worenine enhances the sensitivity of non-small cell lung cancer A549/DDP cells to cisplatin via HIF-1α/BNIP3-mediated mitophagy.
  17. Retraction: Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury.
  18. Uric Acid Stimulates PINK1/Parkin-Mediated Mitophagy via Nrf2/HO-1 Pathway to Protect Against Neuronal Apoptosis in Alzheimer's Disease.
  19. Mitophagy: A double-edged sword in tumor cell death regulation and therapeutic response.
  20. Retraction: Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury.
  21. Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission.
  22. [Mechanisms of mitochondrial dynamics in ischemic stroke and therapeutic strategies].
  23. Interaction Between Rumen Microbiota and Epithelial Mitochondrial Dynamics in Tibetan Sheep: Elucidating the Mechanism of Rumen Epithelial Energy Metabolism.
  24. Intratracheal Administration of Polystyrene Micro(nano)plastics with a Mixed Particle Size Promote Pulmonary Fibrosis in Rats by Activating TGF-β1 Signaling and Destabilizing Mitochondrial Dynamics and Mitophagy in a Dose- and Time-Dependent Manner.
  25. Role of FGF19 in regulating mitochondrial dynamics and macrophage polarization through FGFR4/AMPKα-p38/MAPK Axis in bleomycin-induced pulmonary fibrosis.
  26. Mitochondrial fission inhibitor Mdivi-1 alleviates lipopolysaccharide-induced parvalbumin interneurons dysregulation and cognitive impairments in a mouse model of sepsis-associated encephalopathy.
  27. A classical anti-autophagic viral protein reshapes mitochondria for immune evasion.
  28. [Exercise preconditioning alleviates motor deficits in MPTP-induced Parkinsonian mice by improving mitochondrial function].
  29. Lipopolysaccharide Induces Mitochondrial Fragmentation and Energetic Shift in Reactive Microglia: Evidence for a Cell-Autonomous Program of Metabolic Plasticity.
  30. "Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".
  31. Induced Mitophagy Promotes Cell Cycle Re-Entry in Adult Cardiomyocytes.
  32. Downregulation of Mitophagy, Complex I Biogenesis, and Signaling by ROBO Receptors-Implications for Psoriasis Pathogenesis.
  33. Ameson portunus infection is associated with RK13 mitochondrial abnormalities.
  34. Possible Mitigating Effect of Nobiletin on Rotenone-Induced Parkinsonism in Male Albino Rat Model: Targeting Bmal1/Nrf2 Mediated Ferroptosis and Restoring Mitochondrial Mitophagy.
  35. Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury.
  36. Calcitriol deficiency reduces myocardial ATP production with disturbed mitochondrial dynamics and increased uncoupling protein 2 expression.
  37. The role of the circadian clock in regulating mitochondrial dynamics and their impact on skeletal muscle function and metabolism.
  38. The mitochondrial methylation potential gates mitoribosome assembly.
  39. MICOS.
  40. Aerobic Exercise Alleviates Cardiac Dysfunction Correlated with Lipidomics and Mitochondrial Quality Control.
  41. Parkinson's disease: exploring the systemic immune mechanisms through molecular investigations.
  42. PLK1-mediated PDHA1 phosphorylation drives mitochondrial dysfunction, mitophagy, and cancer progression in Cr(VI)-associated lung cancer.
  43. PPARα activation attenuated heat-induced myocardial injury in mice.
  44. Identification Exploring the Mechanism and Clinical Validation of Mitochondrial Dynamics-Related Genes in Membranous Nephropathy Based on Mendelian Randomization Study and Bioinformatics Analysis.
  45. Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy.
  46. Impact of Diquat on the Intestinal Health and the Composition and Function of the Gut Microbiome.
  47. Mitochondrial fission regulator 2 promotes cell proliferation, migration and invasion in hepatocellular carcinoma through regulating PI3K/AKT signaling pathway.
  48. Mitochondrial and inflammatory dysfunctions underlie perfluorooctane sulfonic acid (PFOS)-induced neurotoxicity in adult zebrafish.
  49. Corrigendum to "Naotaifang formula regulates Drp1-induced remodeling of mitochondrial dynamics following cerebral ischemia-reperfusion injury" [Free Radic. Biol. Med. 229 (2025) 139-153].
  50. Cathodal Transcranial Direct Current Stimulation Attenuates Cerebral Ischemia-Reperfusion Injury by Coordinating Mitophagy Inhibition and Nrf2 Activation Against Ferroptosis.
  51. Integrating mitophagy-associated lncRNAs to predict prognosis and therapeutic response in clear cell renal cell carcinoma.
  52. Mito-fission gene prognostic model for colorectal cancer.
  53. Intermittent ELF-MF exposure effectively ameliorates pathologic features associated with adult AD mice.
  54. Expression of Concern: Mitochondrial dynamic modulation exerts cardiometabolic protection in obese insulin-resistant rats.
  55. Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia.
  1. J Ethnopharmacol. 2025 Jun 21. pii: S0378-8741(25)00879-7. [Epub ahead of print]352 120190
    Qishentaohong granules alleviate heart failure by modulating mitochondrial fission and mitophagy balance.
    Jialin Jin, Yuxuan Li, Sinai Li, Dong Li, Jing Liu, Jinjin Lu, Qiaozhi Dong, Qian Wu, Yan Li, Qian Lin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Heart failure (HF) remains a critical challenge in cardiovascular therapeutics. Qishentaohong granules (QSTH), formulated under the traditional Chinese medicine Qi-Blood theory, have demonstrated clinical efficacy in HF management through randomized controlled trials. However, their precise mechanisms of action remain unclear.
    OBJECTIVE: To investigate the mechanistic role of QSTH in regulating mitochondrial homeostasis for HF amelioration.
    METHODS: HF murine models and cardiomyocyte hypertrophy models were developed for QSTH intervention. Cardiac function and structural integrity were assessed via echocardiography and histopathological staining. Mitochondrial fission (FIS1, MFF) and mitophagy markers (p62, LC3B, PARKIN) were quantified by Western blot in vivo and in vitro. Mitochondrial ultrastructure was analyzed using transmission electron microscopy (TEM) and two-photon excitation polarized fluorescence (TEPF) microscopy. In vitro mechanistic studies employed pathway inhibitors and Pink1 siRNA to validate regulatory pathways. Molecular alterations were evaluated through Western blot, qRT-PCR, and immunofluorescence.
    RESULTS: QSTH ameliorated myocardial pathology and cardiac function in HF mice through suppression of mitochondrial fission proteins (FIS1, MFF) and activation of mitophagy, indicated by elevated LC3B and PARKIN expression coupled with reduced p62 levels. TEPF microscopy revealed enhanced mitochondrial network integrity in QSTH-treated cardiomyocytes. In vitro, QSTH attenuated hypertrophy by modulating reactive oxygen species (ROS), mitochondrial membrane potential, and apoptosis. Mechanistically, QSTH activated PINK1 expression/phosphorylation, inhibited CaMKIIδ T287 phosphorylation, and regulated DRP1 S616 phosphorylation, thereby balancing mitochondrial fission-mitophagy dynamics via the CaMKIIδ-DRP1-PINK1 pathway.
    CONCLUSION: QSTH restores cardiomyocyte mitochondrial homeostasis through modulation of the CaMKIIδ-DRP1-PINK1 pathway, effectively attenuating hypertrophy, improving cardiac function, and reducing fibrosis in HF models.
    Keywords:  Chronic heart failure; Mitochondrial fission; Mitophagy; Qishentaohong granules; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.jep.2025.120190
  2. Hum Mol Genet. 2025 Jun 19. pii: ddaf104. [Epub ahead of print]
    Expression of Concern: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddaf104
  3. Int Immunopharmacol. 2025 Jun 23. pii: S1567-5769(25)01111-7. [Epub ahead of print]162 115121
    Kaempferol improves mitochondrial homeostasis via mitochondrial dynamics and mitophagy in diabetic kidney disease.
    Chenhui Xia, Jiale Zhang, Huixi Chen, Weimin Jiang, Shaofeng Zhou, Huijuan Zheng, Weiwei Sun.
      Mitochondrial homeostasis imbalance plays an important role in the development of diabetic kidney disease (DKD). Kaempferol is a key bioactive compound widely present in the rhizomes of Kaempferia L. and vegetables. Its anti-inflammatory and antioxidant properties have gained increasing attention in treating various metabolic diseases. This study investigated whether kaempferol could improve mitochondrial structure and function by regulating mitochondrial dynamics and mitophagy in DKD. A DKD rat model was established via unilateral nephrectomy and streptozotocin injection. Renal function, histopathology, and inflammatory factors were assessed, along with fibrosis, apoptosis, mitochondrial dynamics, and mitophagy-related proteins. Meanwhile, an AGEs-induced HK-2 cell injury model was used to evaluate autophagic flux and mitochondrial function and morphology through ad-mCherry-GFP-LC3B transduction, JC-1 staining, and MitoTracker probes. In vivo results showed that kaempferol exhibited significant anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in DKD rats. Moreover, kaempferol demonstrated good safety by alleviating hepatic fibrosis. It also restored mitochondrial dynamics by promoting the upregulation of mitochondrial fusion proteins (Mfn1, OPA1) and the downregulation of fission proteins (Drp1, Fis1). In addition, kaempferol enhanced mitochondrial biogenesis by upregulating PGC-1α and TFAM. Notably, kaempferol reactivated mitophagy, as evidenced by increased levels of PINK1, Parkin, LC3, Beclin1, and ATG5, along with a reduction in p62 levels. In vitro, kaempferol further demonstrated its antioxidative potential by increasing SOD levels and decreasing MDA levels. Additionally, it promoted autophagic induction and facilitated the fusion of autophagosomes with lysosomes. These combined effects led to the restoration of mitochondrial membrane potential and structural integrity, while reducing ROS production and enhancing ATP generation. In conclusion, kaempferol promotes mitochondrial fusion, restores mitophagy, enhances autophagy flux, and facilitates mitochondrial clearance, showing the potential to mitigate kidney injury and slow disease progression in DKD.
    Keywords:  Diabetic kidney disease; Inflammation; Kaempferol; Mitochondrial dynamics; Mitophagy; Renal fibrosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115121
  4. J Cell Biol. 2025 Aug 04. pii: e202408025. [Epub ahead of print]224(8):
    A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.
    Joanna Koszela, Anne Rintala-Dempsey, Giulia Salzano, Viveka Pimenta, Outi Kamarainen, Mads Gabrielsen, Aasna L Parui, Gary S Shaw, Helen Walden.
      Mutations in the E3 ubiquitin ligase Parkin gene have been linked to early onset Parkinson's disease. Besides many other roles, Parkin is involved in clearance of damaged mitochondria via mitophagy-a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognizes its substrates for ubiquitination. Here, we characterize a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results may explain fast kinetics of Miro1 ubiquitination by Parkin in recombinant assays and provide a biochemical explanation for Miro1-dependent Parkin recruitment to the mitochondrial membrane observed in cells. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson's disease.
    DOI:  https://doi.org/10.1083/jcb.202408025
  5. Pak J Pharm Sci. 2025 May-Jun;38(3):38(3): 841-852
    Mitophagy as a therapeutic target for myocardial fibrosis: Mechanistic insights and potential pharmacological interventions.
    Jie Wu, Tingjuan Mei, Yang Dong, Fen Zhang, Xingxing Li, Lei Wang.
      Myocardial fibrosis is a central pathological feature of various cardiovascular diseases, including heart failure and hypertension. It involves the activation of cardiac fibroblasts, transforming them into myofibroblasts that secrete pro-fibrotic factors, leading to excessive extracellular matrix deposition and progressive cardiac dysfunction. Mitochondrial dysfunction plays a critical role in the development of myocardial fibrosis, with mitophagy, a selective form of autophagy, essential for maintaining mitochondrial quality by removing damaged mitochondria. This process is vital in mitigating fibrosis progression. Recent studies suggest that pharmacological modulation of mitophagy may offer novel therapeutic strategies for cardiovascular diseases involving fibrosis. This review explores the mechanisms of mitophagy in myocardial fibrosis, highlighting key proteins and molecular pathways involved in fibroblast activation and mitochondrial dysfunction. Additionally, it discusses the therapeutic potential of targeting mitophagy to mitigate myocardial fibrosis, emphasizing the importance of balancing mitophagy modulation. Overall, targeting mitophagy pathways holds promise as a therapeutic approach for managing myocardial fibrosis and improving heart function.
  6. Mar Drugs. 2025 May 27. pii: 228. [Epub ahead of print]23(6):
    Chondroitin Sulfate as a Lysosomal Enhancer Attenuates Lipid-Driven Inflammation via Lipophagy and Mitophagy.
    Ting Sun, Huimin Lv, Huarong Shao, Xiuhua Zhang, Anqi Wang, Wei Zhang, Fei Liu, Peixue Ling.
      Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal-lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development.
    Keywords:  chondroitin sulfate; lipid metabolism; lysosomal acidification; mitochondrial autophagy; non-alcoholic steatohepatitis; subcellular regulation
    DOI:  https://doi.org/10.3390/md23060228
  7. Bone Res. 2025 Jun 23. 13(1): 66
    ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion.
