bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–10–12
fifty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.
  2. Osteoblast dysfunction associated with mitophagy suppression under simulated microgravity.
  3. RHOT1‑mediated molecular mechanism of mitochondrial dysfunction and its phenotypic effects on gastric cancer cells.
  4. PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
  5. Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.
  6. HIF-1α Activates Mitophagy through BNIP3 to Inhibit IPEC-J2 Apoptosis under Heat Stress.
  7. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
  8. Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
  9. Electroacupuncture attenuates intestinal epithelial ferroptosis in inflammatory bowel disease via Piezo1-mediated mitochondrial homeostasis.
  10. TREM-1 Promotes Microglial Pyroptosis and Mitochondrial Fission in Intracerebral Hemorrhage via the PI3K/AKT Pathway.
  11. Mitochondrial protease ClpP deficiency protects against tubulointerstitial damage in diabetic kidney disease.
  12. Aldose Reductase Mediated Mitophagy Promotes Epithelial-Mesenchymal Transition of Hepatocytes.
  13. Ginkgolide a enhances the resistance to pathogen infection through mitochondrial unfolded protein response.
  14. STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  15. Ischemic postconditioning ameliorates diabetic cerebral ischemia via activating the brain-derived neurotrophic factor-tropomyosin receptor kinase B-hypoxia-inducible factor 1α-Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 pathway to induce microglial mitophagy and suppress A1 astrocyte-mediated neuroinflammation.
  16. Sex-Dependent Regional Vulnerability and Recovery Mechanisms in a Mouse Model of Transient Global Cerebral Ischemia.
  17. Porphyromonas gingivalis extracellular vesicles exacerbated osteoporosis by disrupting osteoblast mitochondrial dynamics and inhibiting Cpt2-regulated fatty acid oxidation.
  18. PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis.
  19. Identification of key mitophagy-related genes in osteomyelitis: Insights from differential gene expression and machine learning models.
  20. Increased S-adenosyl methionine strengthens the suppression in mitochondrial unfolded protein response induced by 6-PPD quinone at environmentally relevant concentrations in Caenorhabditis elegans.
  21. Expression of Concern for: "Mitophagy Reduces Oxidative Stress Via Keap1 (Kelch-Like Epichlorohydrin-Associated Protein 1)/Nrf2 (Nuclear Factor-E2-Related Factor 2)/PHB2 (Prohibitin 2) Pathway After Subarachnoid Hemorrhage in Rats".
  22. Transformation of acute kidney injury to chronic kidney disease: the interaction between mitophagy and NLRP3 inflammasome.
  23. P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and 125I brachytherapy sensitization in esophageal carcinoma.
  24. Cytoskeletal dynamics and mitochondrial rearrangements drive cell fate upon antibody-induced complement activation in DLBCL.
  25. Prosapogenin CP4 exacerbates mitophagy to induce apoptosis via AMPK-mTOR and PINK1/Parkin pathways in A549 cells.
  26. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  27. The study of beneficial effect and mechanism of propofol on TNF-α-induced p-Tau increase in HT22 hippocampal neurons.
  28. Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.
  29. Linking GLP-1 activation with steroidogenesis, redox, endoplasmic reticulum stress, mitophagy, and the apoptotic regulatory network unlocks the emerging impacts of semaglutide on 5-fluorouracil-induced testicular toxicity.
  30. Identification of Mitophagy-Related Genes and Analysis of Immune Infiltration in Atherosclerosis.
  31. PM2.5 enhances DRP1-mediated mitochondrial fission to induce ferroptosis and exacerbate asthma through the AHR-HSP90-PKM2 pathway.
  32. AI662270/GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction.
  33. Kai-Xin-San improves aging and associated neuroinflammation through mitochondrial autophagy.
  34. Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
  35. Prenatal exposure to cadmium induces multigenerational inheritance of male testicular damage and mitochondrial biogenesis abnormalities.
  36. [The mechanism of mitochondrial damage in chronic obstructive pulmonary disease induced by cigarette smoke and its therapeutic implications].
  37. L-arginine-loaded microneedle patch enhances diabetic wound healing by regulating macrophage polarisation and mitochondrial homeostasis.
