bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–11–16
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.
  2. STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
  3. Unveiling the Crucial Nexus: Mitochondrial Quality Control as a Central Driver in Metabolic Dysfunction-Associated Steatotic Liver Disease Pathogenesis.
  4. Correction to "A Small-Molecule Drug for the Self-Checking of Mitophagy".
  5. Dual-targeted Mitophagy activation by curcumin-Zn co-delivery mediates neuroprotection in zebrafish through coordinated PINK1/Parkin and PI3K/AKT/mTOR pathway regulation.
  6. Idebenone alleviates rotenone-induced mitochondrial dysfunction through mitophagy and mitochondrial biogenesis in muscle cells.
  7. Integrated bioinformatics of PANoptosis and mitochondrial autophagy related genes in chronic obstructive pulmonary disease and their association with immune cells.
  8. Human papillomavirus E7 inhibits immune responses in keratinocytes by activating HTRA1‑mediated mitophagy.
  9. Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
  10. UPRmt-regulated mitokines: novel strategies for myocardial injury repair.
  11. Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.
  12. Electroacupuncture improves motor function after ischemic stroke via regulating mitochondrial dynamics.
  13. Identification and validation of key mitophagy-related biomarkers in the pathogenesis of proliferative diabetic retinopathy.
  14. An AMPK-Centric Strategy: Foenumoside B Coordinates PINK1/Parkin-Mediated Mitophagy With Nrf2/HO-1 Antioxidant Signaling to Resolve Oxidative Stress in Radiation-Induced Lung Injury.
  15. Mitochondrial dysfunction in type 1 diabetes and its implications for pancreatic beta-cell survival and insulin secretion.
  16. Galangin alleviates vascular aging and endothelial cell senescence by targeting SMAD3 to initiate mitophagy.
  17. Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.
  18. Melatonin ameliorates oxybenzone-induced meiotic defects in mouse oocytes via regulation of mitochondrial dynamics and calcium signaling.
  19. B355252 Targets UCP2 to Rescue Intracerebral Hemorrhage-Induced Injury by Promoting Mitochondrial Fusion and Inhibiting Ferroptosis.
  20. Nicotine Improves Memory Impairment in Aged Rats Through Enhanced Mitochondrial Homeostasis.
  21. Ursolic Acid Activates Mitochondrial Unfolded Protein Response to Enhance Innate Immunity via Transcription Factor ATFS-1/ATF5.
  22. The role of ubiquitylation in cerebral ischemia-reperfusion injury to reduce mitochondrial dysfunction and programmed cell death.
  23. Near-Infrared-Triggered Photoresponsive Nanobombs Overcome Tumor Immunosuppression through Coordinated Pyroptosis Activation and Mitophagy Blockade.
  24. MTFR1 Promotes Proliferation and Metastasis of Triple-Negative Breast Cancer by Regulating Mitochondrial Metabolism.
  25. Developmental Differences in Myocardial Mitochondrial Reticulum Networks in the Offspring Exposed to Diabetic Pregnancy.
  26. LINC03047 promotes mitophagy by recruiting hnRNPF to enhance CTGF mRNA stability in hypoxic pulmonary hypertension.
  27. Z-Ligustilide's antidepressant effects in adolescent depression involve the PTEN-induced putative kinase 1 (PINK1) - protein kinase A (PKA)- Na+/Ca2+ exchanger (NCLX) pathway, facilitating mitochondrial endosymbiosis and promoting mitophagy in microglia.
  28. NF-κB/TOM6/PINK1-mediated mitophagy attenuates vascular calcification: Luteolin as a therapeutic modulator.
  29. MYC affects mitochondrial function in IgA nephropathy by promoting the degradation of MFN1 through HRD1.
  30. HSALR Mice Exhibit Co-Expression of Proteostasis Genes Prior to Development of Muscle Weakness.
  31. Acetylated KLF5 inhibits LACTB transcription, mediates mitochondrial dynamics, and regulates colorectal cancer cell stemness and differentiation.
  32. Ultrasound-responsive piezoelectric hydrogel attenuates oxidative stress-induced nucleus pulposus senescence via AMPK-FOXO1a-mediated mitophagy for intervertebral disc regeneration.
  33. Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death.
  34. Selective autophagy in hepatocellular carcinoma: Mechanisms, roles and therapeutic implications (Review).
  35. Houttuynia cordata-derived nanoparticles stabilize mitochondrial dynamics to alleviate ulcerative colitis via the Nrf2/Ho-1 pathways.
  36. Mdivi-1 promotes lipid droplets-mitochondria contact and ameliorates cardiac lipotoxicity in high-fat diet-fed mice.
  37. Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics.
  38. Targeting olfactory receptor 2 on monocytes for cardioprotection against myocardial ischemia-reperfusion injury via NR4A1-mediated mitochondrial fission.
  39. Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
  40. Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's Disease.
  41. Aberrant Splicing of Dnm1l Impairs Cardiac Bioenergetics and Mitochondrial Dynamics in Myotonic Dystrophy Type I (DM1).
  42. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
  43. Bidens biternata (Lour.) Merr. & Sherff improves liver lipid metabolism disorders in type 2 diabetic mice by activating mitophagy.
  44. Selenium alleviates Staphylococcus aureus-induced mastitis by modulating mitochondrial dynamics and inhibiting the ROS/NLRP3/Pyroptosis pathway.
  45. Polydatin Prevents UVA-Induced Damage in Human Dermal Fibroblasts by Maintaining Mitochondrial Integrity.
  46. Prognostic impact of mitochondrial dynamics-related miRNA levels during the treatment of acute heart failure in the hospital.
  47. Phytochemical-rich Eucommia ulmoides leaf extract extends healthspan in Caenorhabditis elegans via the pmk-1/p38 MAPK pathway and mitochondrial homeostasis.
  48. Nanoparticle-mediated overexpression of RacGAP1 protects against renal ischemia/reperfusion-injury by maintaining mitochondrial homeostasis.
  49. MCUB Inhibits PRKN-Dependent Mitophagic Degradation of PD-L1 to Promote Immune Evasion in Bladder Cancer.
  50. Diatomic Mn/Ca Nanozymes with Jaw Vascular Unit Mimicry for Triple-Enzyme Synergistic Therapy of Osteoradionecrosis.
  51. Cedrol prevents UVB-induced photoaging by restoring mitochondrial function, metabolic homeostasis, and skin barrier integrity in HaCaT cells.
  52. ER stress sensor PERK drives ferroptosis by disrupting MAMs-mediated mitochondrial homeostasis and promoting mtROS accumulation in acute myocardial infarction.
  53. Thyroid Hormone Receptor β1 and PGC1α Coordinately Regulate OPA1/MFN2-Mediated Mitochondrial Fusion and UCP1-Mediated Lipid Browning in ccRCC.
  54. Autophagy modulates the mechanism of flow-mediated dilation upstream of telomerase.
  55. Correction: Targeting the MARCH5-MFN2 axis to enhance mitochondrial fusion and sensitize multiple myeloma cells to venetoclax.
  56. The Multi-Dimensional Action Map of Resveratrol Against Alzheimer's Disease: Mechanism Integration and Treatment Strategy Optimization.
  57. From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
  58. Pharmacological suppression of lactate mitigates postoperative cognitive dysfunction.
  1. Autophagy. 2025 Nov 10.
    Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.
    Juncai Ma, Chaorui Li, Xiaohong Zhuang.
      Mitochondrial dynamics play critical roles in mitochondrial quality control to maintain mitochondrial function. In plants, mitochondria are typically discrete rather than networked, but how damaged mitochondrial contents can be efficiently removed remains unclear. In a recent study, we demonstrate that the plant-specific fission regulator ELM1, together with DRP3 and the autophagic adaptor SH3P2, orchestrates mitochondrial dynamics and mitophagosome assembly for piecemeal mitophagy under heat stress condition. Deficiency in mitochondrial fission activity delays mitophagosome formation and leads to an accumulation of megamitochondria that are partially sequestered by phagophore intermediates positive for ATG8 and NBR1. Further 3D electron tomography analysis reveals that phagophore fragments expand toward the constriction sites of the abnormal protrusions from the mitochondrial body. These findings highlight an unappreciated role of plant mitochondrial fission machinery in coupling with autophagy machinery for mitochondrial segregation and mitophagosome assembly, establishing a mechanistic framework for plant mitophagy in stress resilience.
    Keywords:  ELM1; SH3P2; mitochondrial dynamics; mitochondrial fission; piecemeal mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2587051
  2. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70113
    STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
    Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.
       BACKGROUND: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4), traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
    METHODS: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice (Stx4fl/fl; Tg (HSA-rtTA/TRE-Cre)/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
    RESULTS: We found that non-obese skmSTX4-iKO male mice (> 50% reduced STX4 abundance, soleus and gastrocnemius ***p < 0.001, tibialis anterior (TA) ****p < 0.0001) developed insulin resistance (**p < 0.01), together with reduced energy expenditure (AUC *p < 0.05), respiratory exchange ratio (AUC **p < 0.01) and grip strength (*p < 0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p < 0.0001). Mitochondrial morphological damage was heterogenous in STX4-depleted muscle, presenting with small fragmented mitochondria (****p < 0.0001) and decreased electron transport chain (ETC) abundance (CI ***p < 0.001, CII *p < 0.05, CIV **p < 0.01) in oxidative soleus muscle, whereas glycolytic-rich TA fibres displayed enlarged swollen mitochondria (****p < 0.0001) with no change in ETC abundance. Notably, > 60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p < 0.0001) also decreased ETC abundance (CI **p < 0.01, CII ***p < 0.001, CIV **p < 0.01) without changes in mitochondrial glucose metabolism, as shown by [U-13C]glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p < 0.05) and siSTX4 L6.GLUT4myc myotubes (*p < 0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p < 0.05) and Tfam (*p < 0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA **p < 0.01, protein *p < 0.05), NRF1 (mRNA **p < 0.01 and protein *p < 0.05) and Tfam (mRNA *p < 0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using the mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p < 0.05) and mitochondria-lysosome colocalization (*p < 0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p < 0.05, PINK1 **p < 0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN **p < 0.01, PINK1 *p < 0.05).
    CONCLUSIONS: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.
    Keywords:  STX4; mitochondria; muscle; quality control
    DOI:  https://doi.org/10.1002/jcsm.70113
  3. Cell Prolif. 2025 Nov 09. e70141
    Unveiling the Crucial Nexus: Mitochondrial Quality Control as a Central Driver in Metabolic Dysfunction-Associated Steatotic Liver Disease Pathogenesis.
    Wenkai Fu, Junqi Wang, Nan Lu, Zhijiang Guo, Sang-Bing Ong, Yong Gao, Hao Zhou, Xing Chang, Miao Meng.
      Mitochondrial quality control (MQC) impairment plays a central role in driving the pathogenesis of metabolism-associated steatotic liver disease (MASLD). Specifically, this is manifested as reduced mitophagy; increased mitochondrial fission and decreased fusion; and impaired mitochondrial biogenesis. Key pathological mechanisms of MASLD, such as hepatocyte apoptosis, pyroptosis, and ferroptosis, are activated under the influence of factors including free fatty acids (FFAs), oxidative stress, NLRP3 inflammasome activation, and gut microbiota imbalance. Meanwhile, the letter also lists novel potential therapeutic strategies targeting these pathways, including autophagy enhancers, mitochondrial dynamics regulators, biogenesis promoters, and ferroptosis inhibitors.
    DOI:  https://doi.org/10.1111/cpr.70141
  4. Angew Chem Int Ed Engl. 2025 Nov 10. e23766
    Correction to "A Small-Molecule Drug for the Self-Checking of Mitophagy".
      
    DOI:  https://doi.org/10.1002/anie.202523766
  5. Food Res Int. 2025 Dec;pii: S0963-9969(25)01802-2. [Epub ahead of print]221(Pt 3): 117464
    Dual-targeted Mitophagy activation by curcumin-Zn co-delivery mediates neuroprotection in zebrafish through coordinated PINK1/Parkin and PI3K/AKT/mTOR pathway regulation.
    Xiang Pan, Qi Li, Dan Yuan, Mouming Zhao, Zhenglong Gu, Feibai Zhou.
      Neurodegenerative diseases are currently incurable, but emerging research highlights mitochondrial homeostasis as a key therapeutic target. Concurrently, exploring bioactive compounds from food sources offers a long-term strategy for prevention and adjuvant therapy. Previously, a green and soy protein isolate (SPI)-based curcumin‑zinc ternary nanocomplex was newly developed and shown to exhibit potent in vitro antioxidant and neuroprotective activity. As a continuous study, the present work further investigated the neuroprotective efficiency of complex from the perspective of mitochondrial function modulation, employing both cellular and animal models (zebrafish model of Parkinson's disease (PD)). Crucially, the ternary complex significantly promoted mitophagy, a key mitochondrial quality control process, in HEK-293 T-mtKeima reporter cells. Behavioral, histological, and biochemical analyses demonstrated that, as compared to the PD zebrafish model, the nanocomplex treatment significantly preserved cerebrovascular integrity (increasing vascular density by 71.8%), elevated cerebral mitochondrial density (by 83.9%), and restored locomotor function (improving swimming distance and speed by 1.51- and 1.53-fold, respectively). Mechanistically, the complex attenuated oxidative damage while activating mitophagy through dual modulation of the PINK1/Parkin and PI3K/AKT/mTOR signaling axes, thereby restoring mitochondrial dynamics. These findings highlight the SPI-curcumin‑zinc nanocomplex as a multifaceted neuroprotective agent with translational potential for neurodegenerative disorders.
    Keywords:  Mitophagy; Neuroprotection; PI3K/AKT/mTOR pathway; PINK1/Parkin pathway; SPI-curcumin-Zn ternary complex
    DOI:  https://doi.org/10.1016/j.foodres.2025.117464
  6. Cell Signal. 2025 Nov 07. pii: S0898-6568(25)00636-9. [Epub ahead of print]138 112221
    Idebenone alleviates rotenone-induced mitochondrial dysfunction through mitophagy and mitochondrial biogenesis in muscle cells.
    Chen Zhang, Mei Li, Liying Meng, Wei Xia, Guanzhao Wu.