    Jingyi Cai, Ziyang Min, Chaoyuan Li, Zhihe Zhao, Jun Liu, Dian Jing.
      The effectiveness of cranial suture expansion therapy hinges on the timely and adequate regeneration of bone tissue in response to mechanical stimuli. To optimize clinical outcomes and prevent post-expansion relapse, we delved into the underlying mechanisms governing bone remodeling during the processes of suture expansion and relapse. Our findings revealed that in vitro stretching bolstered mesenchymal stem cells' antioxidative and osteogenic capacity by orchestrating mitochondrial activities, which governed by force-induced endoplasmic reticulum (ER) stress. Nonetheless, this signal transduction occurred through the activation of protein kinase R-like ER kinase (PERK) at the ER-mitochondria interface, rather than ER-mitochondria calcium flow as previously reported. Subsequently, PERK activation triggered TFEB translocation to the nucleus, thus regulating mitochondrial dynamics transcriptionally. Assessment of the mitochondrial pool during expansion and relapse unveiled a sequential, two-phase regulation governed by the ER stress/p-PERK/TFEB signaling cascade. Initially, PERK activation facilitated TFEB nuclear localization, stimulating mitochondrial biogenesis through PGC1-α, thereby addressing energy demands during the initial phase. Subsequently, TFEB shifted focus towards ensuring adequate mitophagy for mitochondrial quality maintenance during the remodeling process. Premature withdrawal of expanding force disrupted this sequential regulation, leading to compromised mitophagy and the accumulation of dysfunctional mitochondria, culminating in suboptimal bone regeneration and relapse. Notably, pharmacological activation of mitophagy effectively mitigated relapse and attenuated bone loss, while its inhibition impeded anticipated bone growth in remodeling progress. Conclusively, we elucidated the ER stress/p-PERK/TFEB signaling orchestrated sequential mitochondria biogenesis and mitophagy under mechanical stretch, thus ensuring antioxidative capacity and osteogenic potential of cranial suture tissues.
    DOI:  https://doi.org/10.1038/s41413-025-00427-y
  8. Front Immunol. 2025 ;16 1577783
    METTL3-mediated m6A modification regulates D-galactose-induced skin fibroblast senescence through miR-208a-5p.
    Gaoxiang Huang, Sainan Sun, Mingde Liao, Jing Wang, Qing Yan, Jing Li, Yi Meng, Qi Wang, Zhen Guo, Jiyong Tan, Jing Li.
       Introduction: As the most abundant epitranscriptomic modification, N6-methyladenosine (m6A) critically influences aging and age-related pathologies. However, its regulatory interplay with microRNAs (miRNAs) in skin aging remains poorly defined.
    Methods: Aging phenotypes were recapitulated using D-galactose (D-gal)-induced senescence models in mouse skin fibroblasts (MSFs) and mice. Interventions included METTL3 overexpression/knockdown, miR-208a-5p mimic/inhibitor transfection, and pharmacological mitophagy induction (GSK). Molecular analyses assessed m⁶A dynamics, gene regulation, and mitochondrial function.
    Results: In D-gal-induced aging models, global RNA hypomethylation and reduced METTL3 expression were observed, while METTL3 overexpression attenuated cellular senescence. Mechanistically, METTL3 depletion elevated miR-208a-5p levels via YTHDF2-mediated m⁶A recognition, establishing epitranscriptional control. This upregulated miR-208a-5p directly targeted the 3'-UTR of OPA1 (optic atrophy type 1), suppressing mitophagic activity. Critically, senescent phenotypes induced by METTL3 knockdown or miR-208a-5p mimicry were reversed by pharmacological mitophagy induction (GSK), confirming mitochondrial homeostasis as the pathway's functional nexus.
    Discussion: These results establish an m6A-dependent METTL3/miR-208a-5p/OPA1 axis that regulates mitophagy and skin aging. Pharmacological rescue of mitophagy highlights this pathway's therapeutic relevance for age-related dermatopathology.
    Keywords:  M6A; METTL3; aging; miR-208a-5p; senescence
    DOI:  https://doi.org/10.3389/fimmu.2025.1577783
  9. Zhen Ci Yan Jiu. 2025 Jun 25. pii: 1000-0607(2025)06-0721-07. [Epub ahead of print]50(6): 721-727
    [Advances of researches on acupuncture treatment of Parkinson's disease by regulating mitochondrial function].
    Ru-Qi Zhang, Bing-Xu Zhu, Xiao-Jie Dong, Lin Chen, Sheng-Chun Wang.
      The pathological mechanism of Parkinson's disease (PD) is complex and affected by multi-system and multi-level factors including mitochondrial dysfunction (MD). It has been demonstrated that all patients with PD have a marked loss of dopaminergic neurons in the substantial nigra pars compacta, and MD is an important initial factor causing dopaminergic neuron degeneration. Clinical practice has shown that acupuncture has a positive role in the treatment of PD. In the present article, we summed up recent research results about the mechanisms of acupuncture underlying improvement of PD from the standpoint of mitochondrial function. Acupuncture has been shown to be able in improving mitochondrial function, and restoring mitochondrial homeostasis, and protecting the normal morphological structure of mitochondria. It can also regulate the expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and Sirtuins (SIRT) to take part in mitochondrial biogenesis; decrease the levels of dynamin-related protein 1 (Drp1), mitochondrial fission factor (MFF), and mitochondrial fission protein 1 (Fis1) protein to preserve mitochondrial dynamic stability; and modulate the expression of PTEN-induced putative kinase 1 (PINK1), Parkin, P62, microtubule-associated protein light chain 3Ⅱ (LC3Ⅱ), and Beclin1 to promote autophagy. In addition, through controlling mitochondrial energy metabolism, preserving calcium homeostasis, reducing oxidative stress, and preventing neuronal apoptosis, acupuncture can also help improve mitochondrial dysfunction and prevent the onset and progression of PD. However, more researches are warranted to fully unravel the underlying mechanisms of acupuncture intervention before it can be popularized in clinical settings.
    Keywords:  Acupuncture; Mechanism; Mitochondrial function; Parkinson’s disease; Review
    DOI:  https://doi.org/10.13702/j.1000-0607.20240406
  10. Am J Respir Cell Mol Biol. 2025 Jun 23.
    PINK1/Parkin Deficiency Enhances Vascular Remodeling and Aggravates Hypoxia-induced Pulmonary Hypertension.
    Rakhshinda Rehman, Paul Dieffenbach, Shamsudheen K Vellarikkal, Alexis M Corcoran, Leilani Pomales, Antonio Arciniegas Rubio, Kaithlin V Zambrano Vera, Fotios Spyropoulos, Kosmas Kosmas, Hillaire Lam, Harilaos Filippakis, Mark A Perrella, Laura E Fredenburgh, Helen Christou.
      Alterations in mitochondrial structure and function contribute to vascular smooth muscle cell (VSMC) phenotypic switching and are causally linked to pulmonary arterial hypertension (PAH) pathogenesis. The PINK1/Parkin-mediated mitophagy pathway is a key mitochondrial quality control program by which defective mitochondria are targeted for removal. The role of PINK1/Parkin-mediated mitophagy in VSMC phenotypic switching and PAH pathogenesis is not known. We sought to evaluate if PINK1/Parkin-induced mitophagy modulates VSMC phenotypic switching and contributes to PAH. Mitophagy and PINK1/Parkin expression were evaluated in human PAH lungs and Pulmonary Artery Smooth Muscle Cells (PASMCs). PINK1 and Parkin were silenced in human and mouse primary PASMCs and global PINK1 and Parkin knockout mice were used. After silencing of PINK1 and Parkin, PASMC proliferation and apoptosis were measured, and experimental pulmonary hypertension was evaluated after exposure to hypoxia. Parkin and PINK1 levels were reduced in the pulmonary vasculature or PASMCs from PAH lungs, accompanied by decreased mitophagy. PINK1 and Parkin knockout animals had an exaggerated pulmonary hypertension phenotype upon exposure to hypoxia. Genetic silencing of PINK1 and Parkin in human and mouse PASMCs led to increased proliferation and apoptosis resistance. We conclude that Reduced PINK1/Parkin-induced mitophagy contributes to pulmonary artery smooth muscle cell phenotypic switching and exacerbates PAH.
    Keywords:  mitophagy, phenotypic switch, vascular smooth muscle, apoptosis resistance, pulmonary hypertension
    DOI:  https://doi.org/10.1165/rcmb.2024-0349OC
  11. Acta Biomater. 2025 Jun 22. pii: S1742-7061(25)00457-X. [Epub ahead of print]
    Redox-responsive dendritic copolymer-drug conjugates enhance therapeutic mitophagy through coordinated microtubule destabilization for synergistic triple-negative breast cancer therapy.
    Guohao Liu, Bing Wang, Ping Chen, Zhiqian Li, Xinying Cheng, Qiyong Gong, Kui Luo.
      Application of microtubule-targeting agents (MTAs) for triple-negative breast cancer (TNBC) is hampered by their limited efficacy and strong systemic toxicity. Herein, we reported dendritic copolymer-drug conjugates to synergistically disrupt microtubule dynamics and induce therapeutic mitochondrial autophagy (mitophagy), thus enhancing therapeutic efficacy of MTAs. Paclitaxel (PTX) and 2-methoxyestradiol (2ME) were conjugated to glutathione-stimuli responsive dendritic copolymers, resulting in DDS-PTX and DDS-2ME, respectively. PTX and 2ME were tumor-specifically released from DDS-PTX and DDS-2ME, and simultaneously acted on microtubule polymerization and depolymerization, respectively. Dual perturbation of microtubules triggered catastrophic microtubule network collapse, prolonged mitotic arrest and amplified mitochondrial stress. Mechanistically, severe mitotic stress activated the PINK1/Parkin pathway, driving excessive mitophagy and caspase-dependent apoptosis. In a murine TNBC model, treatment with combined DDS-PTX and DDS-2ME resulted in a tumor inhibition rate of 95.01 %, and the median survival was significantly extended compared to monotherapies with DDS-PTX or DDS-2ME. This combined formulation also remarkably reduced side effects of free PTX and 2ME. Mitophagy-mediated apoptotic amplification was explored as a therapeutic paradigm in this study to bridge cytoskeletal disruption with organelle-level vulnerability for enhanced tumor therapy. STATEMENT OF SIGNIFICANCE: Distinct redox-responsive dendritic copolymer-drug conjugates (DDS-PTX and DDS-2ME) were constructed to deliver paclitaxel and 2-methoxyestradiol for synergistic triple-negative breast cancer therapy. Tumor-specific drug release enabled spatiotemporal coordination of microtubule stabilization and depolymerization, thus inducing catastrophic microtubule fragmentation, prolonged mitotic arrest, and amplified mitochondrial stress. These effects subsequently triggered PINK1/Parkin-mediated therapeutic mitophagy and caspase-dependent apoptosis, achieving a 95.01 % tumor suppression rate and extending median survival to 56 days in murine models. Notably, the conjugates significantly reduced systemic toxicity compared to free drugs while maintaining hemocompatibility and organ safety. By integrating molecular-scale tumor microenvironment responsiveness with cytoskeletal-organelle crosstalk, this work establishes a mechanistically driven paradigm to amplify subcellular stress responses, offering a transformative strategy for refractory cancers with enhanced efficacy and safety.
    Keywords:  Dendritic copolymer-drug conjugate; Microtubule-targeting agents; Mitophagy; Mitotic arrest; Synergistic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2025.06.038
  12. Biomolecules. 2025 May 24. pii: 759. [Epub ahead of print]15(6):
    CIRBP Enhances the Function of Yak Cumulus Cells by Activating AMPK/mTOR-Mediated Mitophagy.
    Rui Zhang, Yan Cui, Yangyang Pan, Meng Wang, Sijiu Yu, Ruihua Xu, Wenbin Ma, Junqian Wang, Donglan Zhong, Zhengxing Jiao.
      Cold-inducible RNA-binding protein (CIRBP) has been reported to be involved in various cellular functions by regulating programmed cell death (PCD). However, the specific mechanism and function of CIRBP in regulating mitochondrial autophagy are still unclear. In this study, we found that CIRBP induced mitophagy through the AMPK/mTOR pathway to improve the function of yak cumulus cells (YCCs). We observed that low temperatures (32 °C) activated autophagy, increased E2 and P4 secretion, and up-regulated CIRBP expression. CIRBP overexpression activated mitophagy in YCCs, promoted cumulus diffusion, enhanced E2 and P4 synthesis and secretion, and inhibited apoptosis. CIRBP overexpression significantly attenuated the dysfunction of YCCs induced by the inhibition of mitophagy, whereas the activation of mitophagy exerted the same effect as CIRBP overexpression. DOX HCL is an AMPK/mTOR pathway inhibitor. CIRBP overexpression can successfully alleviate the inhibition of mitophagy caused by DOX HCL inhibiting the AMPK/mTOR pathway and can significantly enhance the mitophagy induced by AMPK/mTOR pathway activation in YCCs. Furthermore, we found that the increased expression of CIRBP protein alleviated the apoptosis caused by AKT pathway activation. In summary, CIRBP promoted mitophagy by activating AMPK/mTOR pathway, thereby promoting the synthesis and secretion of steroid hormones and cumulus diffusion in YCCs and enhancing YCCs survival through activating autophagy and AKT signaling pathway, and then improve the function of YCCs. Our research provided new perspectives on CIRBP's regulation of cell death and highlighted its potential role in female reproductive systems.