  38. Taurine can restrict MtdsRNA mediated pyroptosis by enhancing mitophagy in nucleus pulposus cells.
  39. MITOCHONDRIAL REDOX IMBALANCE AND CoQ10 DEFICIENCY IN RETT SYNDROME: INSIGHTS FROM PATIENT-DERIVED FIBROBLASTS.
  40. Onion-Mitochondria Inhibit Lipopolysaccharide-Induced Acute Lung Injury by Shaping Lung Macrophage Mitochondrial Function.
  41. Compromised autophagy in the aging epididymis: Evidence and relevance to male fertility.
  42. Splicing factor Sf3b1 facilitates maintenance of neuronal dendrites by modulating mitochondrial health.
  43. The biophysical mechanism of mitochondrial pearling.
  44. BMAL1 modulation alleviates inflammatory responses in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response in high-altitude hypoxia.
  45. Chronic prostatitis and male infertility: association mechanism and research progress.
  46. HRS sustains mitochondrial homeostasis by anchoring destabilized proteins during tumorigenesis.
  47. Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.
  48. CAMKK2 restored mitochondrial dynamics homeostasis to alleviate pulmonary fibrosis via AMPK/PGC-1α signaling pathway in lung fibroblasts.
  49. Effect of Functional Electrical Stimulation Combined With Physical Exercise on Electron Transport Chain Activity in Peripheral Blood Cells of Stroke Patients.
  50. Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.
  51. PTDSS1 Drives Glycolysis and Malignant Progression of Lung Cancer Through Maintaining Nuclear-Mitochondrial Homeostatic Crosstalk.
  52. Salivary mitofusin levels in periodontal disease: a cross-sectional case-control study.
  53. Neuroprotective Effects of Asiatic Acid on Autophagy and Mitochondrial Integrity in a Parkinson's Disease Cellular Model.
  54. Spermidine enhances macrophages anti-inflammatory and regenerative functions by improving mitochondrial fitness.
  1. Front Biosci (Landmark Ed). 2025 Sep 26. 30(9): 44648
    Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.
    Alina Chaplygina, Daria Zhdanova.
       BACKGROUND: Mitochondrial dynamics-the balance between fission, fusion, and mitophagy-are essential for maintaining cellular homeostasis and are increasingly implicated in the pathogenesis of Alzheimer's disease (AD).
    METHODS: Here, we investigated the effects of targeted modulation of mitochondrial fission and fusion on mitochondrial morphology and metabolic status in primary hippocampal cultures derived from 5xFAD transgenic mice. Mitochondrial dynamics were modulated using the fission inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), the fusion promoter mitochondrial fusion promoter M1 (MFP M1), and exogenous zinc as a fission activator. We evaluated mitochondrial morphology, lipofuscin accumulation, beta-amyloid (Aβ42) levels, and reactive oxygen species (ROS). The general condition of the cultures was assessed morphologically using neuronal and astrocytic markers.
    RESULTS: Modulating mitochondrial dynamics altered mitochondrial morphology, decreased Aβ42, lipofuscin, and ROS levels, and improved cellular organization. Treatments with MFP and Mdivi-1 promoted mitochondrial hyperfusion without complete network integration and were associated with reduced astrogliosis and increased neuronal density. In contrast, zinc induced dose-dependent mitochondrial fragmentation and astrocytic clasmatodendrosis, with lower concentrations enhancing Aβ clearance and higher concentrations inducing toxicity.
    CONCLUSIONS: Mitochondrial fusion and fission significantly influence lipofuscin and amyloid accumulation in 5xFAD cultures, underscoring their potential as therapeutic targets in neurodegenerative diseases. We propose that mitochondrial morphology acts as a key regulator of both cellular homeostasis and disease pathology.
    Keywords:  Alzheimer’s disease; lipofuscin; mitochondria; mitochondrial dynamic; mitochondrial fission; mitochondrial fusion; primary cell culture
    DOI:  https://doi.org/10.31083/FBL44648
  2. Biomed Eng Online. 2025 Oct 06. 24(1): 113
    Osteoblast dysfunction associated with mitophagy suppression under simulated microgravity.