      Idebenone, a synthetic quinone analog of coenzyme Q10, is a well-characterized antioxidant with clinical applications in treating diseases associated with mitochondrial dysfunction. However, it remains unclear whether idebenone can mitigate rotenone-induced oxidative stress and mitochondrial dysfunction in muscle cells. In this study, exposure of C2C12 myoblasts to rotenone resulted in a significant increase in cell death, intracellular and mitochondrial reactive oxygen species, and the activation of mitophagy and autophagy, as evidenced by altered expression levels of PINK1, PARKIN, and p62/SQSTM1. Additionally, elevated mitochondrial fission (measured by DRP1 and FIS1 expression) and a decrease in energy production (assessed via Seahorse analysis) were observed compared to untreated cells. The translocation of cytoplasmic DRP1 to the mitochondria was further demonstrated by its colocalization with TOM20. Remarkably, treatment with idebenone reversed these effects, and pharmacological inhibition of PGC1A abolished the protective effects of idebenone on mitochondrial biogenesis and function. Our findings suggest that idebenone ameliorates rotenone-induced apoptosis, oxidative stress, and mitochondrial damage in C2C12 cells, supporting its potential therapeutic role in the treatment of skeletal muscle atrophy.
    Keywords:  C2C12; Idebenone; Mitochondrial dysfunction; Oxidative stress; Rotenone
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112221
  7. Medicine (Baltimore). 2025 Nov 14. 104(46): e45811
    Integrated bioinformatics of PANoptosis and mitochondrial autophagy related genes in chronic obstructive pulmonary disease and their association with immune cells.
    Tingting Mei, Yuxuan Ren, Zhuying Li.
      Chronic obstructive pulmonary disease (COPD) is a common respiratory issue caused by smoking and pollution, resulting in airway obstruction. The aim of this study was to investigate a prognostic model for genes related to apoptosis and mitophagy in COPD. This study investigates the molecular mechanisms linking COPD with PANoptosis and mitophagy, 2 critical cellular processes. Firstly, we integrated Gene Expression Omnibus datasets (GSE10006 and GSE20257) to analyze the differential expression of genes associated with PANoptosis and mitophagy in COPD. Batch effects were removed using the R package sva, followed by differential expression analysis using limma. Next, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed for PANoptosis and mitochondrial autophagy related genes (PAMRDEGs). Then, STRING and GeneMANIA were used to construct protein-protein interaction network of PAMRDEGs, and ChIPBase and StarBase were used to create regulatory network. Finally, The expression of key genes was verified, the diagnostic efficacy was evaluated by receiver operating characteristic curve analysis, and the immune characteristics related to COPD were explored by immune infiltration analysis. A total of 7 PAMRDEGs were obtained, namely AIM2, DNM1L, MAPK1, CASP8, CDK1, SAMHD1, NLRP3, which showed significant expression changes in COPD, linked to inflammatory response pathways like NOD-like receptor and tumor necrosis factor signaling pathway. Immune infiltration analysis revealed a notable negative correlation with M2 macrophages, highlighting the immune microenvironments importance in COPD progression. This study highlights the critical roles of PANoptosis and mitophagy-related genes in the pathogenesis of COPD, suggesting potential therapeutic targets. In the future, in-depth functional experiments and prospective large sample cohort validation are needed to further clarify the regulatory mechanism of the key targets and promote their clinical translation and application.
    Keywords:  PANoptosis; chronic obstructive pulmonary disease; gene expression; immune infiltration; mitophagy
    DOI:  https://doi.org/10.1097/MD.0000000000045811
  8. Int J Mol Med. 2026 Jan;pii: 22. [Epub ahead of print]57(1):
    Human papillomavirus E7 inhibits immune responses in keratinocytes by activating HTRA1‑mediated mitophagy.
    Boya Zhang, Defeng Kong, Siji Chen, Xuewu Sun, Hao Cheng.
      Persistent infection with human papillomavirus (HPV) can lead to refractory disease. The HPV E7 protein causes persistent viral infection by disrupting the immune balance of keratinocytes; however, its key mechanism is not yet clear. Overexpression of the HPV E7 gene in normal human epidermal keratinocytes can promote mitophagy in the host cells and inhibit the expression of type I interferon (IFN), as previously confirmed by electron microscopy, immunofluorescence and western blot analysis. In the present study, Siha cells with stable knockdown of HPV16 E7 were constructed, and RNA sequencing at the transcription level and isobaric tags for relative and absolute quantitation analysis at the protein level were performed, with the aim of identifying genes related to mitophagy among the differentially expressed genes. Using immunohistochemistry, PCR and western blotting, significant differences were detected in the expression levels of high‑temperature requirement A serine peptidase 1 (HTRA1) between the knockdown and control groups. The results confirmed that HPV E7 could promote the expression of HTRA1. Furthermore, it was demonstrated that the HPV E7 protein interacted with HTRA1 intracellularly to activate the PTEN‑induced kinase 1 (PINK1)/Parkin pathway in keratinocytes, leading to enhanced mitophagy and reduced expression of type I IFN in host cells. In conclusion, HPV E7 could promote the expression of the HTRA1 gene in keratinocytes, thereby activating mitophagy mediated by the PINK1/Parkin pathway. Furthermore, HPV E7 could inhibit the secretion of type I IFN from cells, thus leading to persistent viral infection. These findings provide novel insights into the association between HPV infection and mitophagy, and may elucidate the mechanisms underlying persistent HPV infection.1.
    Keywords:  E7 protein; PTEN‑induced kinase 1/Parkin; human papillomavirus; immune response; mitophagy; type I interferon
    DOI:  https://doi.org/10.3892/ijmm.2025.5693
  9. Autophagy. 2025 Nov 13.
    Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
    Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.
    Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2589909
  10. Front Cell Dev Biol. 2025 ;13 1652353
    UPRmt-regulated mitokines: novel strategies for myocardial injury repair.
    Weinan Gao, Jia Liu, Wenda Zhang, Bin Liu, Luyan Shen.
      Cardiac mitochondria generate ATP, via oxidative phosphorylation (OXPHOS) to sustain continuous and forceful myocardial contraction, thereby meeting systemic metabolic demands. Mitochondrial biogenesis and energy metabolism depend on proteostasis, which can be disrupted by stressors such as hypoxia, leading to impaired cardiac function. As a result, the study of mitochondrial energy metabolism and proteostasis under stress has become a key focus in cardiovascular research. The mitochondrial unfolded protein response (UPRmt) plays a "double-edged sword" role-either protective or detrimental-depending on the type, intensity, and duration of the stressor. This has sparked interest in strategies aimed at enhancing its adaptive signaling while inhibiting maladaptive pathways. Acting as mediators of intercellular communication, mitokines may transmit local mitochondrial stress signals to mitochondria in distant cells and tissues. This review analyzes and summarizes the role of UPRmt in regulating mitochondrial factors and explores the mechanisms through which fibroblast growth factor 21 (FGF21), secreted by the liver and skeletal muscle, influences protein homeostasis in cardiac myocytes. These insights aim to offer new avenues for the development of targeted UPRmt therapies and rehabilitation strategies for heart diseases.
    Keywords:  cardiac diseases; fibroblast growth factor 21 (FGF21); mitochondrial stress; mitochondrial unfolded protein response (UPRmt); mitokines
    DOI:  https://doi.org/10.3389/fcell.2025.1652353
  11. Cells. 2025 Nov 05. pii: 1738. [Epub ahead of print]14(21):
    Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.
    Dhienda C Shahannaz, Tadahisa Sugiura, Brandon E Ferrell, Taizo Yoshida.
      Mitochondrial dysfunction is a key contributor to cardiac injury and heart failure, and extracellular vesicles (EVs) have emerged as promising therapeutic agents due to their ability to deliver mitochondrial-targeted cargo. This review systematically maps the evidence on how EVs modulate mitochondrial dynamics-including fusion, fission, mitophagy, and biogenesis-in regenerative cardiology. We comprehensively searched PubMed, Scopus, and Web of Science up to September 2025 for original studies. A total of 48 studies were included, with most utilizing EVs from mesenchymal stem cells, induced pluripotent stem cells, or cardiac progenitors. The review found that EV cargo influences key pathways such as DRP1 and MFN2, restores mitochondrial membrane potential, reduces ROS accumulation, and improves cardiomyocyte survival. While engineered EVs showed enhanced specificity, a lack of standardized preparation and quantitative assessment methods remains a significant challenge. We conclude that EV-mediated mitochondrial modulation is a promising strategy for cardiac repair, but the field needs harmonized protocols, deeper mechanistic understanding, and improved translational readiness to advance beyond preclinical research. The future of this research lies in integrating systems biology and precision targeting.
    Keywords:  EV-based drug delivery; cardiac regeneration; extracellular vesicles (EVs); heart failure therapy; mitochondrial biogenesis and mitophagy; mitochondrial dynamics; mitochondrial transfer; regenerative cardiology; stem cell-derived EVs; translational cardiovascular medicine
    DOI:  https://doi.org/10.3390/cells14211738
  12. Brain Res Bull. 2025 Nov;pii: S0361-9230(25)00411-3. [Epub ahead of print]232 111599
    Electroacupuncture improves motor function after ischemic stroke via regulating mitochondrial dynamics.
    Zuanfang Li, Xinru Ji, Xiuxiu Wang, Jiawei Wang, Ruhui Lin, Xiaohan Ma, Qingqing Zhang, Shengxiang Liang.
       OBJECTIVE: Previous studies have demonstrated that electroacupuncture (EA) exerts a protective effect in middle cerebral artery occlusion (MCAO) rats and may improve motor function, but the specific mechanism involved remains to be elucidated. This study aimed to further investigate the effects of EA at the Quchi (LI11) and Zusanli (ST36) acupoints on ischemic stroke motor function and the underlying mechanism.
    METHODS: Following the establishment of MCAO model, the rats in EA group were treated at LI11 and ST36 acupoints. Catwalk gait analysis was used to assess ethology. T2 weighted imaging was used to assess cerebral infarct volume. H&E and Nissl staining was used to assess cortical morphology. Glucose metabolism was detected by chemical exchange saturation transfer (CEST). Chemiluminescence was used to detect the cortical adenosine triphosphate (ATP). Mitochondrial morphological changes were observed by transmission electron microscopy(TEM). The protein and mRNA expressions of mitochondrial dynamics related genes Drp1, Fis1, Mfn2, Mfn1 and Opa1 were detected by western blot and qPCR respectively.
    RESULTS: EA intervention improved gait dynamics, reduced cerebral infarct volume, ameliorated cortical pathological morphological changes and neuronal loss. EA significantly alleviated mitochondrial morphological changes. EA improved mitochondrial dynamic disorder by significantly increasing the expression of Opa1 and inhibiting the expression of Drp1, thus improving glucose metabolism and ATP production.
    CONCLUSIONS: EA could regulate mitochondrial dynamics to improve glucose metabolism dysfunction, thereby restoring motor function in MCAO.
    Keywords:  Electroacupuncture; Middle cerebral artery occlusion; Mitochondrial dynamics; Motor function
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111599
  13. Front Endocrinol (Lausanne). 2025 ;16 1652898
    Identification and validation of key mitophagy-related biomarkers in the pathogenesis of proliferative diabetic retinopathy.
    Yifan Liu, Ye Zhou, Jie Chen, Jiahui Jin, Xueying Wang, Xi Wang, Jieping Zhang, Jiao Li, Junfang Zhang, Ling Zhu, Guo-Tong Xu, Yanlong Bi, Qingjian Ou, Caixia Jin.
       Introduction: Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus, and proliferative diabetic retinopathy (PDR) represents its advanced stage. The etiology of PDR is complex. Mitophagy, the selective degradation of dysfunctional mitochondria, is crucial for cellular homeostasis and has been implicated in PDR pathogenesis. However, its specific mechanisms require further investigation.
    Materials and methods: Gene Expression Omnibu (GEO) datasets (GSE102485, GSE60436) were analyzed in R software to identify differentially expressed mitophagy-related genes (DEMRGs). A PDR diagnostic model was constructed by gene ontology (GO) enrichment analysis, genome enrichment analysis (GSEA), and other relevant methods. Immune infiltration was also performed to analyze the changes in immune cells. Finally, the retinal pigment epithelial cell line (ARPE-19) was incubated with high glucose (HG) to simulate a DR model in vitro, hub-gene expression and mitophagy were assessed by qRT-PCR, Western blotting, and immunofluorescence microscopy (IF).
    Results: Eight DEMRGs were identified enabling construction of a PDR diagnostic model and prioritization of two hub genes (CASP8 and COL1A1). Finally, qRT-PCR, Western blotting, and IF were performed to provide preliminary validation of the PDR model and HG stimulation increased mitochondria-lysosome colocalization as well as enhanced the expression of mitophagy-related proteins.
    Conclusion: Integrated bioinformatics and experimental validation suggest that mitophagy contributes to PDR pathogenesis. Five DEMRGs showed up-regulated and immune cell infiltration that may affect the occurrence and PDR development by regulating mitophagy. These findings provide candidate biomarkers and mechanistic insight into PDR.
    Keywords:  CASP8; COL1A1; differentially expressed genes; mitophagy; proliferative diabetic retinopathy
    DOI:  https://doi.org/10.3389/fendo.2025.1652898
  14. FASEB J. 2025 Nov 30. 39(22): e71225
    An AMPK-Centric Strategy: Foenumoside B Coordinates PINK1/Parkin-Mediated Mitophagy With Nrf2/HO-1 Antioxidant Signaling to Resolve Oxidative Stress in Radiation-Induced Lung Injury.
    Xiaoyu Pu, Xiaodong Li, Bohao Liu, Yan Zhang.
      Radiation-induced lung injury (RILI) is a dose-limiting toxicity of thoracic radiotherapy driven by mitochondrial damage-mediated oxidative stress, persistent DNA damage, and senescence, which together destabilize the alveolar-interstitial niche and promote fibrosis. Here, we identify Foenumoside B (FSB), a natural saponin from Lysimachia foenum-graecum, as a dual-action modulator that preserves mitochondrial quality and restores systemic redox homeostasis to attenuate RILI. In a murine total lung irradiation model (20 Gy), oral FSB (10 mg/kg/day) mitigated inflammation and fibrotic remodeling, improved pulmonary mechanics and arterial blood gases, and exhibited no overt hepatorenal toxicity. Mechanistically, FSB activated PINK1/Parkin-dependent mitophagy in alveolar epithelial cells. Pharmacologic autophagy blockade (3-MA) or PINK1 silencing abrogated these benefits, increasing mtROS, γH2AX foci, comet tail moments, and p16/p21 expression, and reducing cell viability, thereby confirming mitophagy as indispensable for FSB's cytoprotection. Molecular docking analysis demonstrates that FSB binds to the catalytic α1 and α2 subunits of AMPK, thereby significantly increasing the p-AMPK/AMPK ratio. Upon pharmacologic inhibition of AMPK, the FSB-mediated improvements in mitophagy, mitochondrial function, redox homeostasis, and tissue protection are markedly attenuated, indicating that FSB's biological effects rely on AMPK activation. FSB also restored Nrf2/HO-1 signaling and antioxidant capacity. Co-IP/ChIP showed AMPK directly associates with Nrf2, enhances its phosphorylation and ARE binding at the HO-1 promoter, and weakens Keap1-mediated degradation. Overall, FSB suppresses reactive oxygen species at their mitochondrial source and, through AMPK-driven mitophagy and Nrf2 activation, enhances endogenous antioxidant defenses, providing a translatable strategy to preserve alveolar architecture during radiotherapy.