    Keywords:  CIRBP; apoptosis; cumulus diffusion; mitophagy; ovarian steroid hormones
    DOI:  https://doi.org/10.3390/biom15060759
  13. Metabolites. 2025 Jun 11. pii: 391. [Epub ahead of print]15(6):
    Oxidative Stress, Energy Metabolism Disorder, Mitochondrial Damage, and miR-144 Participated in Molecular Mechanisms of 4-Octylphenol-Caused Cardiac Autophagic Damage in Common Carps (Cyprinus carpio L.).
    Minna Qiu, Chunyu Jiang, Jiatian Liang, Qin Zhou, Yuhao Liu, Zhiyu Hao, Yuhang Liu, Xiumei Liu, Xiaohua Teng, Wei Sun, You Tang.
      Background/Objectives: In 4-octylphenol (4-OP), a toxic environmental pollutant with endocrine disruptive effect, the use of 4-OP causes pollution in the freshwater environment and poses risks to aquatic organisms. Common carps (Cyprinus carpio L.) live in freshwater and are experimental animals for studying the toxic effects of environmental pollutants on fish. Its heart is susceptible to toxicants. However, whether 4-OP has a toxic effect on common carp heart remains unknown. Methods: Here, we conducted a common carp 4-OP exposure experiment (carp treated with 17 μg/L 4-OP for 45 days), aiming to investigate whether 4-OP has a toxic effect on common carp hearts. We observed the microstructure and ultrastructure of carp heart and detected autophagy genes, mitochondrial fission genes, mitochondrial fusion genes, glycolytic enzymes, AMPK, ATPase, and oxidative stress factors, to investigate the molecular mechanism of 4-OP induced damage in common carp hearts. Results: Our results showed that 4-OP exposure caused mitochondrial damage, autophagy, and damage in common carp hearts. 4-OP exposure increased the levels of miR-144, and eight autophagy factors (Beclin1, RB1CC1, ULK1, LC3-I, LC3-II, ATG5, ATG12, and ATG13), and decreased the levels of four autophagy factors (PI3K, AKT, mTOR, and SQSTM1). Furthermore, 4-OP exposure induced the imbalance between mitochondrial fission and fusion and mitochondrial dynamics imbalance, as demonstrated by the increase in three mitochondrial fission factors (Mff, Drp1, and Fis1) and the decrease in three mitochondrial fusion factors (Mfn1, Mfn2, and Opa1). Moreover, excess 4-OP treatment caused energy metabolism disorder, as demonstrated by the reduction in four ATPase (Na+K+-ATPase, Ca2+Mg2+-ATPase, Ca2+-ATPase, and Mg2+-ATPase), elevation in four glycolysis genes (HK1, HK2, LDHA, and PGK1), reduction in glycolysis gen (PGAM2), and the elevation in energy-sensing AMPK. Finally, 4-OP treatment induced the imbalance between antioxidant and oxidant and oxidative stress, as demonstrated by the increase in oxidant H2O2, and the decreases in five antioxidant factors (CAT, SOD, T-AOC, Nrf2, and HO-1). Conclusions: miR-144 mediated autophagy by targeting PI3K, mTOR, and SQSTM1, and the miR-144/PI3K-AKT-mTOR/ULK1 pathway was involved in 4-OP-induced autophagy. Mff-Drp1 axis took part in 4-OP-caused mitochondrial dynamics imbalance, and mitochondrial dynamics imbalance mediated autophagy via Mfn2-SQSTM1, Mfn2/Beclin1, and Mff-LC3-II axes. Energy metabolism disorder mediated mitochondrial dynamics imbalance through the AMPK-Mff-Drp1 pathway. Oxidative stress mediated energy metabolism disorder via the H2O2-AMPK axis. Taken together, oxidative stress triggered energy metabolism disorder, induced mitochondrial dynamics imbalance, and caused autophagy via the H2O2-AMPK-Mff-LC3-II pathway. Our study provided references for the toxic effects of endocrine disruptor on common carp hearts, and provided a basis for assessing environmental pollutant-induced damage in common carp heart. We only studied the toxic effects of 4-OP on common carp, and the toxic effects of 4-OP on other fish species need to be further studied.
    Keywords:  4-OP; autophagy; energy metabolism disorder; mitochondrial dynamics imbalance; oxidative stress
    DOI:  https://doi.org/10.3390/metabo15060391
  14. Biomaterials. 2025 Jun 18. pii: S0142-9612(25)00435-1. [Epub ahead of print]324 123516
    Bone marrow microenvironment-responsive polymeric-drug/siRNA regulates leukemia stem cells assisting for prevention of AML relapse.
    Shihong Cheng, Xiaohan Kong, Yiqiu Zhang, Jianing Gong, Han Wang, Wei Duan, Chujie Li, Xiyan Wang, Yan Xiao, Qiyue Wang, Yang Liu.
      Acute myeloid leukemia (AML) remains a formidable hematological malignancy with a poor prognosis, largely due to the limited success of existing treatments in effectively targeting leukemia stem cells (LSCs). These cells are adept at migrating into hypoxic niches within the bone marrow, thereby evading chemotherapeutic agents and retaining their stem-like properties. This evasion facilitates their survival and subsequent regeneration following treatment, significantly contributing to disease relapse and highlighting the need for novel therapeutic interventions. Herein, we present the development of an innovative polymer-drug/siRNA delivery system engineered to respond to hypoxic microenvironments within the bone marrow. This system enables the precision co-delivery of the CXCR4 antagonist plerixafor and siRNA targeting mitochondrial fission protein 1 (Fis1), which induces mitophagy to LSCs. By disrupting the CXCR4/CXCL12 axis and downregulating Fis1 expression, the system effectively impedes LSCs migration and concurrently suppresses mitochondrial autophagy, thereby diminishing the stemness of LSCs. Our findings demonstrate that this dual-action delivery system (PPLazo/siFis1@C) significantly enhances the efficacy of conventional chemotherapeutic agents by concurrently inhibiting LSCs migration and impairing stemness. This integrative therapeutic strategy, which targets both the displacement and self-renewal capacity of LSCs, holds significant promise for improving outcomes in AML relapse treatment.
    Keywords:  AML relapse; Bone marrow targeting; Combination therapy; Mitophagy inhibition; Polymer-drug/siRNA delivery system
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123516
  15. Autophagy. 2025 Jun 26.
    Classical swine fever virus hijacks ESCRT-III and VPS4A to promote phagophore closure for accelerating mitophagy.
    Yan Cheng, Yuhang Li, Xiaoqing Bi, Jinxia Chen, Bingqian Zhao, Jishan Bai, Yinbo Ye, Qi Dai, Linke Zou, Jing Chen, Xiuli Feng, Bin Zhou.
      Classical swine fever virus (CSFV) infection induces complete mitophagy, which is essential for the clearance of damaged mitochondria. The endosomal sorting complex required for transport (ESCRT) machinery plays a vital role in mediating phagophore closure and autophagosome-lysosome fusion during starvation-induced autophagy. Nevertheless, its involvement in CSFV-induced mitophagy and the underlying mechanisms remain insufficiently understood. Here, we found that the ESCRT-III subunits including CHMP1A, CHMP1B, and CHMP4B, along with the AAA-ATPase VPS4, were actively recruited to autophagosomes during CSFV-induced mitophagy. Consistent with this, depletion of CHMP1A, CHMP1B, CHMP4B or VPS4A disrupted mitophagic flux, impairing both PINK1-PRKN-dependent and -independent pathways. Further investigations revealed that CSFV transiently recruited these subunits to nascent autophagosomes for phagophore sealing during mitophagy. Remarkably, multiple CSFV nonstructural proteins (NSPs) including NS3, NS4B, NS5A and NS5B interacted with these ESCRT key subunits and colocalized on mitophagosomes. Taken together, our study identifies CHMP1A, CHMP1B, CHMP4B, and VPS4A as pivotal regulators of phagophore closure in CSFV-induced mitophagy, unveiling novel mechanisms by which the virus manipulates host cellular pathways and highlighting potential therapeutic targets for infection control.
    Keywords:  Autophagosomes; CSFV; ESCRT; mitophagy; phagophore closure; viral non-structural proteins
    DOI:  https://doi.org/10.1080/15548627.2025.2523734
  16. Gen Physiol Biophys. 2025 Jul;44(4): 317-326
    Worenine enhances the sensitivity of non-small cell lung cancer A549/DDP cells to cisplatin via HIF-1α/BNIP3-mediated mitophagy.
    Guobiao Yang, Mengmin Xu, Mingliang Wu, Ya Zhang, Feiyan Yang.
      Mitophagy has been implicated in chemoresistance in various cancers. Worenine, an active compound derived from Coptidis rhizome, has exhibited anti-tumor activity. We aimed to clarify the impacts of worenine on regulating the cisplatin (DDP) sensitivity and mitophagy in DDP-resistant non-small cell lung cancer (NSCLC) cells. The DDP-resistant NSCLC cell line (A549/DDP) were established via exposure to escalating DDP concentrations. Its resistance characteristics were confirmed by CCK-8 and flow cytometry assays. Moreover, the effects of worenine and/or DDP on the A549/DDP cells viability, colony formation abilities, apoptosis, and mitophagy-related proteins were evaluated. The A549/DDP cells were successfully established, with markedly higher IC50 value than A549 cells (25.67 μM vs. 9.555 μM). We noted that the HIF-1α/BNIP3-mediated mitophagy was clearly activated in A549/DDP cells. Worenine decreased A549/DDP cell viability and colony formation abilities, promoted apoptosis, and suppressed HIF-1α/BNIP3-mediated mitophagy. Importantly, worenine enhanced the responsiveness of A549/DDP cells to DDP. Besides, the suppressive impacts of worenine on A549/DDP cells were reversed by HIF-1α overexpression. Our findings indicate that worenine may enhance the sensitivity of A549/DDP cells to DDP via suppressing HIF-1α/BNIP3-mediated mitophagy. Targeting mitophagy may be a promising therapeutic strategy for addressing chemoresistance in NSCLC.
    DOI:  https://doi.org/10.4149/gpb_2025012
  17. Clin Sci (Lond). 2025 Jun 23. pii: CS20180510_RET. [Epub ahead of print]139(12):
    Retraction: Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury.
      
    DOI:  https://doi.org/10.1042/CS20180510_RET
  18. Antioxid Redox Signal. 2025 Jun 27.
    Uric Acid Stimulates PINK1/Parkin-Mediated Mitophagy via Nrf2/HO-1 Pathway to Protect Against Neuronal Apoptosis in Alzheimer's Disease.
    Qian Zhang, De Xie, Binyang Chen, Linqian Yu, Jiayu Chen, Yunbo Yan, Mingyan Zhang, Qiang Wang, Yuemei Xi, Tetsuya Yamamoto, Hidenori Koyama, Jidong Cheng.
      Aims: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly. Uric acid (UA), the end product of purine metabolism, functions as a potent free radical scavenger and helps mitigate oxidative stress. Several epidemiological studies revealed that serum UA levels are negatively correlated with the risk of AD; however, the molecular mechanisms remain unclear. Notably, β-amyloid (Aβ) deposition is implicated in the disruption of mitophagy, leading to neuronal apoptosis. In this study, we aim to elucidate the link between UA and AD and explore the underlying mechanisms. Results: We demonstrated that UA improved cognitive impairment in 5×FAD mice and reduced neuronal apoptosis both in vivo and in vitro. UA reversed the expression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), p-ParkinS65, parkin, microtubule-associated protein 1 light chain 3 II/I, and p62 proteins inhibited by Aβ treatment, alleviated Aβ induced mitochondrial dysfunction, and disturbed dynamics. We found that UA activated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1(HO-1) signaling both in vivo and in vitro. Furthermore, ML385, a Nrf2-specific inhibitor, reversed the increase in mitochondrial membrane potential and mitophagy promoted by UA and increased neuronal apoptosis in HT22 cells. The antiapoptotic effects of UA in HT22 cells were prevented by treatment with small interfering RNAs targeting PINK1. Conclusions and Innovation: These data suggest that UA stimulates PINK1/parkin-mediated mitophagy reducing Aβ-induced neuronal apoptosis through the Nrf2/HO-1 pathway, which plays a neuroprotective role in AD. Our findings confirmed that UA effectively reduces neuronal damage and cognitive impairment, highlighting its potential clinical applications in the treatment of AD. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  Alzheimer’s disease; Nrf2/HO-1/PINK1/parkin pathway; apoptosis; mitophagy; uric acid
    DOI:  https://doi.org/10.1089/ars.2024.0837
  19. Biochem Biophys Res Commun. 2025 Jun 24. pii: S0006-291X(25)00969-6. [Epub ahead of print]777 152254
    Mitophagy: A double-edged sword in tumor cell death regulation and therapeutic response.
    Tong Chu, Zifeng Huang, Wenzhe Ma.