    Jindong Xue, Min Wang, Songsong Liu, Congncong Xu, Haoyang Yu, Yong Guo, Biao Han.
       BACKGROUND: Bone loss is a significant health concern during spaceflight and mechanical unloading. Simulated microgravity (SMG) disrupts bone homeostasis by inhibiting osteoblast proliferation and differentiation while promoting apoptosis. Although these functional effects have been reported, the underlying mechanisms remain unclear. Mitochondrial quality control, particularly mitophagy involving the PINK1/Parkin pathway, may play a key role. This study aimed to investigate the relationship between osteogenic dysfunction and mitochondrial damage under SMG conditions and preliminarily validate the potential link using the small molecule probe icariin (ICA).
    METHODS: An SMG model was established using a rotary cell culture system. Cell proliferation was assessed by CCK-8 assay, apoptosis was analyzed via flow cytometry, and osteogenic differentiation was evaluated by alkaline phosphatase (ALP) and Alizarin Red staining. Expression levels of relevant genes and proteins were measured by qPCR and Western blot. Mitochondrial function was assessed through ATP content, reactive oxygen species (ROS) levels, JC-1 staining for mitochondrial membrane potential, and transmission electron microscopy (TEM) for ultrastructural observation. Additionally, cells were treated with the mitochondrial function-related small molecule icariin (ICA) to observe its regulatory effects on mitophagy markers (PINK1, Parkin, p62, LC3B) expression and osteogenic function.
    RESULTS: SMG significantly inhibited osteoblast proliferation and differentiation and induced apoptosis. These changes were accompanied by impaired mitochondrial function and downregulated expression of mitophagy-related genes. TEM revealed mitochondrial swelling and disrupted cristae structure. Treatment with ICA partially restored mitochondrial function and mitophagy marker expression, along with improved expression of osteogenic markers and cell viability.
    CONCLUSIONS: SMG induces osteogenic dysfunction, mitochondrial damage, and downregulation of mitophagy-related gene expression. The results suggest that impaired mitophagy may be a key mechanism underlying unloading-induced bone loss, and ICA, as a small molecule modulator, holds potential as a therapeutic intervention.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Icariin; Microgravity; Mitophagy; Osteoblast
    DOI:  https://doi.org/10.1186/s12938-025-01454-w
  3. Int J Oncol. 2025 Dec;pii: 104. [Epub ahead of print]67(6):
    RHOT1‑mediated molecular mechanism of mitochondrial dysfunction and its phenotypic effects on gastric cancer cells.
    Yanqi Peng, Xiaoming Chen, Fanhao Kong, Jiayi Zhu, Siwen Yang, Ronghua Fan, Ji Wu, Yanyu Peng.
      Mitophagy, a selective autophagy process that targets damaged mitochondria, plays a critical role in cellular homeostasis and disease progression, including tumorigenesis. Ras homolog family member T1 (RHOT1), a mitochondria‑associated protein, has been reported to regulate mitochondrial dynamics and energy metabolism. However, its role in gastric cancer (GC) remains unclear. The present study aimed to investigate the function of RHOT1 in GC progression and its mechanistic link with mitochondrial quality control. To achieve this, RHOT1 was silenced in GC cells and its effect on the PINK1/Parkin pathway, mitochondrial homeostasis and cellular behavior examined. The study employed qPCR and western blotting to evaluate gene and protein expression, siRNA transfection to silence RHOT1 and flow cytometry, CCK‑8 proliferation, wound‑healing, and Transwell assays to investigate mitochondrial function and cellular phenotypes. Silencing RHOT1 reduced PINK1 mRNA expression by 59.75% (P=0.025) and Parkin mRNA expression by 65.12% (P=0.0189), indicating suppressed mitophagy. This was accompanied by an 84.73% increase in reactive oxygen species (P<0.001) and a 36.94% decrease in mitochondrial membrane potential (P=0.0061). Silencing RHOT1 further caused G0/G1 phase arrest and increased apoptosis (P<0.05), thereby markedly inhibiting the proliferation, invasion and migration of GC cells. The present study revealed that RHOT1 drives the malignant phenotype of GC through regulation of mitochondrial quality control and induction of oxidative stress, providing a rationale for developing novel anti‑tumor strategies by targeting mitochondrial function. RHOT1 may serve as a biomarker for prognostic assessment and individualized treatment of GC.