    Keywords:  AMPK; cellular senescence; foenumoside B; mitophagy; oxidative stress; radiation‐induced lung injury
    DOI:  https://doi.org/10.1096/fj.202501880R
  15. Acta Diabetol. 2025 Nov 10.
    Mitochondrial dysfunction in type 1 diabetes and its implications for pancreatic beta-cell survival and insulin secretion.
    Divya Ramesh Singh, Shivam Malviya, Sivaraj Mohana Sundaram.
      Mitochondrial dysfunction plays a crucial role in the pathophysiology of Type 1 Diabetes (T1D), as it compromises beta (β)-cell survival and insulin secretion. Autoimmune-driven inflammation disrupts mitochondrial homeostasis and thereby induces oxidative stress, disturbs calcium signaling, and activates apoptotic cascades that together impair β-cell viability. This review outlines mitochondrial quality control mechanisms, including fusion-fission dynamics, mitophagy, and cardiolipin remodeling, and explains how their dysregulation exacerbates β-cell dysfunction. In particular, mitochondrial proteins such as olfactomedin-4 modulate insulin release and thus provide potential therapeutic targets. Furthermore, crosstalk between the endoplasmic reticulum (ER) and mitochondria also influences β-cell resilience, with ER stress triggering pro-apoptotic signaling, particularly through CHOP-mediated pathways. Pharmacological approaches, including antioxidants, coenzyme Q10, dipeptidyl peptidase IV inhibitors, and imeglimin, together with natural agents such as SIRT3 activators and Vernicia fordii extracts, have shown efficacy in preserving mitochondrial integrity and promoting β-cell functions in animal studies. Further, this review also summarizes critical drug candidates, their mechanisms of action, and cellular outcomes. Collectively, emerging insights underscore mitophagy regulation, lipid metabolism, and calcium balance as promising avenues for restoring mitochondrial function and advancing therapeutic strategies in T1D.
    Keywords:  Beta-cell survival; Insulin secretion; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Reactive oxygen species; Type-1 diabetes
    DOI:  https://doi.org/10.1007/s00592-025-02607-y
  16. Phytomedicine. 2025 Oct 26. pii: S0944-7113(25)01103-1. [Epub ahead of print]148 157466
    Galangin alleviates vascular aging and endothelial cell senescence by targeting SMAD3 to initiate mitophagy.
    Xiao-Qing Ding, Ke-Xin Li, Jing-Wen Liu, Rui-En Zhang, Chun-Ran Lei, Saqirile, Zi-Xin Yi, Ke Li, Peng-Xia Liu, Rui Yang, Chang-Shan Wang.
       BACKGROUND: Senescence of vascular endothelial cells (ECs) plays a critical role in cardiovascular diseases. Galangin (3,5,7-Trihydroxyflavone) is a flavonoid derived from plants and medicinal herbs with various biological activities. However, its effect on endothelial cell senescence and the underlying molecular mechanisms are poorly characterised.
    PURPOSE: This study aimed to evaluate the therapeutic effects of Galangin on endothelial cell senescence and vascular aging, providing a theoretical basis for its clinical application.
    METHODS: Human aortic endothelial cells and mice were treated with d-galactose to induce senescence. The expression levels of aging markers β-galactosidase, P21, P53, and γ-H2AX were detected using western blot. Cell proliferation was determined using CCK-8 assays. Network pharmacology, molecular docking, and molecular dynamics simulations were used to identify Galangin downstream targets. MST, CETSA, and DARTS assays were used to determine the binding of Galangin to SMAD3 protein. ROS levels were measured using flow cytometry. JC-1 staining was used to determine mitochondrial membrane potential. Mitophagy-related markers Parkin, PINK1, LC3, and P62 were detected using western blot and immunohistochemistry. ChIP assay was used to determine p-SMAD3's effect on the downstream genes PINK1 and LC3.
    RESULTS: Our pioneering study reveals a novel protective role of Galangin in vascular aging, primarily through a newly identified mechanism: activating mitophagy by targeting SMAD3. Notably, Galangin directly binds to SMAD3 and promotes the transcriptional regulation of PINK1 and LC3.
    CONCLUSIONS: Our findings demonstrate the protective effect of Galangin in vascular aging and hold promising prospects for both clinical application and future research.
    Keywords:  Endothelial cell senescence; Galangin; Mitophagy; SMAD3; Vascular aging
    DOI:  https://doi.org/10.1016/j.phymed.2025.157466
  17. EMBO J. 2025 Nov 10.
    Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.
    Priyanka Das, Ravi, Jogender Singh.
      Gut microbes play a crucial role in modulating host lifespan. However, the microbial factors that influence host longevity and their mechanisms of action remain poorly understood. Using the expression of Caenorhabditis elegans FAT-7, a stearoyl-CoA 9-desaturase, as a proxy for lifespan modulation, we conduct a genome-wide bacterial mutant screen and identify 26 Escherichia coli mutants that enhance host lifespan. Transcriptomic and biochemical analyses reveal that these mutant diets induce oxidative stress and activate the mitochondrial unfolded protein response (UPRmt). Antioxidant supplementation abolishes lifespan extension, confirming that oxidative stress drives these effects. The extension of lifespan requires the oxidative stress response regulators SKN-1, SEK-1, and HLH-30. Mechanistically, these effects are linked to reduced iron availability, as iron supplementation restores FAT-7 expression, suppresses UPRmt activation, and abolishes lifespan extension. Iron chelation mimics the pro-longevity effects of the mutant diets, highlighting dietary iron as a key modulator of aging. Our findings reveal a bacterial-host metabolic axis that links oxidative stress, iron homeostasis, and longevity in C. elegans.
    Keywords:  HLH-30; Iron; Lifespan; Oxidative Stress; SKN-1
    DOI:  https://doi.org/10.1038/s44318-025-00634-7
  18. Ecotoxicol Environ Saf. 2025 Nov 07. pii: S0147-6513(25)01693-8. [Epub ahead of print]306 119348
    Melatonin ameliorates oxybenzone-induced meiotic defects in mouse oocytes via regulation of mitochondrial dynamics and calcium signaling.
    Ruojin Shi, Haiying Zhu, Bin Zou, Yuying Xiong, Xueling Zhang, Yunqi Wu, Lin Zhu, Yanling Bai, Yudan Shang, Junyuan Liu, Hao Liu, Xian Luo, Liuqing Chen, Fang Wang, Chaohui Li, Chenrui An, Lei Li, Yong Fan, Long Jin.
      Oxybenzone (2-Hydroxy-4-methoxybenzophenone, OBZ) is an organic ultraviolet filter extensively used in sunscreens and cosmetics, and has become a pervasive contaminant in aquatic environments. While its endocrine-disrupting properties and adverse reproductive effects are recognized, potential impacts on oocyte mitochondrial physiology remain incompletely understood. In this study, we investigated whether melatonin (MT), a pineal-derived antioxidant that regulates mitochondrial dynamics, can counteract OBZ-induced oocyte damage. Key indicators were evaluated in both in vivo and in vitro models, including mitochondrial dynamics, Ca²⁺ homeostasis, distribution and membrane potential (ΔΨm), electron transport chain (ETC) gene expression, reactive oxygen species (ROS) generation, antioxidant enzyme activity, and spindle organization. MT supplementation restored mitochondrial homeostasis by promoting fusion gene expression (Mfn1/2, Opa1) and suppressing fission genes (Drp1, Fis1, Mff), while reducing OBZ-induced cytosolic and mitochondrial Ca²⁺ overload. These protective effects reversed OBZ-related abnormalities such as disrupted mitochondrial distribution, spindle disorganization, decreased ΔΨm, downregulated ETC genes, and pronounced oxidative stress characterized by elevated ROS and diminished GSH. Microtranscriptomic analysis further suggested involvement of enhanced Ca²⁺ signaling and ATP-dependent chromatin remodeling in MT-mediated oocyte protection. Overall, our findings indicate that mitochondrial dysfunction is a critical component of OBZ-induced oocyte impairment, and support MT as a potential intervention to preserve oocyte quality under environmental toxicant exposure.
    Keywords:  Melatonin; Mitochondrial dynamics; Oocyte maturation; Oxybenzone
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119348
  19. Mol Neurobiol. 2025 Nov 15. 63(1): 43
    B355252 Targets UCP2 to Rescue Intracerebral Hemorrhage-Induced Injury by Promoting Mitochondrial Fusion and Inhibiting Ferroptosis.
    Bo Han, Changsheng Ma, Yongping Liu, Changku Shi, Jinfen Guo, Min Bai, Mengyuan Duan, Shuchen Meng, Jiaqi Liu, Maotao He.
      Intracerebral hemorrhage (ICH), a subtype of stroke, is associated with extremely high mortality and disability rates. The small-molecule compound B355252 exhibits neuroprotective effects against oxidative stress and ferroptosis. However, whether B355252 exerts protective effects against ICH-induced injury remains undefined. Furthermore, the therapeutic time window of B355252 for ICH has not been systematically elucidated. Therefore, this study aims to investigate the therapeutic effects of B355252 on ICH, elucidate its role and underlying mechanisms in inhibiting ICH progression, and determine its therapeutic time window. In this study, a mouse model of collagenase-induced intracerebral hemorrhage was established. Multifaceted assessments included histopathological analysis, behavioral tests, transmission electron microscopy (TEM), and lipid peroxidation assays. Results showed that B355252 significantly reduced the hematoma volume and improved neurological deficits in ICH mice. Mechanically, B355252 regulated mitochondrial dynamics and enhanced mitochondrial structural integrity by targeting uncoupling protein 2 (UCP2), leading to upregulation of the fusion protein MFN2 and inhibition of the fission protein FIS1. In addition, B355252 significantly inhibited oxidative stress by maintaining mitochondrial homeostasis, thereby reducing lipid peroxidation and alleviating ferroptosis. Notably, safety assessment confirmed no organ toxicity and extended the treatment time window to 8.5 h. In conclusion, B355252 is a novel UCP2 agonist that maintains mitochondrial function by regulating mitochondrial dynamics and inhibits ferroptosis by mitigating oxidative stress. It overcomes the critical 6-h treatment time window limitation in the ICH model, paving the way for novel research directions in ICH treatment.
    Keywords:  B355252; Ferroptosis; Intracerebral hemorrhage (ICH); Oxidative stress; Uncoupling protein 2 (UCP2)
    DOI:  https://doi.org/10.1007/s12035-025-05368-5
  20. Mol Neurobiol. 2025 Nov 14. 63(1): 38
    Nicotine Improves Memory Impairment in Aged Rats Through Enhanced Mitochondrial Homeostasis.
    Zhen Ni, Yingyan Li, Gaoge Wang, Shu Wang, Huan Chen, Hongwei Hou, Qingyuan Hu.
      Aging induces progressive changes that heighten the central nervous system's (CNS) vulnerability to neurological disorders. Emerging evidence suggests that nicotine, an alkaloid primarily derived from plants of the genus Nicotiana, may offer neuroprotective effects against aging. However, its role in maintaining mitochondrial homeostasis during aging remains unexplored. In this study, we demonstrated that nicotine improved recognition memory in aging rats. Additionally, it increased dopamine (DA) levels and upregulated PSD95 and synaptophysin expression in the hippocampus of aged rats. Notably, RNA sequencing (RNA-seq) analysis revealed that nicotine promoted mitochondrial homeostasis in the hippocampus. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that genes enriched in the nicotine-treated group were predominantly associated with axon guidance, cholinergic, GABAergic, and dopaminergic synapses. Similarly, Gene Ontology (GO) enrichment analysis highlighted the involvement of these genes in key biological processes, including learning, memory, and axon guidance. Moreover, nicotine reversed aging-associated gene expression patterns linked to mitochondrial function. Consistently, it upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and Parkin expression both in vivo and in vitro, while also enhancing mitochondrial respiratory capacity in SH-SY5Y cells. Collectively, our findings reveal that nicotine promotes hippocampal PGC-1α expression and mitophagy, thereby preserving mitochondrial homeostasis during aging. This study suggests a potential strategy for mitigating age-related memory decline.
    Keywords:  Aging; Memory; Mitochondria; Nicotine; RNA-seq
    DOI:  https://doi.org/10.1007/s12035-025-05342-1
  21. J Agric Food Chem. 2025 Nov 10.
    Ursolic Acid Activates Mitochondrial Unfolded Protein Response to Enhance Innate Immunity via Transcription Factor ATFS-1/ATF5.
    Jun Xiong, Xiaocong Li, Fangfang Mao, Nengyue Wang, Fang Liu, Yi Xiao.
      Ursolic acid (UA), a pentacyclic triterpenoid found in various plants, exhibits diverse biological activities. The mitochondrial unfolded protein response (UPRmt) acts as a pivotal regulator in orchestrating innate immune responses. However, it remains unclear whether UA modulates innate immunity, and the molecular mechanisms involved have yet to be elucidated. In this study, we established that UA enhances the survival of Caenorhabditis elegans against Pseudomonas aeruginosa PA14 infection by promoting intestinal bacterial clearance, independent of inhibitory effects on bacterial growth or evasion behavior. Mechanistically, UA activates the UPRmt via transcription factor ATFS-1 and its downstream immune-related genes to bolster innate immunity. Furthermore, UA also protects A549 human lung epithelial cells and mice from PA14 infection by activating the UPRmt through ATF5. These findings provide a novel perspective and theoretical foundation for developing UA-based natural immune enhancers against infections, highlighting significant translational potential.
    Keywords:  Caenorhabditis elegans; innate immunity; mice; mitochondrial unfolded protein response; ursolic acid
    DOI:  https://doi.org/10.1021/acs.jafc.5c09928
  22. Eur J Pharmacol. 2025 Nov 06. pii: S0014-2999(25)01091-X. [Epub ahead of print]1008 178337
    The role of ubiquitylation in cerebral ischemia-reperfusion injury to reduce mitochondrial dysfunction and programmed cell death.
    Zheng Li, Jihong Xing.