      Mitophagy, a core mechanism governing cellular homeostasis, plays dual roles in tumorigenesis and therapeutic response by selectively eliminating damaged mitochondria. This review systematically summarizes the molecular mechanisms of mitophagy mediated by receptor-dependent ubiquitin-independent pathways and ubiquitin-dependent pathways, and explores their intricate crosstalk with tumor cell death modalities. Mitophagy dynamically regulates mitochondrial quality to modulate the progression of apoptosis, ferroptosis, necroptosis, immunogenic cell death (ICD), and pyroptosis. Notably, mitophagy exhibits context-dependent roles in tumors: moderate activation suppresses tumor growth by clearing carcinogen-damaged mitochondria, whereas excessive activation may directly induce cell death via functional mitochondrial depletion or synergize with chemotherapy to amplify tumor eradication. Furthermore, this review highlights the challenges in therapeutic strategies targeting the mitophagy-tumor death axis, emphasizing the potential of spatiotemporal-specific regulation and combinatorial interventions across distinct death pathways, thereby providing a theoretical framework for precision oncology.
    Keywords:  Cellular homeostasis; Mitophagy; Tumor cell death; Ubiquitin-dependent pathways; Ubiquitin-independent pathways
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152254
  20. Clin Sci (Lond). 2025 Jun 23. pii: CS20190014_RET. [Epub ahead of print]139(12):
    Retraction: Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury.
      
    DOI:  https://doi.org/10.1042/CS20190014_RET
  21. Mol Cell Endocrinol. 2025 Jun 24. pii: S0303-7207(25)00157-1. [Epub ahead of print] 112606
    Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission.
    Ying He, Xiaoyan Li, Dan Kuai, Huiying Zhang, Yingmei Wang, Kan Wang, Wenyan Tian.
      Targeted metabolomics and ELISAs shown that Mdivi-1 treatment increased the levels of steroid hormones (progesterone and estradiol) in the supernatants of KGN cell culture medium. The purpose of this study was to explore the mechanism of Mdivi-1 promoting steroid hormone synthesis in granulosa cells (GCs). In vitro experiments revealed that Mdivi-1 did not affect the total protein expression of Drp1 in KGN cells or human luteinized GCs but increased Drp1 Ser637 phosphorylation, reduced Drp1 Ser616 phosphorylation, inhibited Drp1 mitochondrial translocation, and upregulated mitochondrial fusion proteins, promoting mitochondrial fusion. In terms of energy production, Mdivi-1 increased the expression of mitochondrial complexes I and V and the ATP concentration in GCs, increasing the energy supply for steroidogenesis. Mdivi-1 exposure significantly increased the expression and mitochondrial localization of StAR and CYP11A1 in the steroid production pathway of GCs. Further in vivo experiments demonstrated that, compared with the controls, Mdivi-1 treatment significantly increased the levels of Drp1 Ser637, StAR and CYP11A1 in ovarian tissue and the serum levels of progesterone and estradiol. Taken together, these findings suggest that Mdivi-1 induces mitochondrial fusion by increasing Drp1 phosphorylation at Ser637 and weakening the interaction between Drp1 and mitochondria. Moreover, mitochondrial fusion increases the cellular bioenergetics and the expression of StAR and CYP11A1 as well as their mitochondrial localization, thereby enhancing the activity of steroidogenesis in GCs.
    Keywords:  Drp1 phosphorylation; Granulosa cells; Mdivi-1; Mitochondrial dynamics; Steroidogenesis
    DOI:  https://doi.org/10.1016/j.mce.2025.112606
  22. Sheng Li Xue Bao. 2025 Jun 25. 77(3): 523-533
    [Mechanisms of mitochondrial dynamics in ischemic stroke and therapeutic strategies].
    Xin-Yue Zheng, Ming Zhang, Kai-Qi Su, Zhi-Min Ding.
      As a common neurological disease in China, stroke has an extremely high rate of death and disability, of which 80% is ischemic stroke (IS), causing a serious burden to individuals and society. Neuronal death is an important factor in the pathogenesis of stroke. Studies have shown that mitochondrial dynamics, as a key mechanism regulating intracellular energy metabolism and cell death, plays an important role in the pathogenesis of IS. In recent years, targeting mitochondrial dynamics has become an emerging therapeutic tool to improve neurological impairment after stroke. This paper reviews the research advance in recent years in IS mitochondrial dynamics, summarizing and discussing the overview of mitochondrial dynamics, the role of mitochondrial dynamics in IS, and the studies on mitochondrial dynamics-based treatment of IS. This paper helps to explore the mechanism of the role of mitochondrial dynamics in IS and effective interventions, and provides a theoretical strategy for targeting mitochondrial dynamics to treat IS in the clinic.
    DOI:  https://doi.org/10.13294/j.aps.2025.0003
  23. BioTech (Basel). 2025 Jun 05. pii: 43. [Epub ahead of print]14(2):
    Interaction Between Rumen Microbiota and Epithelial Mitochondrial Dynamics in Tibetan Sheep: Elucidating the Mechanism of Rumen Epithelial Energy Metabolism.
    Ying Xu, Yuzhu Sha, Xiaowei Chen, Qianling Chen, Xiu Liu, Yanyu He, Wei Huang, Yapeng He, Xu Gao.
      Investigating the functional interactions between rumen microbial fermentation and epithelial mitochondrial dynamics/energy metabolism in Tibetan sheep at different altitudes, this study examined ultrastructural changes in rumen epithelial tissues, expression levels of mitochondrial dynamics-related genes (fusion: Mfn1, Mfn2, OPA1, Mic60; fission: Drp1, Fis1, MFF), and ketogenesis pathway genes (HMGS2, HMGCL) in Tibetan sheep raised at three altitudes (TS 2500m, TS 3500m, TS 4500m). Correlation analysis was performed between rumen microbiota/metabolites and mitochondrial energy metabolism. Results: Ultrastructural variations were observed across altitudes. With increasing altitude, keratinized layer became more compact; desmosome connections between granular layer cells increased; mitochondrial quantity and distribution in spinous and basal layers increased. Mitochondrial dynamics regulation: Fission genes (FIS1, DRP1, MFF) showed significantly higher expression at TS 4500m (p < 0.01); fusion genes (Mfn1, OPA1) exhibited altitude-dependent upregulation. Energy metabolism markers: Pyruvate (PA) decreased significantly at TS 3500m/TS 4500m (p < 0.01); citrate (CA) increased with altitude; NAD+ peaked at TS 3500m but decreased significantly at TS 4500m (p < 0.01); Complex II (SDH) and Complex IV (CO) activities decreased at TS 4500m (p < 0.01). Ketogenesis pathway: β-hydroxybutyrate increased significantly with altitude (p < 0.01); acetoacetate peaked at TS 2500 m/TS 4500 m; HMGCS2 expression exceeded HMGCL, showing altitude-dependent upregulation at TS 4500m (p < 0.01). Microbiome-metabolism correlations: Butyrivibrio_2 and Fibrobacter negatively correlated with Mic60 (p < 0.01); Ruminococcaceae_NK4A214_Group positively correlated with Mfn1/OPA1 (p < 0.05); WGCNA identified 17 metabolite modules, with MEturquoise module positively correlated with DRP1/Mfn2/MFF (p < 0.05). Conclusion: Altitude-induced ultrastructural adaptations in rumen epithelium correlate with mitochondrial dynamics stability and ketogenesis upregulation. Mitochondrial fission predominates at extreme altitudes, while microbiota-metabolite interactions suggest compensatory energy regulation mechanisms.
    Keywords:  Tibetan sheep; energy metabolism; microorganisms; mitochondria; rumen
    DOI:  https://doi.org/10.3390/biotech14020043
  24. Toxics. 2025 Jun 09. pii: 487. [Epub ahead of print]13(6):
    Intratracheal Administration of Polystyrene Micro(nano)plastics with a Mixed Particle Size Promote Pulmonary Fibrosis in Rats by Activating TGF-β1 Signaling and Destabilizing Mitochondrial Dynamics and Mitophagy in a Dose- and Time-Dependent Manner.
    Shuang Xia, Chunli Yuan, Wei Long, Zongcheng Wu, Xiuqin Li, Nan Wang, Mumu Gao, Zhe Li, Peilun Li, Peng Liu, Xiaoxi Qu, Lina Sun.
       BACKGROUND: Microplastics (MPs) can be inhaled by people. However, the relationships between long-term exposure to inhaled MPs, pulmonary fibrosis, and mitochondrial dysfunction are not completely clear.
    METHODS: SD rats were exposed to a 0.0125, 0.125, 0.31, or 1.25 mg/day dosage of mixed polystyrene MPs (PS-MPs), with the particle sizes ranging from 500 nm to 4 µm, via intratracheal administration, for 7 to 35 consecutive days.
    RESULTS: PS-MPs with particle sizes ranging from 1 µm to 4 µm were deposited in the lungs. The contents of NFκB-mediated proinflammatory cytokines were increased in the lungs of the rats after 7 days of PS-MP exposure. After exposure to PS-MPs, the degree of collagen deposition and the expression of TGF-β1/Smad increased significantly, and the levels of phosphorylated Akt (p-Akt) and nuclear β-catenin decreased significantly. The number of healthy mitochondria decreased, the expression of mitochondrial fission and fusion proteins increased, and the level of PINK1/Parkin-mediated mitophagy decreased in the lungs of the rats after 7 days of PS-MP exposure. A benchmark dose (BMD) of 0.151 mg/day and a benchmark dose lower confidence limit (BMDL) of 0.031 mg/day were identified on the basis of the subchronic effects of the intratracheal administration of the PS-MPs.
    CONCLUSIONS: Our study provides an in-depth understanding of the potential impacts of MP pollution on respiratory diseases.
    Keywords:  benchmark dose; inflammation; microplastics; mitochondrial dynamics; mitophagy; pulmonary fibrosis
    DOI:  https://doi.org/10.3390/toxics13060487
  25. Cytokine. 2025 Jun 22. pii: S1043-4666(25)00125-5. [Epub ahead of print]193 156978
    Role of FGF19 in regulating mitochondrial dynamics and macrophage polarization through FGFR4/AMPKα-p38/MAPK Axis in bleomycin-induced pulmonary fibrosis.
    Yang Li, Hong Zhang, Bing Li, Xin Yi, Xinri Zhang.
       BACKGROUND: In the bleomycin (BLM)-induced pulmonary fibrosis model, macrophage polarization and mitochondrial dynamic imbalance are critical drivers of fibrogenesis. Although fibroblast growth factor 19 (FGF19) has been reported to alleviate fibrosis, its mechanism of regulating mitochondrial dynamics and macrophage polarization through the FGFR4/AMPKα-p38/MAPK axis remains unclear.
    OBJECTIVE: To investigate whether FGF19 mitigates alveolar epithelial injury and pulmonary fibrosis by restoring mitochondrial fusion/fission balance and modulating macrophage phenotype switching.
    METHODS: A BLM-induced C57BL/6 mouse fibrosis model was employed, with lung-specific FGF19 overexpression via lentivirus. An in vitro RAW264.7 macrophage-alveolar epithelial cell coculture system was used to assess mitochondrial morphology (transmission electron microscopy), mtDNA content (qPCR), protein expression (MFN1/2, Drp1-pSer616; Western blot), and macrophage polarization (flow cytometry). Pharmacological inhibition (SB203580, a p38/MAPK inhibitor) and MFN1/MFN2 siRNA knockdown were applied to validate pathway specificity.
    RESULTS: (1) FGF19 overexpression significantly attenuated BLM-induced alveolar destruction, collagen deposition, and inflammatory infiltration (H&E, P < 0.01); (2) FGF19 activated the FGFR4/AMPKα-p38/MAPK pathway, upregulated mitochondrial fusion proteins MFN1/2 (P < 0.01), suppressed Drp1 phosphorylation (Ser616)-mediated fission (P < 0.05), and shifted macrophages toward an M2 phenotype (CD206↑, P < 0.01); (3) p38/MAPK inhibition or MFN1/2 knockdown reversed FGF19-driven M2 polarization (P < 0.01); (4) FGF19 reduced alveolar epithelial apoptosis (Annexin V-FITC, P < 0.01) and inflammatory cytokine release (TNF-α, IL-6; ELISA, P < 0.01) by inhibiting M1 polarization.
    CONCLUSION: FGF19 alleviates pulmonary fibrosis by restoring mitochondrial dynamics via the FGFR4/AMPKα-p38/MAPK axis, thereby inhibiting M1 macrophage polarization and epithelial injury. These findings highlight FGF19 as a potential therapeutic target for antifibrotic interventions.
    Keywords:  AMPKα-p38/MAPK axis; Alveolar epithelial injury; FGF19/FGFR4; Macrophage polarization; Mitochondrial dynamics; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.cyto.2025.156978
  26. Front Pharmacol. 2025 ;16 1525028
    Mitochondrial fission inhibitor Mdivi-1 alleviates lipopolysaccharide-induced parvalbumin interneurons dysregulation and cognitive impairments in a mouse model of sepsis-associated encephalopathy.