    Keywords:  Ras homolog family member T1; gastric cancer; mitochondrial dysfunction; mitophagy; oxidative stress; phosphatase and tensin homolog‑induced kinase 1/Parkin pathway
    DOI:  https://doi.org/10.3892/ijo.2025.5810
  4. J Cell Sci. 2025 Oct 09. pii: jcs.263903. [Epub ahead of print]
    PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
    Sudeshna Nag, Kaitlin Szederkenyi, Christopher M Yip, G Angus McQuibban.
      Mitochondrial dynamics relies on the function of dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1). The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) protein can regulate the phosphorylation levels and the function of both MFN2 and DRP1, however, the precise regulation of PGAM5 activity is unknown. We show that PGAM5 oligomerization and localization controls its function. Under depolarization and/or metabolic stress PGAM5 changes its association from dodecamers to dimers. These PGAM5 oligomers have differential affinity towards MFN2 and DRP1. Simultaneously, PGAM5 is cleaved by the inner mitochondrial membrane resident proteases PARL and OMA1 and a fraction of the cleaved PGAM5 translocates to the cytosol. These two events play an important role in regulating mitochondrial dynamics under depolarization and/or metabolic stress. Taken together, our results identify PGAM5 oligomerization and cleavage-induced relocalization as critical regulators of its function.
    Keywords:  DRP1; Glucose-Starvation; MFN2; Mitochondrial morphology; PGAM5
    DOI:  https://doi.org/10.1242/jcs.263903
  5. Front Cell Neurosci. 2025 ;19 1636185
    Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.
    Peizhu Lv, Xia Chen, Shiping Liu, Yu Zhang, Yan Bai, Shun Wang, Yulin Wang.
      This article conducts a systematic search of literature in the fields of neuroscience, cell biology, immunometabolism, etc. from 1990 to 2025, with PubMed/WebofScience as the core database. Experimental and clinical studies covering the core mechanisms of the preprophase of PD (mitochondrial imbalance → NLRP3 activation → lactation modification → α -SYN pathology) were included, and non-interaction mechanisms and clinical-phase studies were excluded. The pathological interaction network of mitochondrial dynamic imbalance, lysosomes - mitochondrial interaction disorder and neuroinflammation in Parkinson's disease (PD) was explained. Construct a three-dimensional pathological network of "energy-inflammation-protein homeostasis" to provide a theoretical basis for early intervention. The imbalance of mitochondrial fission/fusion leads to the accumulation of fragmented mitochondria, triggering energy metabolism disorders and oxidative stress; abnormal aggregation of α-synuclein (α-syn) disrupts mitochondrial-endoplasmic reticulum membrane (MAM) calcium signaling, upregulates Miro protein to inhibit mitochondrial autophagy clearance, forming a vicious cycle of neuronal damage. Defects in the PINK1/Parkin pathway and LRRK2 mutations interfere with the turnover of mitochondrial fission complexes, causing mtDNA leakage, activating the NLRP3 inflammasome, and driving neuroinflammatory cascades. Additionally, lysosomal dysfunction caused by GBA1 mutations exacerbates mitochondrial quality control defects through Rab7 activity imbalance. Abnormal lactate metabolism may influence inflammasome activity through epigenetic regulation, but its role in PD needs further validation. Based on the above mechanisms, a diagnostic strategy for the prodromal phase integrating dynamic monitoring of mitochondrial fragmentation index, lysosomal function markers, and inflammatory factors is proposed, along with new intervention directions targeting Drp1, NLRP3, and the lysosome-mitochondria interface.
    Keywords:  NLRP3 inflammasome; Parkinson’s disease; lactylation modification; mitochondrial dynamics; prodromal phase
    DOI:  https://doi.org/10.3389/fncel.2025.1636185
  6. J Agric Food Chem. 2025 Oct 10.
    HIF-1α Activates Mitophagy through BNIP3 to Inhibit IPEC-J2 Apoptosis under Heat Stress.