      The morbidity and mortality of cardiac arrest are notably high and a major public health issue worldwide. Cerebral ischemia-reperfusion injury (CIRI) is a major cause of mortality and poor neurological outcome in cardiac arrest patients. Mitochondria, the energy centers of most eukaryotic cells, are a "hub" in CIRI development, and regulating mitochondrial dynamics and mitophagy to maintain the relative quantity and quality of mitochondria in the internal environment has gained attention. Modulating key protein expression in the pyroptosis and ferroptosis pathways is an important strategy in treating CIRI. Ubiquitination, a posttranslational modification, is involved in fundamental pathophysiological processes such as neurological disorders, ischemia-reperfusion injury and inflammation, and oxidative stress. This narrative review summarizes the research progress in ubiquitin protease system intervention affecting mitochondrial homeostasis, pyroptosis, and ferroptosis in the context of CIRI. Our aim is to provide a favorable reference for effectively improving the prognosis of patients with cardiac arrest.
    Keywords:  Cerebral ischemia reperfusion injury; Ferroptosis; Mitophagy; Pyroptosis; Ubiquitin proteasome system
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178337
  23. ACS Nano. 2025 Nov 12.
    Near-Infrared-Triggered Photoresponsive Nanobombs Overcome Tumor Immunosuppression through Coordinated Pyroptosis Activation and Mitophagy Blockade.
    Shanshan Zhang, Mengjie Ye, Linlin Han, Hengbo Zhang, Qihan Wang, Menglin Zhang, Fanpeng Ran, Xiaoxiao Shi, Zhigang Xu.
      Solid tumors resemble fortified hypoxic bastions with multifaceted defense mechanisms, wherein the synergistic interplay of hypoxia and immunosuppressive networks severely limits conventional therapies. While reactive oxygen species (ROS)-induced pyroptosis holds promise for remodeling the immunosuppressive tumor microenvironment (TME) and potentiating antitumor immunity, mitochondrial autophagy-mediated oxidative damage repair in cancer cells critically attenuates its efficacy. To address this, we engineered a near-infrared (NIR)-activated ″photocontrolled nanobomb″ (PPLs) that integrates tumor-targeted ROS generation, self-accelerating disintegration, pyroptosis induction, and mitochondrial autophagy blockade for precision ″fortress″ dismantling. Upon NIR irradiation, PPLs rapidly produce cytotoxic ROS, triggering Caspase-1-dependent pyroptosis while undergoing programmed structural collapse. Concurrently, the released lonidamine (LND) inhibits HK2-driven mitochondrial autophagy, synergistically amplifying oxidative damage and immunogenic cell death. This dual-action strategy effectively reprograms the immunosuppressive TME by enhancing dendritic cell maturation and cytotoxic T lymphocyte infiltration, establishing a pro-inflammatory antitumor niche. Our work not only presents an NIR-responsive nanoplatform for spatiotemporal tumor eradication but also deciphers the mechanistic synergy between pyroptosis and mitochondrial autophagy inhibition, offering an effective path for combinatorial immunotherapy.
    Keywords:  mitophagy blockade; near-infrared light response; photodynamic immunotherapy; polyprodrug nanoassemblies; pyroptosis
    DOI:  https://doi.org/10.1021/acsnano.5c16196
  24. IUBMB Life. 2025 Nov;77(11): e70054
    MTFR1 Promotes Proliferation and Metastasis of Triple-Negative Breast Cancer by Regulating Mitochondrial Metabolism.
    Zhengzhi Zhu, Jing Wang, Jianjun Liu, Guoping Sun.
      Mitochondria, as the center of cellular energy metabolism, play multiple key roles in the progression of triple-negative breast cancer (TNBC). Mitochondrial fission regulator 1 (MTFR1) is a mitochondrial regulatory factor that plays a part in regulating mitochondrial fission and cell development. It is still unknown how MTFR1 functions in TNBC. We discovered MTFR1 to be a crucial gene in TNBC with clinical diagnostic value using database mining analysis. The effects of MTFR1 on TNBC cell proliferation, migration, invasion, and mitochondrial function were determined using the Cell Counting Kit-8, wound healing, and Transwell assays. Nude mouse models were established to explore the impact of MTFR1 on TNBC tumor growth and metastasis. Additionally, western blot and transcriptome sequencing (RNA-seq) were used to investigate the mechanism of MTFR1's involvement in TNBC progression. We used database extraction, WGCNA, Cox regression, and ROC (receiver operating characteristic) curve analysis to identify and confirm MTFR1 as a critical gene in TNBC. In TNBC patients, high MTFR1 expression is related to poor prognosis and diagnostic value. Knockdown of MTFR1 inhibits the proliferation and metastasis of TNBC cells and tumor bodies, affecting mitochondrial function. MTFR1 knockdown inhibits the growth, metastasis, and mitochondrial function of TNBC cells and tumors. Furthermore, transcriptome sequencing and western blot experiments confirmed that MTFR1 knockdown inhibits the activation of the NF-κB signaling pathway. In this study, we report for the first time that MTFR1 is a critical gene upregulated in TNBC. MTFR1 is an oncogene in TNBC and is involved in cell growth, migration, and mitochondrial function, and promotes TNBC progression through the NF-κB signaling pathway. Therefore, targeting MTFR1 may be a promising therapeutic target for TNBC patients.
    Keywords:  MTFR1; NF‐κB signaling pathway; migration; mitochondrial function; proliferation; triple‐negative breast cancer
    DOI:  https://doi.org/10.1002/iub.70054
  25. Cells. 2025 Oct 29. pii: 1698. [Epub ahead of print]14(21):
    Developmental Differences in Myocardial Mitochondrial Reticulum Networks in the Offspring Exposed to Diabetic Pregnancy.
    Prathapan Ayyappan, Tyler C T Gandy, David Sturdevant, Tricia D Larsen, Pradeeksha Mukuntharaj, Andrew Paulson, Trace A Christensen, Jeffrey L Salisbury, Michelle L Baack.
      Diabetic pregnancy increases the offspring's risk of neonatal and adult cardiovascular disease (CVD). We previously used a rat model (Sprague-Dawley) to show that diabetic pregnancy impairs mitochondrial bioenergetics, dynamics, mitophagy, and quality control in the offspring's heart, and we hypothesized that mitochondrial dysfunction during early development influences the adult myocardium structure to confer cardiometabolic disease risk with aging. Here, we used 3D serial block face-scanning electron microscopy (SBF-SEM) to analyze perinuclear (PN) and intrafibrillar (IF) mitochondrial networks in the left ventricular sections from control and pregestational diabetes-exposed newborn (NB) rats that were three-week-old and four-month-old. Diabetes-exposed myocardium had 50% fewer PN and 20% fewer IF mitochondria at birth but counts increased more rapidly, resulting in no difference at three weeks and 35% more PN and 49% more IF mitochondria by four months. Despite rising counts, mitochondria volumes remained significantly lower at every developmental timepoint. This shows that diabetic pregnancy causes maldevelopment of the myocardial mitochondrial reticulum which likely contributes to adult CVD.
    Keywords:  diabetic pregnancy; heart disease; mitochondrial dynamics; mitochondrial networks; myocardial development; myocardial reticulum
    DOI:  https://doi.org/10.3390/cells14211698
  26. Free Radic Biol Med. 2025 Nov 11. pii: S0891-5849(25)01352-8. [Epub ahead of print]
    LINC03047 promotes mitophagy by recruiting hnRNPF to enhance CTGF mRNA stability in hypoxic pulmonary hypertension.
    Binbin Zhang, Pulin Li, Ling Huang, Can Wang, Rui Han, Wanrong Wang, Min Li, Chao Cao, Ran Wang.
      Pulmonary hypertension (PH) is a progressive and debilitating vascular disorder characterized by pulmonary vascular remodeling, primarily driven by the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). In this pathogenic process, mitophagy, a selective form of autophagy, has been identified as playing a pivotal role. Long non-coding RNAs (lncRNAs) are increasingly recognized as significant regulatory elements in various diseases; however, their specific functions in the context of PASMCs mitophagy and proliferation remain largely unexplored. This study aims to investigate the role of a hypoxia-associated lncRNA, long intergenic non-protein coding RNA 3047 (LINC03047), in modulating mitophagy and cellular proliferation in hypoxia-induced PASMCs. Our findings reveal that LINC03047 is significantly upregulated in PASMCs under hypoxic conditions and promotes cell proliferation by activating mitophagy. Mechanistically, we demonstrate that LINC03047, which is transcriptionally regulated by the signal transducer and activator of transcription 3 (STAT3), physically binds to heterogeneous nuclear ribonucleoprotein F (hnRNPF). This interaction inhibits the nuclear translocation of hnRNPF and enhances the stability of connective tissue growth factor (CTGF) mRNA, thereby amplifying its downstream effects. Furthermore, in vivo experiments confirmed that targeted inhibition of hnRNPF effectively mitigates the development of hypoxia-induced PH in model systems. Collectively, these findings elucidate a novel regulatory axis and demonstrate that targeting the STAT3/LINC03047/hnRNPF/CTGF signaling pathway offers a promising therapeutic strategy for the treatment of PH.
    Keywords:  Long non-coding RNAs; Mitophagy; Pulmonary hypertension; hnRNPF
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.017
  27. Phytomedicine. 2025 Nov 06. pii: S0944-7113(25)01131-6. [Epub ahead of print]149 157494
    Z-Ligustilide's antidepressant effects in adolescent depression involve the PTEN-induced putative kinase 1 (PINK1) - protein kinase A (PKA)- Na+/Ca2+ exchanger (NCLX) pathway, facilitating mitochondrial endosymbiosis and promoting mitophagy in microglia.
    Tao Yi, Feng Qiu, Jiayi Shi, Dahua Wu, Dandan Li, Xi Zhang, Xu He, Dan Huang, Kaimei Tan, Hongyu Zeng, Yuhong Wang, Jinwen Ge, Zhigang Mei, Xiuli Zhang.
       BACKGROUND: Adolescent depression is a prevalent and escalating public health concern. Z-Ligustilide (Z-LIG), a bioactive phthalide extracted from Angelica sinensis (Oliv.) Diels-a Chinese herbal medicine commonly used for its antidepressant effects-exhibits significant anti-inflammatory properties, extensive brain distribution, and low cytotoxicity. Nevertheless, its underlying mechanism in adolescent depression remains unclear.
    PURPOSE: This study aimed to investigate how the PINK1-PKA-NCLX pathway contributes to Z-LIG-induced M2 microglial polarization to alleviate adolescent depression.
    METHODS: In this study, proteomic analysis followed by molecular docking, surface plasmon resonance (SPR), and tryptophan fluorescence quenching assays identified PINK1 as the target of Z-LIG. This finding was validated using a chronic unpredictable mild stress (CUMS)-induced adolescent rat model. Consequently, the efficacy of Z-LIG in depression-like behaviors and M2 microglial polarization in the hippocampus was confirmed. To explore the role of PINK1-PKA-NCLX pathway in Z-LIG-induced M2 microglial polarization, the NCLX inhibitor CGP-37,157 (CGP) and the PKA inhibitor dihydrochloride (H89) were used after PINK1 overexpression and Z-LIG treatment. The association between PINK1-PKA-NCLX signaling pathway and PINK1-Parkin pathway was investigated in the context of NCLX overexpression, Z-LIG treatment, and their combination with CGP. Finally, AAV-siPINK1 was administered in vivo to fur corroborate the antidepressant effects of Z-LIG through PINK1 targeting.
    RESULTS: PINK1-Parkin-mediated mitophagy and Ca2+ signaling pathways were implicated in adolescent depression. Z-LIG binds strongly to PINK1, thereby enhancing its stability. Z-LIG effectively alleviated depression-like behaviors in adolescent rats by promoting M2 microglia in the hippocampus. PINK1 overexpression and Z-LIG treatment shifted lipopolysaccharide (LPS)-induced M1 microglia to M2 via PINK1-PKA-NCLX and PINK1-Parkin pathways, an effect that was reversed by H89 and CGP. Z-LIG exhibited effects similar to those of NCLX, characterized by reduced cytoplasmic reactive oxygen species (ROS) and DNA levels, while concurrently increasing DNA-mitochondria colocalization and mitochondrial ROS (mtROS) levels in LPS-treated BV2 cells. Furthermore, Z-LIG and NCLX enhanced the AMPK and Parkin phosphorylation. CGP negated the impact of Z-LIG on cytoplasmic ROS, DNA levels, DNA-mitochondria colocalization, and Parkin phosphorylation, but not on mtROS. AAV-si-PINK1 administration abolished the antidepressant effects of Z-LIG.
    CONCLUSIONS: PINK1-PKA-NCLX pathway contributes to the antidepressant effects of Z-LIG in adolescent depression by stabilizing mitochondrial endosymbiosis and promoting the PINK1-Parkin pathway, which together enhances M2 microglia in the hippocampus. This suggests that Z-LIG may serve as a novel treatment for adolescent depression.
    Keywords:  Adolescent depression; Microglia; Mitochondrial endosymbiosis; NCLX; Z-Ligustilide (Z-LIG)
    DOI:  https://doi.org/10.1016/j.phymed.2025.157494
  28. Eur J Pharmacol. 2025 Nov 11. pii: S0014-2999(25)01109-4. [Epub ahead of print]1008 178355
    NF-κB/TOM6/PINK1-mediated mitophagy attenuates vascular calcification: Luteolin as a therapeutic modulator.
    Jinhe Li, Qingchun Liang, Yining Li, Bing Liang, Jinshu Liang, Jianyun Yan, Jun Zhou.
      Vascular calcification (VC), a significant contributor to cardiovascular risk, lacks effective therapies. The natural flavonoid luteolin (LU) shows therapeutic potential, but its mechanism against VC is not fully elucidated. This study identifies a novel pathway wherein LU attenuates VC by restoring mitophagy via the Nuclear Factor Kappa B (NF-κB)/Translocase of Outer Mitochondrial Membrane 6 (TOM6)/PTEN-induced kinase 1 (PINK1) pathway. In vitro, LU dose-dependently inhibited calcification in vascular smooth muscle cells (VSMCs) and arterial rings, suppressing expression of osteogenic markers such as bone morphogenetic protein 2 (BMP2), Runt-related transcription factor 2 (Runx2), and restoring expression of contractile proteins such as alpha-smooth muscle actin (α-SMA), smooth muscle protein 22-alpha (SM22). In vivo, LU ameliorated VC in Vitamin D3 (VitD3)-overloaded mice and rats with chronic kidney disease (CKD). RNA sequencing identified TOM6 as a key gene upregulated during calcification and suppressed by LU. Functionally, TOM6 knockdown attenuated VC, whereas its overexpression exacerbated VC and reversed the anti-calcific effect of LU. Mechanistically, LU enhanced PINK1/Parkin-mediated mitophagy by downregulating TOM6, thereby improving mitochondrial bioenergetics. Furthermore, LU directly binds the inhibitor of nuclear factor kappa-B kinase subunits alpha and beta (IKKα/IKKβ), thereby inhibiting NF-κB nuclear translocation and TOM6 transcription. Collectively, our results identify the NF-κB/TOM6/PINK1 mitophagy axis as a key mechanistic pathway required for LU to mitigate VC, suggesting a novel therapeutic target.