    Lei Dai, Shuxin Gu, Yibao Zhang, Siqi Ma, Peishan Wang, Jingyun Zhang, Cai Wang, Gaowei Su, Qun Fu, Wei Zhou, Yunxia Fan.
       Introduction: Dysregulation of parvalbumin (PV) interneurons has been implicated in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain poorly understood, and effective treatments are lacking. Given the high energy demands of PV interneurons and the emerging role of mitochondrial dynamics in SAE pathophysiology, this study aimed to investigate whether the mitochondrial fission inhibitor Mdivi-1 could alleviate PV interneuron dysfunction and cognitive impairments in a mouse model of SAE.
    Methods: C57BL/6 male mice were injected with lipopolysaccharide (LPS) to establish an animal model of SAE. Mdivi-1 was administered intraperitoneally 1 h before LPS challenge. Hippocampal tissues were harvested 24 h after LPS challenge for biochemical and histochemical analyses, and mitochondrial morphology was evaluated using transmission electron microscopy. In vivo electrophysiology and behavioral tests were performed between 2 and 4 days after LPS challenge to measure neural oscillations in the hippocampus and assess cognitive function.
    Results: Our results showed that LPS induced neuroinflammation, mitochondrial fission abnormalities, ATP depletion, and downregulation of PV interneurons in the hippocampus, collectively contributing to reduced gamma oscillations and cognitive impairments in mice. However, these effects were mitigated by Mdivi-1 treatment.
    Conclusion: Our study suggests that Mdivi-1 may offer a promising therapeutic approach for attenuating PV interneurons dysfunction and cognitive impairments in SAE.
    Keywords:  Mdivi-1; cognitive impairment; neuroinflammation; parvalbumin interneurons; sepsis-associated encephalopathy
    DOI:  https://doi.org/10.3389/fphar.2025.1525028
  27. Autophagy. 2025 Jun 26.
    A classical anti-autophagic viral protein reshapes mitochondria for immune evasion.
    Qing Zhu, Chengyu Liang.
      Viral subversion of macroautophagy/autophagy is a well-established immune evasion strategy, with BCL2 homologs from γ-herpesviruses serving as prototypical inhibitors through BECN1 (beclin 1) sequestration. Yet the full spectrum of their functions remains incompletely understood. In our recent study, we uncovered a non-canonical role for the Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded BCL2 homolog (vBCL2) during late lytic replication. Unexpectedly, vBCL2 hijacks the host NDP kinase NME2/NM23-H2 to activate the mitochondrial fission GTPase DNM1L/DRP1, promoting mitochondrial fragmentation. This organelle remodeling dismantles MAVS-mediated antiviral signaling and facilitates virion assembly. A vBCL2 mutant unable to bind NME2 fails to induce fission or complete the viral lifecycle. These findings provide a long-sought answer to why vBCL2 is indispensable during lytic infection, and uncover a new immune evasion strategy centered on mitochondrial control. Our work expands the current view of virus-organelle interactions beyond canonical autophagy control and offers new targets for therapeutic intervention.
    Keywords:  DRP1; NM23-H2; herpesvirus; innate immunity; mitochondrial fission; vBCL2
    DOI:  https://doi.org/10.1080/15548627.2025.2522130
  28. Sheng Li Xue Bao. 2025 Jun 25. 77(3): 419-431
    [Exercise preconditioning alleviates motor deficits in MPTP-induced Parkinsonian mice by improving mitochondrial function].
    Miao-Miao Xu, Dan-Ting Hu, Qiao Zhang, Xiao-Guang Liu, Zhao-Wei Li, Li-Ming Lu.
      Parkinson's disease (PD) is a common neurodegenerative disorder mainly related to mitochondrial dysfunction of dopaminergic neurons in the midbrain substantia nigra. This study aimed to investigate the effects of exercise preconditioning on motor deficits and mitochondrial function in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Eight-week-old male C57BL/6J mice were randomly divided into four groups: sedentary + saline (SS), sedentary + MPTP (SM), exercise + saline (ES), and exercise + MPTP (EM) groups. Mice in the ES and EM groups received 4 weeks of treadmill training, and then SM and EM groups were treated with MPTP for 5 days. Motor function was assessed by behavioral tests, and morphological and functional changes in dopaminergic neurons and mitochondria in the substantia nigra of the midbrain were evaluated using immunohistochemistry, Western blot, and transmission electron microscopy technology. The results showed that, compared with the SM group, the EM group exhibited significantly improved motor ability, up-regulated protein expression levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the midbrain, and down-regulated protein expression of α-synuclein (α-Syn) in the mitochondria of substantia nigra. Compared with the SM group, the EM group showed up-regulated protein expression levels of mitochondrial fusion proteins, including optical atrophy protein 1 (OPA1) and mitofusin 2 (MFN2), and biogenesis-related proteins, including peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), while the protein expression levels of dynamin-related protein 1 (DRP1) and mitochondrial fission protein 1 (FIS1) were significantly down-regulated. Compared with the SM group, the EM group showed significantly reduced damage to substantia nigra mitochondria, restored mitochondrial membrane potential and ATP production, and decreased levels of reactive oxygen species (ROS). These results suggest that 4-week treadmill pre-training can alleviate MPTP-induced motor impairments in PD mice by improving mitochondrial function, providing a theoretical basis for early exercise-based prevention of PD.
    DOI:  https://doi.org/10.13294/j.aps.2025.0049
  29. Toxins (Basel). 2025 Jun 09. pii: 293. [Epub ahead of print]17(6):
    Lipopolysaccharide Induces Mitochondrial Fragmentation and Energetic Shift in Reactive Microglia: Evidence for a Cell-Autonomous Program of Metabolic Plasticity.
    Marcelle Pereira Dos Santos, Vitor Emanuel Leocadio, Lívia de Sá Hayashide, Mariana Marques, Clara Fernandes Carvalho, Antonio Galina, Luan Pereira Diniz.
      Microglia, the resident immune cells of the central nervous system (CNS), play essential roles in maintaining brain homeostasis. While transient activation is protective, chronic microglial reactivity contributes to neuroinflammatory damage and neurodegeneration. The mitochondrial mechanisms underlying this shift remain poorly understood. Here, we investigated whether lipopolysaccharide (LPS) induces coordinated mitochondrial and metabolic alterations in BV-2 microglial cells. LPS stimulation (100 ng/mL, 24 h) induced a reactive phenotype, with increased Iba1 (+82%), F4/80 (+132%), and Cd68 (+44%), alongside elevated hydrogen peroxide (~6-fold) and nitrite (~45-fold). Cytotoxicity increased by 40% (LDH assay), and cell viability dropped to ~80% of the control (MTT). Extracellular lactate increased, indicating glycolytic reprogramming. However, LPS-primed cells showed greater ATP depletion under antimycin A challenge, reflecting impaired metabolic flexibility. Hoechst staining revealed a ~4-fold increase in pyknotic nuclei, indicating apoptosis. Mitochondrial dysfunction was confirmed by a 30-40% reduction in membrane potential (TMRE, JC-1), a ~30% loss of Tomm20, and changes in dynamics: phospho-Drp1 increased (+23%), while Mfn1/2 decreased (33%). Despite a ~70% rise in Lamp2 signal, Tomm20-Lamp2 colocalization decreased, suggesting impaired mitophagy. High-resolution respirometry revealed decreased basal (-22%), ATP-linked (24%), and spare respiratory capacity (41%), with increased non-mitochondrial oxygen consumption. These findings demonstrate that LPS induces mitochondrial dysfunction, loss of metabolic adaptability, and increased apoptotic susceptibility in microglia. Mitochondrial quality control and energy flexibility emerge as relevant targets to better understand and potentially modulate microglial responses in neuroinflammatory and neurodegenerative conditions.
    Keywords:  BV-2 Cell Line; LPS; central nervous system; energetic failure; metabolic dysfunction; microglia; mitochondrial fragmentation; mitophagy; neuroinflammation; nitric oxide; reactive oxygen species
    DOI:  https://doi.org/10.3390/toxins17060293
  30. Free Radic Biol Med. 2025 Jun 24. pii: S0891-5849(25)00789-0. [Epub ahead of print]
    "Therapeutic Transplantation of Mitochondria and Extracellular Vesicles: Mechanistic Insights into mitochondria bioenergetics, redox signaling, and organelle dynamics in preclinical models".
    Quentin Perrier, Veronica Lisi, Kelsey Fisherwellman, Sandrine Lablanche, Amish Asthana, Giuseppe Orlando, Sophie Maiocchi.
      Mitochondrial and extracellular vesicles (EV) transplantation have emerged as promising therapeutic strategies targeting mitochondrial dysfunction, a central feature of numerous pathologies. This review synthesizes preclinical data on artificial mitochondrial and EV transfer, emphasizing their therapeutic potential and underlying mechanisms. A systematic analysis of 123 animal studies revealed consistent benefits across diverse models, including ischemia-reperfusion injury (IRI), neurological disorders, drug-induced toxicities, and sepsis. Mitochondrial transfer improved organ function, reduced inflammation and apoptosis, and enhanced survival. Mechanistic insights revealed restored bioenergetics, increased oxidative phosphorylation, redox balance through activation of specific pathways, and modulation of mitochondrial dynamics via fusion/fission proteins. Mitochondrial homeostasis was supported through elevated mitophagy and biogenesis, alongside the preservation of mitochondrial-associated membranes. EV demonstrated similar effects, offering a potentially more targeted therapeutic alternative. Although pre-clinical studies have demonstrated safety and feasibility, broader application is limited by variability in isolation methods, lack of mechanistic clarity, and minimal human data. Standardization and mechanistic validation are critical to advance clinical translation. This review underscores the therapeutic promise of mitochondrial and EV transfer while highlighting the need for continued research to refine these interventions and unlock their full potential in regenerative medicine.
    Keywords:  Artificial Mitochondrial transfer; Extracellular vesicles; Microvesicles; Mitochondrial Transplantation; Pre-clinical data; Therapeutic; Treatment
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.040
  31. Cells. 2025 Jun 06. pii: 853. [Epub ahead of print]14(12):
    Induced Mitophagy Promotes Cell Cycle Re-Entry in Adult Cardiomyocytes.
    Rafeeq P H Ahmed, Onur Kanisicak, Perwez Alam.
      Background: The limited regenerative capacity of adult mammalian cardiomyocytes (CMs) poses a significant challenge for cardiac repair following myocardial infarction. In contrast to adult mammals, CMs in zebrafish and newt hearts retain a lifelong capacity for proliferation and cardiac regeneration. Likewise, neonatal mice exhibit a brief postnatal period, during which CMs retain the ability to proliferate and contribute to myocardial repair, which markedly diminishes within the first week of life. Emerging evidence indicates that adult CM cell cycle progression is critically influenced by oxidative stress. Adult mammalian CMs possess a high mitochondrial content to meet their substantial energy demands. However, this also leads to elevated reactive oxygen species (ROS) production, resulting in DNA damage and subsequent cell cycle arrest. We hypothesize that reducing the mitochondrial content in adult CMs will mitigate ROS production, thereby facilitating cell cycle progression. Methods: Adult CMs were isolated from adult rats (≥12 weeks old). To induce mitophagy, adult CMs were transfected with parkin-expressing plasmid and then treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a mitochondrial protonophore, for 7 days. Post-treatment assessments included the quantification of adult CM proliferation, mitochondrial content, and ROS levels. Results: CCCP-treated adult CMs exhibited a significant increase in proliferation markers, including EdU incorporation, KI67, phospho-histone H3, and Aurora B. Furthermore, CCCP treatment significantly reduced the mitochondrial content, as evidenced by decreased MitoTracker, TMRM, and Tom20 staining compared to controls. This was accompanied by electron microscopy analysis, which showed a significant reduction in the mitochondrial number in the adult CM after CCCP treatment. Moreover, our results also demonstrate a marked reduction in oxidative stress, demonstrated by lower 123-dihydro-rhodamine (123-DHR), CellROX signals, and VDAC. Conclusions: Our findings demonstrate that CCCP-mediated mitochondrial depletion reduces oxidative stress and promotes cell cycle re-entry in adult CM. This study provides direct experimental evidence and substantiates the role of elevated mitochondria and ROS levels in adult CM cell cycle exit.
    Keywords:  adult cardiomyocyte; cell cycle; mitochondria; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/cells14120853
  32. Int J Mol Sci. 2025 Jun 10. pii: 5546. [Epub ahead of print]26(12):
    Downregulation of Mitophagy, Complex I Biogenesis, and Signaling by ROBO Receptors-Implications for Psoriasis Pathogenesis.
    Malin Assarsson, Jan Söderman, Olaf Dienus, Oliver Seifert.