    Hui Li, Xuefeng Bai, Ting Yang, Caixia Wu, Yang Liu, Chunlan Shan, Rutao Lin, Xin Wen, Anchun Cheng.
      Hypoxia caused by heat stress (HS) exacerbates intestinal epithelial cell apoptosis, and mitochondrial dysfunction plays a central role in this process. Increased hypoxia-inducible factor 1α (HIF-1α) shows an obvious antiapoptotic effect under HS. Based on the relationship between HIF-1α, mitochondrial homeostasis and BNIP3, we hypothesize that HIF-1α promotes BNIP3-mediated mitophagy to protect intestinal epithelial cells from HS-induced apoptosis. The results showed that HS destroyed the physical barrier of porcine small intestinal mucosa (disorganized microvilli, disrupted tight junctions) in vivo, accompanied by mitochondrial structure damage. The ratio of LC3II/I (p < 0.001) in the duodenum, jejunum, and ileum increased in a time-dependent manner under 72 h HS, while P62 (p < 0.001) and the Bcl-2/BAX ratio (p < 0.001) decreased continuously. In vitro, proteomic sequencing of HS-treated IPEC-J2 confirmed a negative correlation between mitochondrial function and HS, indicating HS disrupted mitochondrial homeostasis. Further experiments showed that increased HIF-1α improved mitochondrial function and promoted mitophagy; the expression of HIF-1α (p < 0.001), BNIP3 (p < 0.001), p-AMPK/AMPK (p < 0.001), Parkin (p < 0.001), and LC3II/I (p < 0.001) was synchronously upregulated under HS, whereas P62 (p < 0.001) showed the opposite trend. Critically, inhibition of BNIP3 disrupted the effect of HIF-1α on mitophagy, indicating that HIF-1α promotes IPEC-J2 mitophagy through BNIP3 under HS. What was more, increased HIF-1α alleviated HS-induced cell apoptosis (p < 0.001), while inhibition of BNIP3 could block the antiapoptotic effect of HIF-1α. In conclusion, we first clarify HIF-1α alleviates HS-induced IPEC-J2 apoptosis through BNIP3-activated mitophagy, and this regulatory axis provides a molecular target for mitigating HS-induced intestinal damage in the swine industry.
    Keywords:  BNIP3; HIF-1α; apoptosis; heat stress; mitophagy
    DOI:  https://doi.org/10.1021/acs.jafc.5c09057
  7. Sci Adv. 2025 Oct 10. 11(41): eadw4153
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1126/sciadv.adw4153
  8. Placenta. 2025 Oct 01. pii: S0143-4004(25)00704-0. [Epub ahead of print]171 140-149
    Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
    Leena Kadam, Kaylee Chan, Ethan Tawater, Leslie Myatt.
       INTRODUCTION: The placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in male and female placentas of pregnancies complicated by obesity and GDM. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria.
    METHODS: We collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner.
    RESULTS: Only placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1α and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), but GDM placentas failed to mount this response.
    DISCUSSION: Obesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.
    Keywords:  Diabetes; Mitochondria; Obesity; Placenta; Pregnancy
    DOI:  https://doi.org/10.1016/j.placenta.2025.09.019
  9. Chin Med. 2025 Oct 06. 20(1): 161
    Electroacupuncture attenuates intestinal epithelial ferroptosis in inflammatory bowel disease via Piezo1-mediated mitochondrial homeostasis.
    Haolong He, Jingying Zhou, Sihui Cao, Weiai Liu, Zhigang Mei, Mi Liu.
       BACKGROUND: Inflammatory bowel disease (IBD) involves pathological mechanical forces transduced by mechanosensitive Piezo1 channels. While electroacupuncture (EA) alleviates IBD injury, its relationship with Piezo1-mediated ferroptosis remains unknown.
    METHODS: Dextran sulfate sodium (DSS)-induced IBD mice and mechanically stressed HIEC-6 intestinal epithelial cells received EA or pharmacological modulators. Pathological scoring, transmission electron microscopy (TEM), inflammatory cytokine assays, Western blotting, and immunofluorescence evaluated mitochondrial dynamics and ferroptosis markers to elucidate the Piezo1-ferroptosis axis and EA's regulatory role.