    Keywords:  Luteolin; Mitophagy; PINK1; TOM6; Vascular calcification; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178355
  29. Immunol Res. 2025 Nov 15. 73(1): 166
    MYC affects mitochondrial function in IgA nephropathy by promoting the degradation of MFN1 through HRD1.
    Xueping Wu, Lei Liu, Ruiping Zhao, Weidong Chen.
      IgA nephropathy is characterized by the deposition of IgA and complement C3 in the glomerular mesangial region. Recent research has pointed out the critical role of mitochondrial damage during the occurrence and development of IgAN. During IgAN progression, elevated myc promotes the transcription of HRD1, which in turn induces the ubiquitination of MFN1, leading to mitochondrial dysfunction. We found that the expression levels of myc and HRD1 were elevated in IgAN. Down-regulation of HRD1 and myc successfully alleviated IgAN progression by promoting cell survival, reducing renal injury and improving mitochondrial homeostasis. Additionally, we observed reduced levels of MFN1 expression in IgAN. Overexpression of MFN1 significantly inhibited IgAN progression, while the deficiency of MFN1 exacerbated IgAN injury. In summary, our findings revealed that myc plays a critical role in regulating mitochondrial function in IgAN by promoting HRD1 transcription and inducing MFN1 ubiquitination. These results suggested that targeting myc/HRD1/MFN1 axis may offer a novel therapeutic strategy to combat IgAN progression.
    Keywords:  HRD1; IgA nephropathy; MFN1; Mitochondrial; Myc
    DOI:  https://doi.org/10.1007/s12026-025-09695-6
  30. Int J Mol Sci. 2025 Nov 06. pii: 10793. [Epub ahead of print]26(21):
    HSALR Mice Exhibit Co-Expression of Proteostasis Genes Prior to Development of Muscle Weakness.
    Dusan M Lazic, Vladimir M Jovanovic, Jelena Karanovic, Dusanka Savic-Pavicevic, Bogdan Jovanovic.
      Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by a CTG repeat expansion in the DMPK gene. The toxic mutant mRNA sequesters MBNL proteins, disrupting global RNA metabolism. Although alternative splicing in DM1 skeletal muscle pathology has been extensively studied, early-stage transcriptomic changes remained uncharacterized. To gain deeper and contextual insight into DM1 transcriptome, we performed the first Weighted Gene Co-expression Network Analysis (WGCNA) on skeletal muscle RNA sequencing data from the widely used DM1 mouse model HSALR (~250 CTG repeats). We identified 532 core genes using data from 16-week-old mice, an age before the onset of muscle weakness. Additional differential expression analysis across multiple HSALR datasets revealed 42 common up-regulated coding and non-coding genes. Within identified core genes, the pathway gene-pair signature analysis enabled contextual selection of functionally related genes involved in maintaining proteostasis, including endoplasmic reticulum (ER) protein processing, the ubiquitin-proteasome system (UPS), macroautophagy and mitophagy, and muscle contraction. The enrichment of ER protein processing with prevailing core genes related to ER-associated degradation suggests adaptive chaperone and UPS activation, while core genes such as Ambra1, Mfn2, and Usp30 indicate adaptations in mitochondrial quality control. Coordinated early alterations in processes maintaining protein homeostasis, critical for muscle mass and function, possibly reflect a response to cellular stress due to repeat expansion and appears before muscle weakness development. Although the study relies exclusively on transcriptomic analyses, it offers a comprehensive, hypothesis-generating perspective that pinpoints candidate pathways, preceding muscle weakness, for future mechanistic validation.
    Keywords:  ER-associated degradation; HSALR; WGCNA; autophagy; mitophagy; myotonic dystrophy type 1; protein homeostasis; proteostasis; repeat expansions; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3390/ijms262110793
  31. Int J Biol Macromol. 2025 Nov 08. pii: S0141-8130(25)09462-0. [Epub ahead of print] 148905
    Acetylated KLF5 inhibits LACTB transcription, mediates mitochondrial dynamics, and regulates colorectal cancer cell stemness and differentiation.
    Lili Ma, Chun Lin, Zebin Xiao, Guan Huang, Chao Liu, Hongmei Wu, Tian Qin, Qiang Tu, Zhihua Liu, Qingling Zhang, Yang Luo.
      This study aims to investigate the role of LACTB (Serine beta-lactamase-like protein) in colorectal cancer (CRC) cell stemness and differentiation. In the current study, we assessed LACTB expression levels by analyzing data from database and our collected CRC samples. The association between LACTB level and clinical characteristics was further explored. HT29 and SW480 cell lines were employed for the in vitro experiments. A series of experiments were performed to investigate protein-protein and protein-DNA interactions. KLF5 knockout cell lines were established using CRISPR/Cas9 double-knockout plasmids. Acetylated K369 mimic KLF5 and deacetylated K369 mimic KLF5 were constructed to investigate the function of K369 acetylation. Finally, the functional significance of these findings was validated in a xenograft model. Our results showed that compared with adjacent normal tissues, LACTB exhibited low expression levels in CRC tissues, with particularly low levels observed in poorly differentiated carcinomas. Functional studies revealed that LACTB overexpression promoted cell differentiation while suppressing cell stemness. Mechanistically, LACTB exerted its function by destabilizing OMA1 protein, thereby modulating OPA1-mediated mitochondrial fusion. Further experiments identified KLF5 as a transcriptional repressor of LACTB, with its suppressive effect dependent on acetylation at lysine 369 (K369). An acetylated-mimic KLF5 mutant exhibited enhanced capacity to promote stemness and block differentiation, whereas a deacetylation-mimic form displayed opposite effects. Collectively, our findings revealed that acetylated KLF5 inhibited LACTB transcription, which subsequently orchestrates mitochondrial dynamics through the OMA1/OPA1 axis, ultimately governing CRC cell stemness, differentiation and tumor progression.
    Keywords:  Cell differentiation; Cell stemness; Colorectal cancer; KLF5; LACTB
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148905
  32. Biomaterials. 2025 Nov 01. pii: S0142-9612(25)00747-1. [Epub ahead of print]328 123828
    Ultrasound-responsive piezoelectric hydrogel attenuates oxidative stress-induced nucleus pulposus senescence via AMPK-FOXO1a-mediated mitophagy for intervertebral disc regeneration.
    Wenbo Wu, Zhangrong Cheng, Pengzhi Shi, Haiyang Gao, Yuhang Chen, Anran Zhang, Xianglong Chen, Wang Wu, Yukun Zhang.
      The progression of intervertebral disc degeneration (IDD) is closely linked to the nucleus pulposus cells (NPCs) senescence driven by oxidative stress and extracellular matrix (ECM) abnormalities. This study presents an ultrasound-responsive, temperature-sensitive piezoelectric hydrogel (TT@P-Gel) that enables dual therapy combining electrical stimulation (ES) and controlled drug release, fabricated by incorporating pyrrole/barium titanate nanoparticles (PB NPs) loaded with tannic acid (TA) and transforming growth factor-β (TGF-β). Experiments have demonstrated that TT@P-Gel can initiate the electrically controlled release of TGF-β and facilitate the gradual TA release to neutralize reactive oxygen species (ROS) via ultrasound in vitro, thereby reducing β-galactosidase expression and restoring the mitochondrial membrane potential ΔΨm in senescent NPCs. Under ultrasound stimulation (US), TT@P-Gel via ES activated the AMPK-FOXO1a signaling pathway and promoted FOXO1a nuclear translocation. Additionally, ES and TA released from the hydrogel enhance SIRT1 expression, which stabilizes nuclear FOXO1a through deacetylation, thereby regulating the expression of downstream genes. Furthermore, TT@P-Gel stimulated the BNIP3-PINK1-Parkin pathway via FOXO1a to augment mitophagy, eliminate defective mitochondria, and counteract TBHP-induced cellular senescence. In vivo investigations indicated that TT@P-Gel combined with ultrasound, markedly enhanced the disc height index and Pfirrmann score while diminishing the expression of p16/p21, a marker of senescence, in a rat model of intervertebral disc degeneration. This study introduces an "electro-chemical synergy" strategy to modulate energy metabolism and mitophagy in senescent NPCs under oxidative stress, utilizing an ultrasound-responsive piezoelectric hydrogel, thereby offering a novel approach for the repair and treatment of intervertebral disc degeneration.
    Keywords:  Cellular senescence; Intervertebral disc degeneration; Mitophagy; Oxidative stress; Piezoelectric hydrogel
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123828
  33. J Pharmacol Exp Ther. 2025 Oct 15. pii: S0022-3565(25)40264-X. [Epub ahead of print]392(11): 103751
    Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death.
    Chun Cai, Michael W Spinrad, Lauren C Gattie, Rui Wang, Mohammad Amir Afjal, Jun Yang, Nour Yadak, David Shibata, Wei Li, Amandeep Bajwa, Evan S Glazer.
      Pancreatic ductal adenocarcinoma (PDA) is an almost universally fatal disease. Recent advances in the understanding of PDA bioenergetic dynamic equilibrium have illuminated a potential therapeutic target in bromodomain-related protein 4 (BRD4), the most active member of the bromo- and extraterminal domain (BET) protein family of transcription factors. We previously demonstrated that BET inhibitors (BETi) decrease PDA cell proliferation and enhance chemosensitivity. We hypothesized that BETi activates mitophagy and ferroptosis in PDA. Using pharmacological and genetic BRD4 inhibition in PDA patient-derived models, we investigated the effects of BETi on mitochondrial function, mitochondrial protein complex production, ATP production, cellular respiration, autophagy/mitophagy, and murine tumor growth with BMS-986158, a BETi. We determined the role of BRD4 in PDA by evaluating mitophagy and autophagy. In PDA models, we found that BETi decreased cellular respiration (P < .01), decreased ATP production (P < .001), and increased intracellular iron uptake (P < .01) while inducing mitophagy through dysregulated mitochondria complex protein levels. Murine PDA tumors grew slower and were smaller when treated with BETi compared with the control treatment. PDA tumors from experimentally treated mice contained more lipid vacuoles than those from the vehicle control group (P < .01), consistent with ferroptosis. BETi therapy decreased isocitrate dehydrogenase-1 expression, indicating increased chemosensitivity. BETi dysregulate mitochondrial complexes inducing mitophagy. BETi is a promising therapeutic strategy for attacking oncogenic mitochondrial behavior in PDA. We demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death. This treatment controls tumors and increases chemosensitivity, offering a novel therapeutic strategy. SIGNIFICANCE STATEMENT: Bromo- and extraterminal domain inhibition is a novel therapeutic strategy for attacking oncogenic mitochondrial behavior in pancreatic ductal adenocarcinoma. Using this strategy in patient-derived models, this study demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death and tumor control.
    Keywords:  Bromo- and extraterminal domain; Cancer therapeutics; Mitochondrial stress; Mitophagy; Pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.jpet.2025.103751
  34. Exp Ther Med. 2025 Dec;30(6): 245
    Selective autophagy in hepatocellular carcinoma: Mechanisms, roles and therapeutic implications (Review).
    Ching-Hua Hsieh.
      Selective autophagy, which is the targeted degradation of specific cellular components through lysosomes, serves a complex role in hepatocellular carcinoma (HCC). The present review explores the following 10 distinct selective autophagy pathways in HCC: Mitophagy, lysophagy, reticulophagy, pexophagy, nucleophagy, ribophagy, lipophagy, glycophagy, ferritinophagy and fluidophagy. In HCC, mitophagy can support therapy resistance by clearing damaged mitochondria, whereas lysophagy maintains lysosomal homeostasis through receptor recycling, such as coiled-coil domain containing 50. Reticulophagy, mediated by family with sequence similarity 134 member B (FAM134B), protects HCC cells from ferroptosis during kinase inhibitor treatment. Ferritinophagy, driven by nuclear receptor coactivator 4, regulates iron availability and sensitivity to ferroptotic cell death. Lipophagy has dual functions, where it provides energy substrates for tumor survival whilst potentially suppressing tumor growth through BCL2-interacting protein 3-mediated mechanism in fatty livers. Altogether, these aforementioned pathways offer therapeutic opportunities through inhibition, activation or synthetic lethality approaches. Promising strategies include combining ferroptosis inducers with autophagy inhibitors, targeting specific receptors, (such as FAM134B) and modulating mitophagy regulators (such as dynamin-related protein 1). In addition, autophagy-related biomarkers (sequestosome 1, LC-3B and beclin-1) are associated with clinical outcomes and may guide patient stratification. Given the bidirectional nature of selective autophagy in HCC, personalized approaches based on tumor context, specific pathway dependencies and disease stage are essential for effective therapeutic intervention.
    Keywords:  ferritinophagy; hepatocellular carcinoma; mitophagy; selective autophagy; therapeutic targeting
    DOI:  https://doi.org/10.3892/etm.2025.12995
  35. Phytomedicine. 2025 Nov 01. pii: S0944-7113(25)01142-0. [Epub ahead of print]148 157505
    Houttuynia cordata-derived nanoparticles stabilize mitochondrial dynamics to alleviate ulcerative colitis via the Nrf2/Ho-1 pathways.
    Wenyi Zhuang, Mengqi Qu, Yang Guan, Jieli Pan, Yan Tai, Guanqun Xie, Xiaohui Chen, Feiye Zhu.
       BACKGROUND: Ulcerative colitis (UC), a chronic inflammatory bowel disease, faces limited treatment efficacy and safety concerns. Extracellular vesicles (EVs) offer a promising nanoplatform for targeted therapy.
    PURPOSE: This study aimed to isolate and characterize houttuynia cordata-derived nanoparticles (HDNPs) and evaluate their therapeutic potential in UC by targeting dual pathological axes: mitochondrial dynamics dysregulation and oxidative-inflammatory cascades, aiming to address unmet needs in current UC therapies.
    METHODS: In vitro studies using LPS-stimulated Caco-2 cells (modeling inflamed intestinal epithelia) to evaluate mitochondrial dynamics, Nrf2/Ho-1 activation, oxidative stress. In vivo validation was performed in a DSS-induced murine UC model, assessing clinical parameters, histopathology and molecular markers.
    RESULTS: HDNPs administration significantly attenuated DSS-induced weight loss and elevated disease activity index, while preserving intestinal mucosal integrity. In vitro, HDNPs markedly reduced intracellular oxidative markers, activated Nrf2 signaling, and upregulated Ho-1 synthesis. Notably, Nrf2 inhibition abolished HDNPs' protective effects, confirming the critical role of this pathway in mediating therapeutic outcomes.