      The pathogenesis of psoriasis is complex and many specific immunopathogenic mechanisms still remain unclear. Our goal was to identify novel pathways involved in the pathogenesis of psoriasis by analyzing differentially expressed genes, and to conduct pathway and cluster analysis by comparing lesional and non-lesional skin with healthy controls. Accordingly, 2 mm punch biopsies were taken from lesional elbow skin and non-affected adjacent skin of 23 patients with plaque-type psoriasis and from the elbow skin of 25 healthy controls. Differentially expressed genes were analyzed through RNA sequencing, and gene set enrichment analysis was used to analyze biological pathways. Our results showed downregulation of the pathway clusters "Mitophagy" and "Respiratory Electron Transport" when comparing both lesional and non-lesional skin to control skin. The pathway "Signaling by ROBO receptors" was downregulated in all three comparisons. Conversely, pathways relating to SUMOylation were upregulated when comparing lesional skin to both non-lesional and control skin, and those relating to the synthesis of PIPs at the early endosome membrane were found to be upregulated in lesional skin compared to control skin. The dysregulation of pathways relating to mitophagy (involved in the removal of damaged mitochondria), complex I biogenesis (a component of the mitochondrial respiratory chain), signaling by ROBO receptors (important for cell migration), and the synthesis of PIPs at the early endosome membrane (with a pivotal role in endocytic pathways and autophagy) suggests their potential role in psoriasis. Further research into the mechanisms of these dysregulated pathways, along with confirmation of protein expression levels, is necessary to validate their roles in psoriasis pathogenesis.
    Keywords:  GSEA; RNA sequencing; complex I biogenesis; mitophagy; psoriasis
    DOI:  https://doi.org/10.3390/ijms26125546
  33. J Invertebr Pathol. 2025 Jun 19. pii: S0022-2011(25)00124-7. [Epub ahead of print]212 108390
    Ameson portunus infection is associated with RK13 mitochondrial abnormalities.
    Min Zhou, Zixuan Yang, Xintong Zhang, Zhiqiang Zhu, Yali Xu, Zhaozhe Xin, Jinyong Zhang.
      Microsporidia are obligate intracellular parasites with an extremely broad host range from invertebrates to vertebrates. Although host mitochondria were proved to be critical for the intracellular survival and propagation, their precise morphological and functional variation during microsporidian infection remain largely unclear. In this study, we firstly developed a feasible approach to track microsporidia proliferation by using a live-cell fluorescent dye DiI in the Ameson portunus-RK13 model. DiI-labeled A. portunus was observed to be surround by host mitochondria at 6 hpi (hours post infection) and gradually induced mitochondrial fragmentation in RK13 cells at 8 dpi (days post infection). Ultrastructural observation further revealed some mitochondria exhibited distinct swelling, and dissolution and fragmentation of cristae. Then, RNA sequencing of A. portunus-infected and uninfected RK13 cells at 8 dpi was employed to uncover the possible mechanisms underlying these mitochondrial abnormities. GSEA analysis revealed 11 mitochondrial structure- and function-related process were upregulated upon the infection of A. portunus. The expression alteration of genes related to mitochondrial fusion and fission might contribute to mitochondrial fragmentation, and the upregulation of genes encoding the components of mitochondrial respiratory chain and ATPsynthesiscoupledprotontransport implied the increase of ATP production upon microsporidian infection. Upregulated expression of genes associated with the maintenance of mitochondrial morphology was possibly associated with mitochondrial swelling, and cristae dissolution and fragmentation. The upregulation of genes involved in mitophagy and mitochondrial protein biosynthesis was suggested to be involved in the maintenance of mitochondrial homeostasis against the infection. Collectively, our findings provide further information on the host mitochondria-involved pathophysiological responses to this microsporidian infection.
    Keywords:  Ameson portunus; DiI; Microsporidia; Mitochondria
    DOI:  https://doi.org/10.1016/j.jip.2025.108390
  34. Neurochem Res. 2025 Jun 25. 50(4): 208
    Possible Mitigating Effect of Nobiletin on Rotenone-Induced Parkinsonism in Male Albino Rat Model: Targeting Bmal1/Nrf2 Mediated Ferroptosis and Restoring Mitochondrial Mitophagy.
    Sarah Ragab Abd El-Khalik, Norhan Ahmed AbuoHashish, Elham Nasif, Heba M Arakeep, Noha El-Anwar, Doaa Mohammed Yousef, Nada Hashem Ayad.
      Ferroptosis and circadian disruption might be implicated in Parkinson disease (PD), a neurodegenerative disorder due to degeneration of dopaminergic neurons in the substantia nigra. As such, the ability to preserve mitochondrial and therefore neuronal homeostasis is essential. In PD, Nobiletin (NOB) may have neuroprotective effects. Still, further clarification is needed about the processes behind these impacts. To evaluate the positive effect of NOB against rotenone induced PD in rats via the Bmal1/ NRF2 axis regulation. Four groups of thirty-two male Albino rats were randomly assigned: Control, NOB treated, rotenone treated, and combined Rotenone and NOB treated groups. The validation of the neuroprotective potential of NOB entailed a behavioral examination, RT-PCR and colorimetric evaluation of biochemical markers, as well as immunohistopathological study of brain tissues. The relative gene expression of Bmal1 increased with NOB therapy significantly reducing the circadian rhythm disruption. Furthermore, as shown by the elevated Nrf2-DNA binding activity, increased levels of GPx4, and decreased levels of GSH with comparable low levels of MDA and Fe+2 in the brain tissue, NOB ameliorated oxidative stress and ferroptosis. NOB stimulated both mitophagy and autophagy through the activation of Bmal1/Nrf2 pathway as characterized by upregulated expression of PINK-1 & Parkin genes and enhanced beclin-1 and LC3-II immunoreaction. This study showed that NOB ameliorated rotenone-induced PD by modulating dysregulated behavioral & cognitive dysfunction, attenuating ferroptosis & redox imbalance, and promoting mitophagy & autophagy through modulation of disrupted circadian rhythm through Bmal1/Nrf2 pathway.
    Keywords:  Circadian rhythm; Ferroptosis; Mitophagy; Nobiletin; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s11064-025-04438-3
  35. Phytomedicine. 2025 Jun 16. pii: S0944-7113(25)00621-X. [Epub ahead of print]145 156982
    Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury.
    Xiangyi Pu, Qiaomin Wu, Zhaoqi Yan, Siyuan Zhou, Qin Zhang, Xinai Zhang, Yongyuan Cai, Zhiming Liu, Ruxiu Liu, Xing Chang.
       BACKGROUND: Traditional Chinese medicine (TCM) has demonstrated significant advantages in the treatment of coronary microvascular injury, offering novel therapeutic strategies for cardiovascular diseases. Among its active compounds, Tanshinone IIA (TS) has been shown to regulate mitochondrial and endoplasmic reticulum (ER) function. However, the precise mechanisms through which TS exerts its effects, particularly via METTL3- and SIRT5-mediated unfolded protein response (UPR) pathways in microvascular endothelial cells (MECs), remain poorly understood.
    PURPOSE: This study aims to elucidate the role of SIRT5 and METTL3 in mediating the protective effects of TS on mitochondrial and ER function in MECs, focusing on the UPR pathways.
    STUDY DESIGN: Cardiomyocyte-specific knockout and transgenic mice were utilized to investigate the role of SIRT5 and METTL3. MECs from experimental groups were treated with TS, and various cellular functions were analyzed.
    METHODS: The study employed confocal microscopy, electron microscopy, JC-1 assay, MTT assay, and molecular docking techniques to assess mitochondrial and ER functions. Key markers, including mitochondrial membrane potential, protein expression (PINK1, Parkin, PERK, CHOP, and Nrf-1), and transcription levels (PGC1-α, TFAM, and ATF5), were quantified. Calcium ion levels and mitochondrial respiratory functions were also evaluated.
    RESULTS: TS treatment enhanced mitochondrial stability, restored mitochondrial membrane potential, and regulated calcium overload through METTL3- and SIRT5-mediated UPR pathways. It upregulated protective proteins (PGC1-α, TFAM, and Nrf-1) while reducing oxidative stress and ER stress markers (CHOP, PERK, and ATF5). Molecular docking confirmed a direct interaction between SIRT5 and METTL3. These changes collectively mitigated microvascular endothelial damage and normalized mitochondrial biogenesis.
    CONCLUSION: TS exerts protective effects on MECs by stabilizing mitochondrial function, alleviating calcium overload, and modulating UPR signaling via METTL3 and SIRT5.
    Keywords:  Endothelial protection; METTL3; Mitochondrial function; SIRT5; Tanshinone iia; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.phymed.2025.156982
  36. Eur J Pharmacol. 2025 Jun 18. pii: S0014-2999(25)00612-0. [Epub ahead of print]1002 177858
    Calcitriol deficiency reduces myocardial ATP production with disturbed mitochondrial dynamics and increased uncoupling protein 2 expression.
    Ting-Wei Lee, Ting-I Lee, Satoshi Higa, Yu-Hsun Kao, Yi-Jen Chen.
      Vitamin D deficiency and myocardial ATP depletion are associated with heart failure. Although vitamin D may regulate mitochondrial function, its effect on cardiac ATP synthesis remains unclear. This study investigated whether calcitriol deficiency directly modulates ATP production in cardiomyocytes and explored the underlying mechanisms. Seahorse Extracellular Flux Analyzer, PCR, enzyme activity microplate assay, fluorescence staining, and immunoblotting were used to study mitochondrial bioenergetics, mitochondrial DNA copy number, citrate synthase activity, mitochondrial dynamics and morphology, mitochondrial membrane potential, and protein expressions of uncoupling protein 2 (UCP2) and Akt in HL-1 cardiomyocytes without (calcitriol deficiency) and with calcitriol (0.1 nM for 24 h). Calcitriol-deficient cardiomyocytes exhibited lower ATP production and suppressed mitochondrial respiration than calcitriol-treated cells. Calcitriol-deficient cells had fewer mitochondrial DNA copies, diminished citrate synthase activity, smaller and fragmented mitochondria, a more positive mitochondrial membrane potential as well as lower expression levels of mitofusin 1, optic atrophy 1, and phosphorylated Akt proteins, alongside higher expression levels of mitochondrial fission 1 and UCP2 proteins than calcitriol-treated cells. Akt inhibition significantly attenuated the effects of calcitriol on increasing cardiac ATP production, enhancing mitochondrial respiration, upregulating mitofusin 1 and optic atrophy 1, and downregulating mitochondrial fission 1. In conclusion, calcitriol deficiency suppresses Akt activation and subsequently alters mitochondrial dynamics. Moreover, it upregulates UCP2 expression. These effects reduce ATP production in cardiomyocytes, thus increasing the risk of heart failure.
    Keywords:  Adenosine triphosphate; Cardiomyocyte; Heart failure; Mitochondria; Vitamin D
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177858
  37. J Physiol. 2025 Jun 25.
    The role of the circadian clock in regulating mitochondrial dynamics and their impact on skeletal muscle function and metabolism.
    Alfonso Carriel-Nesvara, Cristóbal Muñoz-Medina, Louise Deldicque, Mauricio Castro-Sepulveda.
      Disruptions in both circadian clock and mitochondrial dynamics in the skeletal muscle (SkM) have been associated with insulin resistance and sarcopenia. Emerging evidence, in resting conditions and in response to metabolic challenges like exercise, suggests the intricate interplay between the circadian clock, mitochondrial dynamics and SkM function. However the molecular mechanisms that connect the circadian clock to mitochondrial dynamics and SkM function remain poorly understood. This review focuses on the role of circadian clock proteins, particularly brain and muscle Arnt-like protein-1 (BMAL1), in regulating mitochondrial dynamics and examines how their dysregulation contributes to metabolic and SkM deterioration. By exploring their interaction we aim to identify potential therapeutic targets that could improve metabolic health and muscle function.
    Keywords:  circadian clock; insulin resistance; metabolism; mitochondrial dynamics; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP289019
  38. Nat Commun. 2025 Jun 25. 16(1): 5388
    The mitochondrial methylation potential gates mitoribosome assembly.
    Ruth I C Glasgow, Vivek Singh, Lucía Peña-Pérez, Alissa Wilhalm, Marco F Moedas, David Moore, Florian A Rosenberger, Xinping Li, Ilian Atanassov, Mira Saba, Miriam Cipullo, Joanna Rorbach, Anna Wedell, Christoph Freyer, Alexey Amunts, Anna Wredenberg.
      S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
    DOI:  https://doi.org/10.1038/s41467-025-60977-x
  39. Curr Biol. 2025 Jun 23. pii: S0960-9822(25)00576-7. [Epub ahead of print]35(12): R595-R597
    MICOS.
    Karina von der Malsburg, Anastasiia Maitova, Martin van der Laan.
      von der Malsburg et al. introduce the mitochondrial contact site and cristae organizing system, a complex that localises to the inner mitochondrial membrane at crista junctions and stabilises these curved membrane domains.
    DOI:  https://doi.org/10.1016/j.cub.2025.05.001
  40. Antioxidants (Basel). 2025 Jun 17. pii: 748. [Epub ahead of print]14(6):
    Aerobic Exercise Alleviates Cardiac Dysfunction Correlated with Lipidomics and Mitochondrial Quality Control.
    Kunzhe Li, Sujuan Li, Hao Jia, Yinping Song, Zhixin Chen, Youhua Wang.