    CONCLUSION: HDNPs stabilize mitochondrial dynamics to restore epithelial energy homeostasis and activating the Nrf2/Ho-1 axis to suppress oxidative-inflammatory cascades, addressing critical limitations of conventional UC therapies and offering translational potential for clinical application.
    Keywords:  Anti-inflammation; Anti-oxidation; HDNPs; Houttuynia cordata-derived nanoparticles; Mitochondria; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.phymed.2025.157505
  36. Pharmacol Res. 2025 Nov 06. pii: S1043-6618(25)00453-0. [Epub ahead of print] 108028
    Mdivi-1 promotes lipid droplets-mitochondria contact and ameliorates cardiac lipotoxicity in high-fat diet-fed mice.
    Zujie Xu, Zheying Ma, Huiqian Ren, Yaming Yang, Xiaoqin Zhao, Bing Zhang.
      Myocardial lipid overload triggers excessive mitochondrial fission and impairs lipid droplets (LDs)-mitochondrial contact, thereby contributing to the development of lipotoxic cardiomyopathy. This study aimed to investigate whether the mitochondrial fission inhibitor Mdivi-1 could alleviate cardiac lipotoxicity by restoring LDs-mitochondria contact in high-fat diet (HFD)-fed mice. In vivo, male C57BL/6 HFD-fed mice were intraperitoneally injected with the mitochondrial fission inhibitor Mdivi-1 for 8 weeks. In vitro, H9C2 cardiomyoblasts were exposed to palmitic acid (PA), followed by treatment with Mdivi-1. Comprehensive assessments of cardiac function, along with molecular, biochemical, histological, cellular, and morphological analyses were performed. Results showed that Mdivi-1 treatment exerted protective effects against metabolic disorder and cardiac dysfunction in HFD-fed mice. Mdivi-1 promoted LDs-mitochondria contact by upregulating Plin2 and Plin5 expression, thereby alleviating cardiac lipotoxicity. Furthermore, PA disrupted the LDs-mitochondrial contact and induced lipotoxicity in a dose-dependent manner in H9C2 cardiomyoblasts. Mdivi-1 effectively inhibited PA-induced mitochondrial fission, restored LDs-mitochondrial contact, and facilitated the transport of fatty acids from LDs to the mitochondria for fatty acid oxidation in H9C2 cells. In conclusion, our study identifies Mdivi-1 as a novel cardioprotective agent capable of ameliorating cardiac lipotoxicity and promoting LDs-mitochondria contact.
    Keywords:  Cardiac lipotoxicity; Mdivi-1, Lipid droplets-mitochondria contact, High-fat diet (HFD)
    DOI:  https://doi.org/10.1016/j.phrs.2025.108028
  37. J Neurochem. 2025 Nov;169(11): e70272
    Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics.
    María S Marcora, Maximiliano J Katz, Azul Galo, Pablo Bochicchio, Vinicius Bongiovanni, Diego H Bodín, Mario R Pagani, Jorge D Correale, María J Pasquini.
      Iron deficiency (ID) is the most common micronutrient deficiency globally. ID in pre- and post-natal periods has been associated with impaired neurological development and altered behavior, which may persist despite iron supplementation. However, the neurobiological changes responsible for these findings have not been fully identified yet. Here, we develop an invertebrate experimental model using Drosophila melanogaster to study the impact of ID on glial cells. ID induced by dietary deferoxamine altered locomotor activity in adult flies. Glial-specific downregulation of the iron transporter Malvolio (Mvl) resulted in reduced locomotion, an effect prevented by iron supplementation in the fly medium. We confirmed that Mvl downregulation led to ID in the brain, where Mvl is partially expressed. Interestingly, Mvl reduction in ensheathing glia replicated locomotor activity deficits, which suggests that this glial subpopulation is particularly sensitive to iron levels. Mvl downregulation also altered mitochondrial morphology and size, in correlation with altered expression of mitochondrial fission and fusion genes, and mitochondrial electron transport chain complex genes. These results suggest that glial ID impairs normal mitochondrial dynamics and impacts energy production. Additionally, glial overexpression of mitochondrial ferritin, Fer3HCH, known to induce ID in the cytosol and mitochondria, also impaired locomotor activity, which highlights the importance of iron availability in both compartments. These findings demonstrate, for the first time, the importance of iron availability in Drosophila glial cells and its impact on behavior and mitochondrial dynamics. Most importantly, the Drosophila model proves useful in unveiling previously unknown cellular and molecular mechanisms associated with ID in glial cells.
    Keywords:   Drosophila ; Malvolio; glia; iron; mitochondria
    DOI:  https://doi.org/10.1111/jnc.70272
  38. Cardiovasc Res. 2025 Nov 12. pii: cvaf232. [Epub ahead of print]
    Targeting olfactory receptor 2 on monocytes for cardioprotection against myocardial ischemia-reperfusion injury via NR4A1-mediated mitochondrial fission.
    Yahao Zhang, Tingting Xiao, Jiandong Ding, Hao Jin, Yong Wu, Orion I R Chiara Villamil, Dong Wang, Mingming Yang, Junyan Cai, Genshan Ma, Wenbin Lu.
       AIMS: Acute myocardial infarction results in significant mortality and chronic heart failure, with reperfusion frequently inducing myocardial ischemia-reperfusion (IR) injury mediated by infiltrating monocytes and monocyte-derived macrophages (iMacs). The olfactory receptor 2 (Olfr2) is hypothesized to serve as a pivotal inflammatory mediator in this context. This study aimed to elucidate the regulatory role of Olfr2 in mitochondrial homeostasis and inflammation in iMacs during myocardial IR injury.
    METHODS AND RESULTS: The surface expression of OR6A2 (human ortholog of Olfr2) on monocyte subsets was assessed to determine its association with major adverse cardiovascular events (MACEs) in IR-injured patients. The mechanistic role of Olfr2 in modulating iMacs during myocardial IR injury was investigated using both in vivo and in vitro interventions targeting Olfr2. Elevated OR6A2 levels on human monocytes and octanal, an OR6A2 agonist, were significantly associated with an increased risk of MACEs and correlated with increased oxidative stress and pro-inflammatory responses in patients with IR injury. The genetic ablation of Olfr2 in mice demonstrated significant attenuation of mitochondrial reactive oxygen species (mtROS) and pro-inflammatory cytokine in iMacs, accompanied by diminished immune cell infiltration and reduced cardiomyocyte apoptosis, ultimately ameliorating myocardial IR injury. Mechanistically, Olfr2 activated nuclear receptor subfamily 4 group A member 1 (NR4A1) via cAMP/PKA signaling, promoting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which led to mitochondrial mtROS overproduction, mitochondrial membrane potential disruption, mitochondrial apoptosis, and the subsequent release of pro-inflammatory factors through NLRP3 inflammasome activation. Notably, monocyte/macrophage-specific NR4A1 overexpression in Olfr2 knockout mice negated the cardiovascular protection observed during IR injury.
    CONCLUSIONS: Elevated OR6A2 expression and octanal levels were significantly associated with an increased risk of MACEs. Our findings identified the Olfr2/cAMP/PKA/NR4A1 axis as a novel signaling pathway contributing to cardiac IR injury by promoting Drp1-mediated mitochondrial fission and subsequent production of pro-inflammatory cytokines.
    Keywords:  NR4A1; inflammation; mitochondrial fission; myocardial ischemia-reperfusion injury; olfactory receptor 2
    DOI:  https://doi.org/10.1093/cvr/cvaf232
  39. Cells. 2025 Oct 23. pii: 1657. [Epub ahead of print]14(21):
    Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
    Aya Attia, Katarzyna Majstrowicz, Samruddhi Shembekar, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Martin Bähler.
      Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs.
    Keywords:  Miro1/2; Myosin 19; OXPHOS; TRAK; cristae; mitochondria; outer mitochondrial membrane
    DOI:  https://doi.org/10.3390/cells14211657
  40. Dis Model Mech. 2025 Nov 14. pii: dmm.052146. [Epub ahead of print]
    Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's Disease.
    Mrudula Dileep, Anamika Sharma, Nandashree Kasturacharya, Syed Kavish Nizami, Steffy Manjila, Ashita Bhan, Gaiti Hasan.
      Our understanding of mechanisms underlying familial Parkinson's Disease (PD) have benefitted from studies in Drosophila models of PD. However, in a majority of PD patients the disease occurs sporadically and cellular phenotypes that arise early in sporadic PD remain to be understood. A genetic predisposition, arising from mutations in pathways that impact dopaminergic neuron health could be one cause of sporadic PD. Here, we studied Drosophila with single copies of recessive IP3R gene (itpr) mutants placed in combination with a recessive null mutant for the parkin gene. Whereas individual mutants appear normal, in combination they synergise to exhibit flight motor deficits with a focus in a subset of central dopaminergic neurons. Surprisingly, mitophagy and mitochondrial Ca2+ are barely affected. Instead, flight motor deficits correlate with elevated levels of mitochondrial H2O2 and reducing H2O2 levels by genetic means restored mitochondrial function and flight to a significant extent. This study underlines the importance of mitochondrial oxidative stress as an early phenotype in PD and suggests that humans with recessive mutations in either pathway have a higher chance of developing sporadic PD.
    Keywords:  Calcium homeostasis; Dopaminergic neurons; Flight; Motor function; PPL1
    DOI:  https://doi.org/10.1242/dmm.052146
  41. Circ Genom Precis Med. 2025 Nov 10.
    Aberrant Splicing of Dnm1l Impairs Cardiac Bioenergetics and Mitochondrial Dynamics in Myotonic Dystrophy Type I (DM1).
    Oluwafolajimi Adesanya, Pouya Nabie, Alexandra Betancourt, Auinash Kalsotra.
      Background: DM1 is caused by a (CTG)n trinucleotide repeat expansion in the 3'UTR of the DMPK gene. Once expressed, repeat RNA form toxic hairpins that sequester the muscle blind-like (MBNL) family of splicing factors. This disrupts tissue alternative splicing landscape, triggering multisystemic manifestations - myotonia, muscle weakness, cardiac contractile defects, arrhythmia, and neurologic disturbances. While impaired mitochondrial function has been reported in brain, skeletal muscle, and fibroblasts of DM1 patients, they have not been reported in the heart, nor have their contribution to the DM1 cardiac pathogenesis been explored. Here, we probed the bioenergetic profile of DM1-afflicted heart tissues and explored the mechanistic basis of DM1-induced cardiac bioenergetic defects. Methods: Using an inducible, heart-specific DM1 mouse model, we performed extracellular flux analyses, measured total ATP and NAD(H) concentrations, and performed immunofluorescence staining and transmission electron microscopy to characterize DM1-induced cardiac bioenergetics and mitochondrial structural defects. We analyzed eCLIP-Seq data to identify mitochondria-related missplicing events, which we validated in human and mouse DM1 heart tissues. Finally, we used antisense oligonucleotides (ASO) to replicate these events and to test the recapitulation of DM1-like bioenergetic and structural defects in vitro. Results: DM1 induced a multi-state decrease in oxygen consumption rate (OCR) with a corresponding reduction in ATP and NAD(H) concentrations, indicating impaired oxidative phosphorylation in DM1-afflicted mouse hearts. We also found significant cardiac mitochondria fragmentation, which correlated with the missplicing of transcripts encoding mitochondria fission factor (Mff, encodes MFF protein) and dynamin related protein 1 (Dnm1l, encodes DRP1 protein) in DM1-afflicted human and mouse hearts. ASO-mediated redirection of Dnm1l alternative splicing reproduced DM1-like impairment in cardiac bioenergetics and mitochondrial dynamics in wild type HL-1 cardiomyocytes. Conclusions: Together, these findings reveal that expanded (CUG)n RNA toxicity in DM1 disrupts cardiac bioenergetics through missplicing of critical mitochondrial fission transcripts. These misspliced transcripts represent potential therapeutic targets for improving mitochondrial function and cardiac symptoms of DM1.
    DOI:  https://doi.org/10.1161/CIRCGEN.125.005492
  42. Nature. 2025 Nov 12.
    Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
    Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.
      Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.
    DOI:  https://doi.org/10.1038/s41586-025-09745-x
  43. J Ethnopharmacol. 2025 Nov 08. pii: S0378-8741(25)01569-7. [Epub ahead of print] 120877
    Bidens biternata (Lour.) Merr. & Sherff improves liver lipid metabolism disorders in type 2 diabetic mice by activating mitophagy.
    Yi Li, Shuyu Kang, Qiwen Wang, Congyan Zeng, Gengting Dong.
       ETHNOPHARMACOLOGICAL RELEVANCE: Bidens biternata (Lour.) Merr. et Sherff (JZYP), a congener of the well-studied hypoglycemic herb Bidens pilosa L, remains pharmacologically underexplored despite shared traditional use for metabolic disorders. While Bidens pilosa L. demonstrates validated anti-diabetic and hepatoprotective properties, this study pioneers the mechanistic investigation of JZYP's therapeutic potential in type 2 diabetes mellitus (T2DM).
    AIM OF THE STUDY: The aim of this study was to elucidate the anti-steatotic effects of JZYP on T2DM-associated hepatic lipid accumulation and investigate the underlying mechanisms.
    MATERIALS AND METHODS: JZYP extract was prepared and analyzed by UPLC-Q-TOF/MS. HFD-fed ob/ob mice were used to establish a model of T2DM with hepatic lipid metabolic dysfunction and then administered with JZYP (3.9, 7.8 g/kg) for 6 weeks. Biochemical lipid parameter were analysis alongside Hematoxylin-eosin (HE) and Oil Red O staining. Western blotting was used to evaluate hepatic lipid metabolism-related proteins. Liver metabolomic profiling were used to explore the metabolome changes and subsequent pathway. The occurrence of mitophagy was detected using fluorescence co-localization, and the real-time quantitative (RT-qPCR) and immunohistochemistry (IHC) were utilized to quantify the mitophagy-associated gene and protein expressions.
    RESULTS: 245 chemical constituents were identified in JZYP, with 88 detected in positive ion mode, and 157 negative ion mode. It effectively alleviated metabolic disorders, reduced hepatic pathological damage, and down-regulated the expression of lipid-related proteins in the livers of HFD.-fed mice. The study further identified 47 significantly altered lipid compounds, most of which were enriched in Glycerophospholipid metabolism. The JZYP group showed elevated level of PC/PE compared to the model group. Immunofluorescence analysis of TOM20 and LC3 demonstrated a strong correlation, suggesting the activation of mitophagy. PCR and IHC confirmed that JZYP activated the mitophagy pathway.
    CONCLUSIONS: This study demonstrated that beneficial effects of JZYP on ameliorating hepatic lipid accumulation in T2DM mice, potentially through enhancing mitophagy and suppressing de novo lipogenesis. These findings positions JZYP as a promising botanical candidate for managing metabolic syndrome-related hepatopathies.
    Keywords:  Bidens biternata (Lour.) Merr. & Sherff; Type 2 diabetes; lipid accumulation; lipidomics; mitophagy
    DOI:  https://doi.org/10.1016/j.jep.2025.120877
  44. Mol Biol Rep. 2025 Nov 15. 53(1): 82
    Selenium alleviates Staphylococcus aureus-induced mastitis by modulating mitochondrial dynamics and inhibiting the ROS/NLRP3/Pyroptosis pathway.
    Xue Qi, Yanjun Hu, Jinghan Yang, Mingxuan Jiang, Junhao Zhang, Yanting Du, Changmin Hu.
       BACKGROUND: The pathogenesis of bovine mastitis involves inflammation and cell death, with pyroptosis being a key factor in its development. Currently, antibiotics remain the primary therapeutic option for bovine mastitis, however, the increasing prevalence of antibiotic resistance constitutes a major public health threat. Selenium (Se) has been reported to alleviate inflammation primarily through its antioxidant properties, but the mechanism by which Se regulates pyroptosis in bovine mastitis remains unclear.
    METHODS AND RESULTS: In this study, an in vitro mastitis model was established by infecting MAC-T cells with inactivated Staphylococcus aureus (S. aureus) (MOI = 10, 12 h). The results revealed that the mitochondrial membrane potential of the MAC-T cells in the infection group decreased significantly. Moreover, the accumulation of Reactive oxygen species (ROS) was accompanied by the activation of NOD-like receptor family containing pyrin domain 3 (NLRP3), the expression of the pyroptosis-related genes gasdermin D amino terminal fragment (GSDMD-N), and cysteine ​​aspartate specific protease 1 (cleaved-caspase 1). Pretreatment with Se, the NLRP3 inhibitor MCC950 and the antioxidant N-acetylcysteine ​​(NAC) attenuated mitochondrial damage, ROS accumulation, and the inhibition of pyroptosis. An in vivo mastitis model was established in mice fed a high-selenium diet (containing 1.5 mg/kg Se) and intramammarily injected with inactivated S. aureus (1 × 108 CFU/mL). Histological analysis revealed intact alveolar structure and reduced inflammatory cell infiltration in mice fed the high-selenium diet. The expression of the inflammasome NLRP3 downregulated, and the expression of GSDMD-N, a direct executor of pyroptosis, upregulated.
    CONCLUSION: Our in vitro and in vivo results confirmed that Se alleviate mitochondrial damage and pyroptosis by inhibiting the NLRP3 pathway, ultimately alleviating mastitis.
    Keywords:  Mastitis; Mitochondrial damage; Pyroptosis; ROS/NLRP3; Selenium
    DOI:  https://doi.org/10.1007/s11033-025-11164-0
  45. Cells. 2025 Oct 30. pii: 1702. [Epub ahead of print]14(21):
    Polydatin Prevents UVA-Induced Damage in Human Dermal Fibroblasts by Maintaining Mitochondrial Integrity.
    Benedetta Niccolini, Alessia Riente, Duaa Hatem, Patrizia Bottoni, Michela Pizzoferrato, Giuseppe Tringali, Elisabetta Tabolacci, Giuseppe Maulucci, Stefano Marini, Chiara Ciaccio, Maria Elisabetta Clementi.
      UVA radiation induces oxidative stress, mitochondrial dysfunction, and cell death in human dermal fibroblasts, contributing to skin aging and damage. In this study, we investigated the protective effects of polydatin, a natural polyphenol, against UVA-induced cell damage. Our results show that polydatin preserves cell viability and reduces intracellular reactive oxygen species (ROS) levels after UVA exposure. In addition, polydatin maintains mitochondrial integrity by preserving mitochondrial membrane potential and improving mitochondrial respiration. From a molecular perspective, polydatin regulates the expression of Nrf2, a key regulator of the cellular antioxidant response, thereby promoting cellular defense mechanisms. Additionally, polydatin attenuates UVA-induced mitochondrial fission, supporting a balanced mitochondrial dynamic profile. These results suggest that polydatin exerts a protective effect on UVA-irradiated fibroblasts, highlighting its potential for cosmetic and dermatological applications aimed at preventing photoaging and oxidative skin damage.
    Keywords:  UVA-induced damage; antioxidant compounds; mitochondrial function; oxidative stress; polydatin
    DOI:  https://doi.org/10.3390/cells14211702
  46. Sci Rep. 2025 Nov 14. 15(1): 39938
    Prognostic impact of mitochondrial dynamics-related miRNA levels during the treatment of acute heart failure in the hospital.
    Akihiro Shirakabe, Yoshiyuki Ikeda, Yoshihiro Uchikado, Hirotake Okazaki, Masato Matsushita, Tomofumi Sawatani, Shota Shigihara, Kenichi Tani, Masaki Morooka, Masahito Takahashi, Nobuaki Kobayashi, Mitsuru Ohishi, Junichi Sadoshima, Kuniya Asai.
      Mitochondrial dynamics-related RNAs during hospitalization for acute heart failure (AHF) were rarely evaluated in various points. In total, 234 patients who visited the emergency room for AHF were retrospectively evaluated. Blood samples were collected within 15 min of admission (day 1), after 48-72 h, and between days 7 and 21. Low miR-140-3p during hospitalization was defined as the level being categorized as Q1 more than once (on days 1, 3 and/or 14), and normal-140-3p during hospitalization as the level never being categorized as Q1. The median miR-140-3p levels were significantly decreased on days 3 and 14 (2.53 [1.06-6.42] and 3.65 [1.41-9.05], respectively) in comparison to the value on day 1 (6.71 [2.66-14.0]). Kaplan-Meier curves indicated that all-cause mortality within 1000 days was significantly higher in the low-miR-140-3p group than in the other-miR-140-3p group on days 1 and 14. Moreover, the survival rate was significantly lower and the rate of HF events was significantly higher in the low-miR-140-3p group than in the normal-miR-140-3p group. The miRNA levels of patients further decreased during treatment for AHF. Low levels of mitochondrial fission-related miRNAs during AHF treatment were independently associated with an increased risk of long-term adverse outcomes.
    Keywords:  Acute decompensated heart failure;  Mitochindrial fusion;  Mitochondrial fission;  Time-dependent changes and Prognosis
    DOI:  https://doi.org/10.1038/s41598-025-23792-4
  47. Front Nutr. 2025 ;12 1680518
    Phytochemical-rich Eucommia ulmoides leaf extract extends healthspan in Caenorhabditis elegans via the pmk-1/p38 MAPK pathway and mitochondrial homeostasis.
    Jiaxu Zhang, Quhuan Ma, Jiaojiao Li, Xingwen Xie, Xiaofeng Shi.
       Objectives: As a medicinal and edible resource, Eucommia ulmoides leaf (EUL) shows considerable promise in facilitating healthy aging. However, its precise biological mechanisms remain unclear. This study aimed to investigate the anti-aging efficacy and underlying pathways of Eucommia ulmoides leaf extract (EULE) using the Caenorhabditis elegans (C. elegans) model.
    Methods: Phytochemical profiling of the extract was performed. C. elegans were supplemented with the extract, and the effects on lifespan, healthspan indicators (muscle deterioration, intestinal barrier function, mitochondrial homeostasis), and gene expression were evaluated via transcriptomic analysis.
    Results: Phytochemical analysis revealed that the extract is abundant in bioactive compounds such as flavonoids, iridoids, and lignans. Supplementation with the extract significantly prolonged the lifespan of C. elegans by up to 14.69% and improved healthspan by alleviating age-related muscle deterioration, preserving intestinal barrier function, and regulating mitochondrial homeostasis. Transcriptomic analysis identified the mitogen activated protein kinase (MAPK) signaling pathway as the primary mediator of these anti-aging benefits.
    Conclusions: These results provide robust evidence supporting the use of EUL as a natural dietary supplement to prolong healthspan, establishing a scientific rationale for its application in promoting healthy aging.
    Keywords:  Caenorhabditis elegans; Eucommia ulmoides leaf; MAPK; healthspan; mitochondrion
    DOI:  https://doi.org/10.3389/fnut.2025.1680518
  48. Clin Sci (Lond). 2025 Nov 10. pii: CS20256110. [Epub ahead of print]
    Nanoparticle-mediated overexpression of RacGAP1 protects against renal ischemia/reperfusion-injury by maintaining mitochondrial homeostasis.
    Weiran Zhou, Shiqiang Tong, Jinbo Yu, Jun Chen, Yi Fang, Yuxin Nie, Yiqin Shi, Nana Song, Xuesen Cao, Xiaoqiang Ding, Shuan Zhao.
      Acute kidney injury (AKI) is recognized as a critical clinical problem, and pharmacological therapeutic options for AKI remain limited. Our previous study confirmed that Rac GTPase-activating protein 1 (RacGAP1) effectively promoted the repair of tubular epithelial cells in vitro. Further investigation is needed to determine whether boosting the expression of RacGAP1 in vivo helps protect against AKI. Herein, lipid-coated calcium phosphate (LCP) nanoparticles loaded with RacGAP1 plasmids (pRacGAP1-LCP) were generated and subsequently characterized based on their size, zeta potential, and morphological features. Animal models of AKI induced by ischemia/reperfusion (I/R) injury (IRI) were established in C57BL/6 mice and pRacGAP1-LCP was injected into the tail vein to explore the role of RacGAP1 on renal IRI in vivo. The therapeutic efficacy of pRacGAP1-LCP against IRI was assessed through western blotting, real-time PCR, and histological analyses. The effects of RacGAP1 on mitochondrial homeostasis were further examined in mouse renal tubular epithelial cells (mRTECs). Serial administrations of pRacGAP1-LCP injections led to a significant increase in RacGAP1 expression in murine kidneys. This therapeutic intervention effectively attenuated AKI, as evidenced by downregulation of AKI biomarkers, amelioration of renal histopathological damage, and suppression of both apoptosis and inflammatory responses. Characteristic mitochondrial abnormalities, diminished ATP production, and excessive lipid droplet accumulation were observed in tubular cells of IRI mice. Notably, pRacGAP1-LCP treatment reversed these pathological alterations and up-regulated the expression of PGC-1α and CPT-1α, indicating that RacGAP1 exerted its reno-protective effects through enhanced mitochondrial biogenesis and fatty acid oxidation (FAO).To further investigate the role of RacGAP1 in mitochondrial homeostasis, we employed an ATP depletion-repletion (ATP D-R) model in mRTECs. Crucially, RacGAP1 effectively restored ATP production, mtDNA copy number, and oxygen consumption (OCR) in mRTECs after ATP D-R treatment. RacGAP1 overexpression also suppressed mitochondrial depolarization, fragmentation, and reactive oxygen species (ROS) generation. Conversely, RacGAP1 knockdown exacerbated mitochondrial defects in mRTECs exposed to ATP D-R. In summary, this study uncovers that RacGAP1 overexpression protects against renal injury and mitochondrial dysfunction, highlighting its therapeutic promise for AKI. The LCP nanoparticle exhibits potential as a precise and efficient delivery platform and presents a viable option for AKI therapy.
    Keywords:  LCP; RacGAP1; acute kidney injury; mitochondrial homeostasis; nanoparticles
    DOI:  https://doi.org/10.1042/CS20256110
  49. Adv Sci (Weinh). 2025 Nov 12. e14764
    MCUB Inhibits PRKN-Dependent Mitophagic Degradation of PD-L1 to Promote Immune Evasion in Bladder Cancer.
    Yuan Huang, Chen Chen, Mingqiang Su, Dongqing Li, Jinge Zhang, Kuangye Long, Wenbin Nie, Shu Wei, Wei Chen, Haiyong Chen, Zhangfeng Zhong, Lina Hou, Wanlong Tan, Fei Li.
      Muscle-invasive bladder cancer (MIBC) poses a severe threat to patient survival due to its high invasiveness and metastatic potential. Although immunotherapy has revolutionized treatment strategies for MIBC, immune evasion remains a major obstacle limiting therapeutic efficacy. In this study, the mitochondrial calcium uniporter regulatory subunit (MCUB) is investigated for its role in immune evasion in MIBC. Bulk RNA-seq, scRNA-seq, and proteomic analyses revealed a progressive upregulation of MCUB from normal to MIBC tissues, and strong positive correlations are uncovered between MCUB expression and both PD-L1/PD-1 signaling and poor outcomes. Spatial transcriptomics and clinical tissue staining confirmed spatial co-localization of MCUB and PD-L1. Functional experiments demonstrated that MCUB stabilized PD-L1 protein by reducing its lysosomal degradation through inhibition of PRKN-dependent mitophagy. Mechanistically, MCUB suppressed mitochondrial calcium uptake to reduce PRKN activation and physically interacted with the PRKN-Arg51 residue to inhibit its function. In vivo, MCUB knockdown led to reduced tumor growth, enhanced CD8⁺ T cell infiltration, and improved response to anti-PD-1 therapy. This study identified the MCUB-PRKN-PD-L1 axis as a novel driver of immune evasion in MIBC and proposed that targeting the MCUB-PRKN interaction may serve as a precise therapeutic strategy to overcome immune resistance with minimal toxicity to normal tissues.
    Keywords:  MCUB, mitophagy; PD‐L1; bladder cancer; immune evasion
    DOI:  https://doi.org/10.1002/advs.202514764
  50. Adv Mater. 2025 Nov 14. e17968
    Diatomic Mn/Ca Nanozymes with Jaw Vascular Unit Mimicry for Triple-Enzyme Synergistic Therapy of Osteoradionecrosis.
    Ziyu Chen, Junlin Wang, Yuhao Ruan, Jikang Cao, Huijun Jiang, Jiandong Jiang, Fan Wu, Shuilin Wu, Yuli Wang.