      Cardiac adaptations induced by aerobic exercise have been shown to reduce the risk of cardiovascular disease, and the autonomic nervous system is closely associated with the development of cardiovascular disease. Aerobic exercise intervention has been shown to enhance cardiac function and mitigate myocardial fibrosis and hypertrophy in heart failure mice. Further insights reveal that cardiomyocytes experiencing chronic heart failure undergo modifications in their lipidomic profile, including remodeling of multiple myocardial membrane phospholipids. Notably, there is a decrease in the total content of cardiolipin, as well as in the levels of total lysolipid CL and the CL (22:6). These alterations disrupt mitochondrial quality control processes, leading to abnormal expressions of proteins such as Drp1, MFN2, OPA1, and BNIP3, thereby resulting in a disrupted mitochondrial dynamic network. Whereas aerobic exercise ameliorated mitochondrial damage to a large extent by activating parasympathetic nerves, this beneficial effect was accomplished by modulating myocardial membrane phospholipid remodeling and restoring the mitochondrial dynamic network. In conclusion, aerobic exercise activated the parasympathetic state in mice and attenuated lipid peroxidation and oxidative stress injury, thereby maintaining mitochondrial dynamic homeostasis and improving cardiac function.
    Keywords:  aerobic exercise; heart failure; lipidomics; mitochondrial dysfunction; parasympathetic nerve
    DOI:  https://doi.org/10.3390/antiox14060748
  41. Inflammopharmacology. 2025 Jun 23.
    Parkinson's disease: exploring the systemic immune mechanisms through molecular investigations.
    Maneesh Mohan, Ashi Mannan, Thakur Gurjeet Singh.
      Parkinson's disease (PD) is a neurodegenerative disorder that is mainly caused by the degeneration of dopaminergic neurons of the substantia nigra. Although the pathological feature involves α-synuclein aggregation, recent findings suggest that systemic immune dysregulation is a key process in initiating and advancing the disease. This article seeks to untangle the complex molecular mechanisms that contribute to the immune response in PD, with specific emphasis on innate and adaptive immune processes. α-Synuclein-induced T-cell-mediated neuronal degeneration reveals a causal relationship between peripheral immunity and central neurodegeneration. At the same time, stimulation of innate immune sensors like the NLRP3 inflammasome in microglia has been found to accelerate neuroinflammation and lead to neuronal loss. Mitochondrial dysfunction, another key hallmark of PD, leads to defective mitophagy and release of mitochondrial danger-associated molecular patterns (DAMPs), further exaggerating inflammatory signals through NLRP3 and other mechanisms. Moreover, defective autophagic and lysosomal degradation machinery may perpetuate chronic inflammation and immune cell activation. Gut microbiota-gut-associated lymphoid tissue-peripheral immune cell interaction with the blood-brain barrier also comes into play as a key player in PD neuroimmune cross-talk. We specifically address therapeutic implications, focusing on the promise of immune checkpoint targeting, inhibition of inflammasomes, and mitophagy improvement as new disease-modifying approaches. Elucidation of these complex immune mechanisms offers key insights into PD pathophysiology and opens promising immunomodulatory therapeutic paths. This review integrates cutting-edge discoveries and outlines a shared model to improve understanding of the systemic immune setting in Parkinson's disease.
    Keywords:  Gut–brain axis; Mitophagy; NLRP3 inflammasome; Neuroinflammation; Parkinson’s disease; Systemic immune response; α-Synuclein
    DOI:  https://doi.org/10.1007/s10787-025-01816-9
  42. J Biol Chem. 2025 Jun 20. pii: S0021-9258(25)02256-2. [Epub ahead of print] 110406
    PLK1-mediated PDHA1 phosphorylation drives mitochondrial dysfunction, mitophagy, and cancer progression in Cr(VI)-associated lung cancer.
    Qiongsi Zhang, Jia Peng, Zhiguo Li, Xiongjian Rao, Derek B Allison, Qi Qiao, Zhuangzhuang Zhang, Yifan Kong, Yanquan Zhang, Ruixin Wang, Jinghui Liu, Xinyi Wang, Chaohao Li, Fengyi Mao, Qing Shao, Tianyan Gao, Xiaoqi Liu.
      Hexavalent chromium (Cr(VI)) is a class I environmental carcinogen that induces lung epithelial cell transformation and promotes lung cancer progression by altering cell cycle regulation and cellular energy metabolism. In this study, we investigated the role of polo-like kinase 1 (PLK1) in Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and found that PLK1 expression was significantly upregulated in these cells, leading to impaired mitochondrial function and enhanced mitophagy, which in turn stimulated cell proliferation both in vitro and in vivo. Mechanistically, we demonstrated that PLK1 directly phosphorylates the pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) at Thr57, leading to its destabilization and disruption of pyruvate dehydrogenase complex (PDHc) integrity. This modification inhibits oxidative phosphorylation (OXPHOS) and induces mitochondrial dysfunction. Furthermore, mitochondrial dysfunction triggers mitophagy and accelerates PDHA1 degradation, establishing a positive feedback loop that amplifies mitochondrial impairment and mitophagy, ultimately promoting cancer cell proliferation. These findings underscore the pivotal role of PLK1 in Cr(VI)-associated cancer progression and offer new insights into potential therapeutic targets to inhibit Cr(VI)-induced tumorigenesis.
    Keywords:  Hexavalent Chromium (Cr(VI)); Mitochondrial Dysfunction; Mitophagy; Polo-like Kinase 1 (PLK1)
    DOI:  https://doi.org/10.1016/j.jbc.2025.110406
  43. Ecotoxicol Environ Saf. 2025 Jun 18. pii: S0147-6513(25)00865-6. [Epub ahead of print]302 118520
    PPARα activation attenuated heat-induced myocardial injury in mice.
    Zhoufan Hu, Lisha Zhao, Xiaowen Ma, Ran Li, Li Qin, Lu Zhang, Tong Hou, Guoqing Zhang, Cuiqing Liu.
      With climate change and global warming, extreme heatwaves occurred with more intense and higher frequency, significantly increasing the mortality rate associated with cardiovascular diseases. Using a mouse model of heat stress, the study aimed to clarify the adverse effects on heart, elucidate the underlying mechanism and explore the potential preventative strategies. Firstly, heat stress induced significant myocardial injury, which was further exacerbated even after termination of heat exposure. Next, PPARα (Peroxisome Proliferator-Activated Receptor Alpha) was screened and its downregulation in response to heat stress was confirmed at mRNA and protein levels. Then, pre-treatment with PPARα agonist fenofibrate significantly mitigated myocardial injury, accompanied with improved mitochondrial function in the myocardial tissues. In addition, PPARα activation may restore the mitochondrial homeostasis through enhancement of both antioxidation and mitophagy. These findings will highlight the pivotal role of PPARα in alleviating heat-induced myocardial injury and cardiovascular incidence, providing valuable target for drug development to prevent/treat heat stress-related diseases.
    Keywords:  Fenofibrate; Heat stress; Mitophagy; Myocardial injury; PPARα
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118520
  44. Biomedicines. 2025 Jun 17. pii: 1489. [Epub ahead of print]13(6):
    Identification Exploring the Mechanism and Clinical Validation of Mitochondrial Dynamics-Related Genes in Membranous Nephropathy Based on Mendelian Randomization Study and Bioinformatics Analysis.
    Qiuyuan Shao, Nan Li, Huimin Qiu, Min Zhao, Chunming Jiang, Cheng Wan.
      Background: Membranous nephropathy (MN), a prevalent glomerular disorder, remains poorly understood in terms of its association with mitochondrial dynamics (MD). This study investigated the mechanistic involvement of mitochondrial dynamics-related genes (MDGs) in the pathogenesis of MN. Methods: Comprehensive bioinformatics analyses-encompassing Mendelian randomization, machine-learning algorithms, and single-cell RNA sequencing (scRNA-seq)-were employed to interrogate transcriptomic datasets (GSE200828, GSE73953, and GSE241302). Core MDGs were further validated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Results: Four key MDGs-RTTN, MYO9A, USP40, and NFKBIZ-emerged as critical determinants, predominantly enriched in olfactory transduction pathways. A nomogram model exhibited exceptional diagnostic performance (area under the curve [AUC] = 1). Seventeen immune cell subsets, including regulatory T cells and activated dendritic cells, demonstrated significant differential infiltration in MN. Regulatory network analyses revealed ATF2 co-regulation mediated by RTTN and MYO9A, along with RTTN-driven modulation of ELOA-AS1 via hsa-mir-431-5p. scRNA-seq analysis identified mesenchymal-epithelial transitioning cells as key contributors, with pseudotime trajectory mapping indicating distinct temporal expression profiles: NFKBIZ (initial upregulation followed by decline), USP40 (gradual fluctuation), and RTTN (persistently low expression). RT-qPCR results corroborated a significant downregulation of all four genes in MN samples compared to controls (p < 0.05). Conclusions: These findings elucidate the molecular underpinnings of MDG-mediated mechanisms in MN, revealing novel diagnostic biomarkers and therapeutic targets. The data underscore the interplay between mitochondrial dynamics and immune dysregulation in MN progression, providing a foundation for precision medicine strategies.
    Keywords:  machine learning; membranous nephropathy; mendelian randomization; mitochondrial dynamics; single-cell analysis
    DOI:  https://doi.org/10.3390/biomedicines13061489
  45. Antioxidants (Basel). 2025 Jun 16. pii: 741. [Epub ahead of print]14(6):
    Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy.
    José Manuel Romero-Domínguez, Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Diana Reche-López, Ana Romero-González, Mónica Álvarez-Córdoba, Alejandra López-Cabrera, Marta Castro De Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo, Angeles Aroca, José A Sánchez-Alcázar.
      Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H2S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H2S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants.
    Keywords:  ETHE1; H2S; SIRT3; bioenergetics; ethylmalonic encephalopathy; mitochondrial diseases; mtUPR; protein persulfidation
    DOI:  https://doi.org/10.3390/antiox14060741
  46. Antioxidants (Basel). 2025 Jun 12. pii: 721. [Epub ahead of print]14(6):
    Impact of Diquat on the Intestinal Health and the Composition and Function of the Gut Microbiome.
    Jiao He, Qing Tang, Yan-Cun Liu, Li-Jun Wang, Yan-Fen Chai.
      Diquat (DQ) is extensively utilized as a herbicide in farming, and its intake can result in serious systemic toxicity due to its induction of oxidative stress (OS) and disruption of intestinal homeostasis. The gastrointestinal tract is one of the first systems exposed to DQ, and damage to this system can influence the general health of the host. Our review summarizes the toxic effects of DQ on the intestinal barrier integrity, gut microbiome, and microbial metabolites (e.g., short-chain fatty acids [SCFAs], bile acids). By elucidating the mechanisms linking DQ-induced OS to gut dysbiosis, mitochondrial dysfunction, and inflammation, our work provides critical insights into novel therapeutic strategies, including probiotics, antioxidants (e.g., hydroxytyrosol, curcumin), and selenium nanoparticles. These findings address a pressing gap in understanding environmental toxin-related gut pathology and offer potential interventions to mitigate systemic oxidative damage.
    Keywords:  antioxidants; diquat; inflammation; intestinal microbiome; metabolic products; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/antiox14060721
  47. Cell Div. 2025 Jun 25. 20(1): 16
    Mitochondrial fission regulator 2 promotes cell proliferation, migration and invasion in hepatocellular carcinoma through regulating PI3K/AKT signaling pathway.
    Qiang Sun, Kaikun Liu, Fangjie Zheng, Xinwei Chen.
       OBJECTIVE: Mitochondrial fission regulator 2 (MTFR2) is upregulated in multiple cancers, including hepatocellular carcinoma (HCC); however, its mechanistic role in HCC progression remains poorly understood.
    METHODS: MTFR2 expression in HCC tissues was analyzed using TCGA and GEO databases. Validation of MTFR2 expression levels in clinical samples and HCC cell lines was performed through qRT-PCR and western blot. Functional effects of MTFR2 overexpression and knockdown on HCC cell proliferation, migration, and invasion were assessed via CCK-8, colony formation, wound healing, and transwell assays. In vivo tumor growth was evaluated in xenograft mouse models.
    RESULTS: MTFR2 was significantly overexpressed in HCC tissues and cell lines. Enhanced proliferation, migration, invasion, and colony formation were observed in MTFR2-overexpressing HCC cells, whereas knockdown of MTFR2 suppressed these malignant phenotypes. Mechanistic studies demonstrated that MTFR2 promotes proliferation, migration, and invasion of HCC cells via the PI3K/AKT signaling pathway. Additionally, MTFR2 knockdown significantly attenuated tumor growth in xenograft models.
    CONCLUSION: These findings demonstrate that MTFR2 promotes HCC progression via modulation of the PI3K/AKT pathway, underscoring its potential as a therapeutic target for HCC.
    Keywords:  Hepatocellular carcinoma (HCC); Invasion; Mitochondrial fission regulator 2 (MTFR2); PI3K/AKT; Proliferation
    DOI:  https://doi.org/10.1186/s13008-025-00160-2
  48. Sci Total Environ. 2025 Jun 25. pii: S0048-9697(25)01612-2. [Epub ahead of print]992 179972
    Mitochondrial and inflammatory dysfunctions underlie perfluorooctane sulfonic acid (PFOS)-induced neurotoxicity in adult zebrafish.
    Gabriel Teixeira de Macedo, Mariana Torri Claro, Sabrina Antunes Ferreira, Julia Sepel Loreto, Babajide Oluwaseun Ajayi, Alessandro de Souza Prestes, Isaac Adegboyega Adedara, Talise Ellwanger Müller, Matheus Mülling Dos Santos, Nilda de Vargas Barbosa.
      Perfluorooctane sulfonic acid (PFOS) is a persistent environmental contaminant widely detected in aquatic ecosystems and associated with neurotoxicity. However, the mechanisms underlying its neurological effects remain unclear. This study investigated acute and chronic neurotoxic effects of PFOS in adult zebrafish (Danio rerio), focusing on behavioral alterations, mitochondrial dysfunction, neuroinflammation, and histological abnormalities in different brain regions. Adult zebrafish were exposed to PFOS at 0.1, 1, and 10 μM for 30 min (acute) and 14 days (chronic). Behavioral assays evaluated exploration, social preference, and aggression. High-resolution respirometry assessed brain mitochondrial functionality, while gene expression and histological analyses examined markers of neuroinflammation, neural plasticity, and cell death after chronic exposure. Acute exposure showed no significant behavioral changes but trends of reduced exploration and aggression. Chronic exposure at 10 μM significantly reduced aggression. Mitochondrial respirometry revealed contrasting effects between acute and chronic exposures: acute PFOS resulted in increased oxidative phosphorylation capacity and bioenergetic efficiency, while chronic exposure impaired oxidative phosphorylation, bioenergetic efficiency, and electron transport chain activity. Gene expression supported dysregulation in mitochondrial dynamics, with mffa and mfn1a downregulated. Additionally, inflammation-related genes (il6, il10) and apoptosis/neural activation-related genes (casp3a, cyc1, fosaa, egr1) were altered. Histopathological evaluation showed neuronal vacuolation, architectural disorganization, cell damage, and increased inflammation in telencephalon, optic tectum, and cerebellum reinforcing neurotoxicity. Our findings indicate mitochondrial dysfunction and inflammatory dysregulation are key events underlying PFOS-induced neurotoxicity in adult zebrafish. Given the environmental persistence and bioaccumulative nature of PFOS, further research is needed to assess long-term neurotoxic risks and develop mitigation strategies.
    Keywords:  Brain; Environmental toxicology; Immune dysregulation; Mitochondrial dynamics; PFOS; Zebrafish
    DOI:  https://doi.org/10.1016/j.scitotenv.2025.179972
  49. Free Radic Biol Med. 2025 Jun 27. pii: S0891-5849(25)00788-9. [Epub ahead of print]
    Corrigendum to "Naotaifang formula regulates Drp1-induced remodeling of mitochondrial dynamics following cerebral ischemia-reperfusion injury" [Free Radic. Biol. Med. 229 (2025) 139-153].
    Ruining She, Heyan Tian, Feiyue Sun, Jinwen Ge, Zhigang Mei.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.038
  50. Antioxid Redox Signal. 2025 Jun 26.
    Cathodal Transcranial Direct Current Stimulation Attenuates Cerebral Ischemia-Reperfusion Injury by Coordinating Mitophagy Inhibition and Nrf2 Activation Against Ferroptosis.
    Xian-Dong Li, Yue-Xin Ning, Yi-Feng Pei, Jing-Yuan Niu, Jian Luo, Yi-Na Zhang, Zi-Ai Zhao, Xiao-Wen Hou, Qian-Kun Zhao, Tian-Ce Xu, Hui-Sheng Chen.
      Aims: Cathodal transcranial direct current stimulation (C-tDCS), a noninvasive physical therapy, has potential neuroprotective effects in acute ischemic stroke. However, the rational timing of its application and the underlying mechanisms remain inadequately understood. This study aims to investigate its neuroprotective effects and the involved mechanisms. Results: Our in vivo results indicated that C-tDCS applied during the reperfusion phase but not during the ischemic phase significantly improved neurological outcomes, reduced infarct volume, and mitigated histopathological damage in middle cerebral artery occlusion/reperfusion rats. C-tDCS during the reperfusion phase suppressed ferroptosis, activated nuclear factor erythroid 2-related factor 2 (Nrf2), and inhibited mitophagy. In vitro, the ferroptosis inducer RSL3 negated the protective effects of cathodal direct current stimulation on HT22 neuronal cells subjected to oxygen-glucose deprivation/reoxygenation injury. Furthermore, the Nrf2 inhibitor ML385 and the mitophagy activator FCCP reversed the inhibitory effects of C-tDCS on ferroptosis, with FCCP also affecting Nrf2 activation by C-tDCS. Innovation and Conclusions: These results demonstrate that C-tDCS during reperfusion attenuates cerebral ischemia-reperfusion injury by coordinating mitophagy inhibition and Nrf2 activation to counteract ferroptosis, which provides new evidence for its potential translational clinical applications. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  Nrf2; ferroptosis; mitophagy; reperfusion injury; transcranial direct current stimulation
    DOI:  https://doi.org/10.1089/ars.2025.0914
  51. Int Urol Nephrol. 2025 Jun 27.
    Integrating mitophagy-associated lncRNAs to predict prognosis and therapeutic response in clear cell renal cell carcinoma.
    Guofan Hu, Shuangze Zhong, Hansheng Lin, Jingwei He.
       PURPOSE: Clear cell renal cell carcinoma (ccRCC) is a heterogeneous malignancy with limited prognostic biomarkers. This study aimed to explore the prognostic value of mitophagy-related long non-coding RNAs (MRlncRNAs) and construct a risk model to assist survival prediction and clinical decision-making.
    METHODS: Transcriptomic, clinical, and somatic mutation data of ccRCC patients were obtained from The Cancer Genome Atlas (TCGA). MRlncRNAs were identified through co-expression with mitophagy-related genes. A prognostic risk model was constructed using Cox and LASSO regression analyses and validated in independent cohorts. Functional analyses explored associations with the immune microenvironment, tumor mutation burden (TMB), and drug sensitivity.
    RESULTS: Five MRlncRNAs (AC002070.1, AC092953.2, AC103706.1, LINC01943, and LINC02027) were identified as independent prognostic biomarkers. The risk model effectively stratified patients into high- and low-risk groups with significant differences in overall survival (OS) and progression-free survival. Low-risk patients exhibited enhanced anti-tumor immune activity and greater sensitivity to drugs such as bortezomib, while high-risk patients showed immune suppression, higher TMB, and increased responsiveness to agents targeting EGFR and TGF-β pathways.
    CONCLUSION: This study developed and validated a robust MRlncRNA-based prognostic model for ccRCC that integrates mitophagy-related molecular features with immune and therapeutic profiles. This model provides novel insights for prognostic evaluation and offers a promising tool for guiding individualized treatment strategies.
    Keywords:  Clear cell renal cell carcinoma; Immunotherapy; Long non-coding RNA; Mitophagy; Prognostic model
    DOI:  https://doi.org/10.1007/s11255-025-04626-8
  52. PeerJ. 2025 ;13 e19522
    Mito-fission gene prognostic model for colorectal cancer.
    Chao Liu, Sheng Xu, Yuanyuan Liu, Zhixing Lu, Jianrong Yang.
       Background: Dysregulated cellular metabolism is one of the major causes of colorectal cancer (CRC), including mitochondrial fission. Therefore, this study focuses on the specific regulatory mechanisms of mitochondrial dysfunction on CRC, which will provide theoretical guidance for CRC in the future.
    Methods: The Cancer Genome Atlas (TCGA)-CRC dataset, GSE103479 dataset and 40 mitochondrial fission-related genes (MFRGs) were downloaded in this study. The differentially expressed genes (DEGs) were analyzed in TCGA-CRC samples. Using MFRGs scores as traits, key module genes associated with its scores were screened by weighted gene co-expression network analysis (WGCNA). Then, differentially expressed MFRGs (DE-MFRGs) were obtained by intersecting DEGs and key module genes. Next, DE-MFRGs were subjected to univariate Cox, least absolute shrinkage and selection operator (LASSO), multivariate Cox and stepwise regression analysis to scree hub genes and to construct the risk model. The risk model was validated in GSE103479. Finally, the hub genes were comprehensively investigated through a multi-faceted approach encompassing clinical characteristic analysis, Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, and drug sensitivity prediction. Subsequently, the expression levels of the identified key genes were validated utilizing quantitative real-time fluorescence PCR (qRT-PCR), reinforcing the findings and ensuring their accuracy.
    Results: The 49 DE-MFRGs were gained by intersecting 3,310 DEGs and 1,952 key module genes. Then, CCDC68, FAM151A and MC1R were screened as hub genes. Also, the risk model validated in GSE103479 showed that the higher the risk score, the worse the survival of CRC patients. Furthermore, T/N/M stages were differences in risk scores between subgroups of clinical characteristics. The memory CD4+ T cell and plasma cell were more significant differences in the low-risk group samples. The 51 drugs were showed a better response in the high-risk group patients. RT-qPCR validation results showed that CCDC68 and FAM151A were down-regulated in CRC, while MC1R was up-regulated, consistent with the validation set results. And FAM151A and MC1R showed highly significant difference between CRC and normal samples (P < 0.0001).
    Conclusion: In this study, we found CCDC68, FAM151A and MC1R as potential hub genes in CRC, and analyzed the molecular mechanism of mitochondrial affecting CRC, which would provide theoretical reference value for CRC.
    Keywords:  Colorectal cancer; Gene; Mitochondria; Pan-cancer analysis; Risk model
    DOI:  https://doi.org/10.7717/peerj.19522
  53. Brain Res. 2025 Jun 20. pii: S0006-8993(25)00357-9. [Epub ahead of print] 149796
    Intermittent ELF-MF exposure effectively ameliorates pathologic features associated with adult AD mice.
    Duyan Geng, Aoge Liu, Yuxin Yan, Weiran Zheng.
       OBJECTIVE: Extremely low frequency magnetic fields (ELF-MF) have been confirmed to have potentially positive effects on Alzheimer's disease (AD). However, the therapeutic effects are influenced by the exposure mode and the pathological process. Currently, there is no optimized treatment plan for the pathological process of AD. This study aims to optimize the exposure mode of ELF-MF to improve the therapeutic effect on AD mice with different degrees of dementia.
    METHOD: This study employed 40 Hz, 10mT continuous pulsed ELF-MF stimulation, intermittent (stimulating for 30 min every 12 h) and continuous (stimulating for 60 min every 24 h) ELF-MF exposure. Through calculating various behavioral data, the changes in spatial working memory (SWM) of each group of mice were compared; the time-frequency distribution analysis method was applied to compare the changes in the theta band and gamma band neural oscillations of local field potentials (LFPs) signals in the CA1 region of the hippocampus during the object location task (OLT) of each group of mice; by analyzing the immunofluorescence images of Amyloid-beta 42 (Aβ42) and dynamin-related protein 1 (Drp1) in the hippocampal region of each group of mice, the changes in Aβ42 and Drp1 contents were compared.
    RESULTS: ELF-MF stimulation can improve the SWM ability of AD model mice. Among them, intermittent stimulation in the adult group shows a better effect, while continuous stimulation in the aged group is superior. Further LFPs analysis reveals that AD leads to a decrease in theta and gamma frequency band energy in the CA1 area of the hippocampus, while ELF-MF stimulation can significantly enhance its energy. Moreover, in the adult group, the improvement of theta and gamma frequency bands under intermittent stimulation is more obvious, and in the aged group, the improvement of theta frequency band under continuous stimulation is more significant. The results of immunofluorescence detection indicate that ELF-MF stimulation can reduce the abnormal accumulation of Aβ42 and Drp1 in the hippocampus, and the effect of intermittent stimulation in the adult group is more significant.
    CONCLUSION: Intermittent ELF-MF exposure may be an effective therapeutic strategy, especially in adult AD mice. This study highlights the potential significance of the ELF-MF exposure pattern in AD treatment and reveals the heterogeneous effects of ELF-MF exposure on the physiological and pathological conditions of AD mice, which has important guiding significance for the formulation of personalized treatment plans in the future.
    Keywords:  Alzheimer’s disease; Amyloid-β; Drp1; Extremely low-frequency magnetic field; Magnetic stimulation mode; Mitochondrial dynamics; Neural oscillation
    DOI:  https://doi.org/10.1016/j.brainres.2025.149796
  54. Clin Sci (Lond). 2025 06 19. pii: CS20190960_EOC. [Epub ahead of print]139(12):
    Expression of Concern: Mitochondrial dynamic modulation exerts cardiometabolic protection in obese insulin-resistant rats.
      
    DOI:  https://doi.org/10.1042/CS20190960_EOC
  55. Elife. 2025 Jun 23. pii: RP99986. [Epub ahead of print]13
    Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia.
    Zhengming Tian, Yuning Li, Feiyang Jin, Zirui Xu, Yakun Gu, Mengyuan Guo, Qianqian Shao, Yingxia Liu, Hanjiang Luo, Yue Wang, Suyu Zhang, Chenlu Yang, Xin Liu, Xunming Ji, Jia Liu.
      Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell-cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of 'mutual aid' in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.
    Keywords:  brain-derived extracellular vesicles; hemoglobin; hypoxia; mitochondrial homeostasis; mouse; nerve injury; neuroscience
    DOI:  https://doi.org/10.7554/eLife.99986
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