      Osteoradionecrosis of the jaw (ORNJ) causes debilitating complications, while current therapies risk tissue damage and vascular insufficiency. Herein, jaw vascular unit (JVU)-biomimetic nanozymes are developed by coating Mn/Ca diatomic sites nanozymes (Mn-CaDSN) with hybrid membranes (HM) from M2 macrophages and osteogenically induced human bone marrow mesenchymal stem cells (HBMSCs). Mn-CaDSN exhibited synergistic superoxide dismutase-like, catalase-like, and glutathione peroxidase (GPx)-like activities, and the maximized GPx-like catalytic activity of Mn-CaDSN (Vmax = 0.69 mm·min-1) is 2.1-fold higher than Mn single-atom controls (Vmax = 0.33 mm·min-1). Density functional theory calculations revealed that Ca sites optimized substrate adsorption and O─H bond cleavage via d-band center modulation. HM coating enabled targeted JVU delivery, enhancing cellular uptake and reprogramming irradiated macrophages toward M2 polarization (ARG-1+ cells increasing 3.8-fold) and osteogenic differentiation (ALP area uprising 4.2-fold). In irradiated cells, the nanozymes concurrently eliminated reactive oxygen/nitrogen species (RONS), activates mitophagy (mitochondrial-lysosomal colocalization colocalization uprising 50%), and suppresses cuproptosis (HSP70 decreasing 45%; intracellular Cu2+ decreasing 30%). Loaded Dl-3-n-butylphthalide (NBP) further enhanced angiogenesis in vivo. In rat ORNJ models, NBP@Mn-CaDSN@HM promoted mucosal healing and increased bone volume fraction (BV/TV increasing 2.3-fold vs irradiated controls) by rebalancing immune-vascular-osteogenic microenvironments. This work establishes a paradigm of JVU biomimetics integrated with diatomic nanozymes for comprehensive ORNJ therapy.
    Keywords:  JVU‐biomimetic nanozymes; RONS scavenging; hybrid membrane coating; mitophagy; osteoradionecrosis of the jaw
    DOI:  https://doi.org/10.1002/adma.202517968
  51. Pharm Biol. 2025 Dec;63(1): 859-876
    Cedrol prevents UVB-induced photoaging by restoring mitochondrial function, metabolic homeostasis, and skin barrier integrity in HaCaT cells.
    Mo-Rong Xu, Chia-Hsin Lin, Hsun-Hua Lee, Sheng-Yang Wang.
       CONTEXT: Ultraviolet B (UVB) radiation is a key environmental contributor to skin photoaging, primarily by inducing oxidative stress, mitochondrial dysfunction, metabolic imbalance, and downregulation of tight junction (TJ) proteins. Cedrol, the major component of the essential oil from Cunninghamia lanceolata var. konishii, a tree species endemic to Taiwan, exhibits antioxidant properties. However, its restorative effects against UVB-induced skin damage have not been fully elucidated.
    OBJECTIVE: In this study, HaCaT keratinocytes were used to evaluate the post-treatment effects of cedrol on UVB-induced damage to skin cells.
    MATERIALS AND METHODS: HaCaT cells were exposed to UVB irradiation followed by cedrol treatment. Cell viability, intracellular reactive oxygen species (ROS), mitochondrial membrane potential, ATP levels, mitochondrial biogenesis-related proteins (SIRT1, PGC-1α, Nrf2, TFAM), and TJ proteins (ZO-1, occludin, claudin-3) were assessed. Additionally, 1H-NMR-based metabolomics was conducted to evaluate UVB-induced metabolic changes.
    RESULTS: Cedrol significantly improved cell viability post-UVB exposure, decreased intracellular reactive oxygen species (ROS), and restored mitochondrial membrane potential and ATP levels. It also upregulated mitochondrial biogenesis-related proteins (SIRT1, PGC-1α, Nrf2, and TFAM) and maintained TJ protein expression (ZO-1, occludin, and claudin-3), thereby preserving epithelial barrier integrity. Furthermore, 1H-NMR-based metabolomics revealed that cedrol mitigated UVB-induced metabolic disturbances, particularly in amino acid and energy pathways.
    DISCUSSION AND CONCLUSION: Cedrol alleviates UVB-induced cellular damage by modulating mitochondrial function and metabolic homeostasis, indicating its potential as a natural agent for promoting skin recovery after UV exposure.
    Keywords:  Cedrol; HaCaT; metabolomics; mitochondrial biogenesis; oxidative stress; tight junction proteins; ultraviolet B (UVB) radiation
    DOI:  https://doi.org/10.1080/13880209.2025.2583837
  52. Pharmacol Res. 2025 Nov 07. pii: S1043-6618(25)00454-2. [Epub ahead of print]222 108029
    ER stress sensor PERK drives ferroptosis by disrupting MAMs-mediated mitochondrial homeostasis and promoting mtROS accumulation in acute myocardial infarction.
    Xueshu Tao, Yunxiang Zhang, Jiao Pang, Zihan Liao, Gaohan Chen, Xue Zhong, Xingrui Cao, Ying Lin, Dawei Guan, Yuan Tian, Liang Hao, Rui Zhao, Zhipeng Cao.
      Acute myocardial infarction (AMI) is a life-threatening condition in which ferroptosis represents an important form of regulated cardiomyocyte death, yet its upstream regulatory mechanisms remain incompletely understood. In this study, we investigated the role of the endoplasmic reticulum (ER) stress sensor PERK in the control of ferroptosis during ischemic injury. Using cardiac-specific PERK knockout mice, oxygen-glucose-deprived cardiomyocytes, and myocardial tissues from patients with AMI, we examined cardiac injury responses, mitochondrial function, ferroptosis-related protein expression, and the interaction between PERK and the mitochondrial fusion protein MFN2. We found that PERK expression and activation were markedly elevated in both murine and human AMI hearts. PERK activation disrupted mitochondria-ER contacts (MAMs), caused mitochondrial depolarization and excessive oxidative stress, and suppressed key antioxidant proteins, including xCT, GPX4, and FTH1, thereby promoting ferroptotic cell death. Conversely, genetic deletion or pharmacological inhibition of PERK preserved mitochondrial integrity, restored redox homeostasis, reduced infarct size, and improved cardiac function. Mechanistically, PERK interacted with MFN2 to modulate MAM stability, and transcriptomic analysis together with human validation supported a central role for the PERK-MAM-mtROS axis in ischemic injury. These findings demonstrate that PERK drives cardiomyocyte ferroptosis by destabilizing MAMs and enhancing mitochondrial oxidative stress, and they identify PERK as a promising therapeutic target for AMI.
    Keywords:  Acute myocardial infarction; Ferroptosis; MAMs; Mitochondrial dysfunction; PERK; mtROS
    DOI:  https://doi.org/10.1016/j.phrs.2025.108029
  53. Adv Sci (Weinh). 2025 Nov 09. e08571
    Thyroid Hormone Receptor β1 and PGC1α Coordinately Regulate OPA1/MFN2-Mediated Mitochondrial Fusion and UCP1-Mediated Lipid Browning in ccRCC.
    Xiangui Meng, Tiexi Yu, Fang Lv, Weiquan Li, Hongmei Yang, Xiaoping Zhang, Wen Xiao.
      The abnormal accumulation of lipids is a hallmark of clear cell renal cell carcinoma (ccRCC). Both the thyroid hormone receptor β1 (TRβ) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) are key regulators of mitochondrial function and lipid metabolism. However, their specific interaction and influence on ccRCC development and lipid accumulation remain poorly understood. This study identified genes jointly regulated by TRβ and PGC1α, which are implicated in lipid browning and mitochondrial fusion. Mechanistically, T3-activated TRβ interacts with PGC1α to transcriptionally upregulate PGC1α, UCP1, and mitochondrial fusion genes OPA1 and MFN2, thereby enhancing mitochondrial activity, promoting lipid utilization, and suppressing ccRCC progression. These results indicate that the mitochondrial and metabolic effects of TRβ in ccRCC are mediated through PGC1α expression and function. Activation of the TRβ/PGC1α through hormonal and pharmacological means may offer a promising therapeutic approach for ccRCC.
    Keywords:  ccRCC; lipid browning; mitochondrial fusion; the peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α); the thyroid hormone receptor β1 (TRβ)
    DOI:  https://doi.org/10.1002/advs.202508571
  54. Basic Res Cardiol. 2025 Nov 14.
    Autophagy modulates the mechanism of flow-mediated dilation upstream of telomerase.
    William E Hughes, Shelby N Hader, Kate Astbury, Lukas Brandt, Karima Ait-Aissa, David D Gutterman, Andreas M Beyer.
      The non-canonical functions of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase play a critical role in maintaining microvascular homeostasis utilizing both human and rodent models. Previously, we have demonstrated that intact autophagic flux is necessary for the beneficial effects of TERT to maintain microvascular function and redox status in human resistance arterioles. The purpose of this investigation was to examine (1) whether loss of TERT function in vivo resulted in reductions in autophagy/mitophagy and concomitant changes in the mediator of microvascular FMD; (2) whether restoration of autophagy can reverse this pathological switch in dilator mechanism, reduce shear-induced mitochondrial H2O2 production while enhancing NO production. TERT mutant rats were generated and compared to their WT counterparts. Rats were given an autophagy activator (2% trehalose) for 28-days. Isolated mesenteric arteries were used for videomicroscopy, and aortic tissue was collected for immunoblotting. FMD and autophagic flux were measured in arteries in all groups. Loss of TERT function resulted in a switch from NOS-dependent to H2O2-dependent FMD, repressed microvascular shear-induced autophagic flux and NO production, and increased mitochondrial H2O2 production. Activation of autophagy restored NO-mediated dilation in TERT mutant rats, and enhanced shear-induced autophagic flux. We provide evidence that autophagy is necessary for the beneficial role of TERT within maintaining microvascular function, positioning this pathway as a modifiable target to maintain microvascular health by rescuing the endothelial dysfunction caused by loss of TERT signaling.
    Keywords:  Autophagy; FMD; Microcirculation; Mitochondria; Mitophagy; TERT
    DOI:  https://doi.org/10.1007/s00395-025-01146-5
  55. J Transl Med. 2025 Nov 11. 23(1): 1258
    Correction: Targeting the MARCH5-MFN2 axis to enhance mitochondrial fusion and sensitize multiple myeloma cells to venetoclax.
    Ilenia Valentino, Maria Eugenia Gallo Cantafio, Roberta Torcasio, Pierpaolo Murfone, Ludovica Ganino, Alessia Gallo, Nicola Cuscino, Ida Perrotta, Federico Tallarigo, Maria Mesuraca, Massimo Gentile, Giuseppe Viglietto, Nicola Amodio.
      
    DOI:  https://doi.org/10.1186/s12967-025-07052-7
  56. Nutrients. 2025 Oct 31. pii: 3451. [Epub ahead of print]17(21):
    The Multi-Dimensional Action Map of Resveratrol Against Alzheimer's Disease: Mechanism Integration and Treatment Strategy Optimization.
    Yichen Liu, Yadan Dong, Zhen Cao, Yixuan Ji, Xiaoxin Cheng, Xu Zheng.
      Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder marked by a gradual decline in cognitive and behavioral functions. Despite advancements in elucidating several potential mechanisms underlying the pathogenesis of AD, there remains a limitation in effective supplements or medications for its intervention. Resveratrol, a natural antioxidant, has emerged as a significant player in the treatment of AD. This article reviews the role of resveratrol in four key aspects: amyloid plaque deposition and neurofibrillary tangles, inflammatory response and oxidative stress, energy metabolism and mitochondrial homeostasis, and neuroprotection and regeneration. Furthermore, we also explore treatment strategies to enhance the therapeutic effect of resveratrol.
    Keywords:  Alzheimer’s disease; anti-inflammatory; mitochondrial homeostasis; neuroprotection; resveratrol
    DOI:  https://doi.org/10.3390/nu17213451
  57. J Extracell Vesicles. 2025 Nov;14(11): e70192
    From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
    Rostyslav Horbay, Vasyl Syrvatka, Artem Bedzay, Mikaela van der Merwe, Dylan Burger, Shawn T Beug.
      According to the endosymbiotic theory of mitochondrial origin, an α-proteobacterium entered a prokaryotic cell and, through symbiosis, evolved into the mitochondria-the powerhouse of the cell. Like other bacteria, the α-proteobacteria generate their own extracellular vesicles (EVs), a trait that was passed onto the mitochondria, enabling them to generate mitochondria-derived vesicles (MDVs). MDVs, similar to small EVs (sEVs), are vesicles ranging from 30 to 200 nm in diameter and carry cargo for degradation by lysosomes and peroxisomes. MDVs share several features with sEVs, including targeted cargo degradation, biogenesis, packaging into multivesicular bodies, nucleic acid and protein transportation, induction of immune responses, and surface antigen presentation. MDVs may also be released from the cell in a manner similar to sEVs, potentially influencing intercellular communication and immune responses. Furthermore, the presence of MDVs presents opportunities for early disease detection, including neurodegenerative disorders and cancer. In this review, we explore the differences and similarities between MDVs and EVs, including their roles in immunity.
    Keywords:  endosomal sorting complex required for transportation (ESCRT); endosome; lysosome; mitochondria‐derived vesicles (MDVs); mitophagy; multivesicular body (MVB); peroxisome; small extracellular vesicles (sEVs)
    DOI:  https://doi.org/10.1002/jev2.70192
  58. Exp Neurol. 2025 Nov 12. pii: S0014-4886(25)00418-2. [Epub ahead of print] 115553
    Pharmacological suppression of lactate mitigates postoperative cognitive dysfunction.
    Wei Wang, Wenqin Song, Ping Gong, Xueshan Bu, Lei Zhang, Bo Zhao.
      Hippocampal metabolic reprogramming from oxidative phosphorylation to glycolysis is a pathological feature in postoperative cognitive dysfunction (POCD). However, the relationship between elevated lactate levels and cognitive deficits following surgical trauma needs to be further illuminated. The lactate dehydrogenase-A (LDHA) inhibitor oxamate (OXA) and the lactate transporter inhibitor α-cyano-4-hydroxycinnamate (4-CIN) were delivered by intraperitoneal administration before POCD modeling. Recombinant adeno-associated virus 9 (AAV9)-Syn to knockdown Synaptosomal-associated protein 25 (SNAP25) was used to investigate whether neuronal-specific SNAP25 ablation blunts OXA-mediated phenotypes. Lactate accumulates in the hippocampus and hippocampal neurons after isoflurane anesthesia and aseptic laparotomy. Both OXA and 4-CIN attenuated cognitive impairment arising from anesthesia and surgery, enhanced SNAP25, PINK1, and LC3B protein, increased dendritic spine density and thickness of the postsynaptic densities, and attenuated pyroptosis-pertinent elements including cleaved caspase-3, N-GSDME, IL-1β and IL-18. SNAP25 knockdown counteracted the favorable effects of OXA on cognitive function, as confirmed by impaired synaptic plasticity, insufficient PINK1-mediated mitophagy, and activation of caspase-3/GSDME-mediated pyroptosis. Our findings suggest that pharmacological inhibition of lactate may be considered as a novel neuroprotective strategy for POCD.
    Keywords:  Lactate; Mitophagy; Postoperative cognitive dysfunction; Pyroptosis; SNAP25
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115553
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒28 at 23:08.