    RESULTS: EA significantly reduced disease activity index (DAI), histopathological scores, colon shortening, and pro-inflammatory cytokines in IBD mice. By inhibiting fission, indicated by a decrease in dynamin-related protein 1 (DRP1), and mitophagy, shown by a reduction in Parkinson protein 2 (PARK2), EA maintained mitochondrial homeostasis. This effect was similar to ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, EA lessened RSL3-induced exacerbation of ferroptosis. In vitro, mechanical stress or the Piezo1 agonist Yoda1 induced ferroptosis, which was evident from increased acyl-CoA synthetase Long-chain family member 4 (ACSL4), reactive oxygen species (ROS), malondialdehyde (MDA) and Fe2⁺ levels, while decreased glutathione peroxidase 4 (GPX4), ferritin (FTH) and glutathione (GSH) levels. Critically, EA inhibited Piezo1 activation and counteracted Yoda1-aggravated epithelial ferroptosis in vivo.
    CONCLUSION: Piezo1-mediated mitochondrial dyshomeostasis critically drives intestinal epithelial ferroptosis in IBD. EA regulates Piezo1 to maintain mitochondrial homeostasis and suppresses ferroptosis, offering a potential therapeutic strategy for IBD.
    Keywords:  Electroacupuncture; Ferroptosis; Inflammatory bowel disease; Mitochondrial homeostasis; Piezo1
    DOI:  https://doi.org/10.1186/s13020-025-01218-7
  10. FASEB J. 2025 Oct 15. 39(19): e71115
    TREM-1 Promotes Microglial Pyroptosis and Mitochondrial Fission in Intracerebral Hemorrhage via the PI3K/AKT Pathway.
    Yuan An, Tingting Zhai, Fang Wang, Kaiyuan Zhang, Mengzhao Feng, Dengpan Song, Zhihua Li, Fuyou Guo.
      TREM-1, a pro-inflammatory factor, aggravates neuroinflammation following intracerebral hemorrhage (ICH). Both pyroptosis and mitochondrial dysfunction play a vital role in the further injury of ICH. However, whether TREM-1 regulates microglial pyroptosis and mitochondrial fission, and the potential mechanisms underlying these processes, remains unclear. A mouse model of ICH was established via stereotactic injection of collagenase VII-S. To knock down TREM-1 in vivo, AAV9-Iba1-TREM-1 was injected into the right basal ganglia. Additionally, the TREM-1-specific inhibitor LP17 was administered intranasally. Neurological function was assessed using behavioral assessments. In vitro, BV2 was stimulated with hemin to mimic ICH. LP17, NLRP3 inhibitor MCC950, TREM-1 agonist antibody Mab1187, and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were used to investigate the mechanisms underlying TREM-1-mediated microglial pyroptosis and mitochondrial fission. Immunofluorescence staining, Western blot, RT-qPCR, and transmission electron microscopy were employed to evaluate microglial pyroptosis and mitochondrial fission. Both pharmacological inhibition and AAV-mediated knockdown of TREM-1 significantly improved neurological function, attenuated microglial pyroptosis and mitochondrial fission in ICH mice. TREM-1 was shown to drive microglial pyroptosis through the NLRP3 inflammasome. Furthermore, the PI3K/AKT signaling pathway was demonstrated to regulate TREM-1-induced microglial pyroptosis and mitochondrial fission. This study provides the first evidence that TREM-1 promotes microglial pyroptosis and mitochondrial fission following ICH via the PI3K/AKT signaling pathway. These findings highlight TREM-1 as a potential therapeutic target for mitigating neuroinflammation and neuronal damage in ICH.
    Keywords:  TREM‐1; intracerebral hemorrhage; microglial; mitochondrial fission; neuroinflammation; pyroptosis
    DOI:  https://doi.org/10.1096/fj.202501909R
  11. Int Immunopharmacol. 2025 Oct 06. pii: S1567-5769(25)01632-7. [Epub ahead of print]166 115641
    Mitochondrial protease ClpP deficiency protects against tubulointerstitial damage in diabetic kidney disease.
    Huafen Wang, Yifei Liu, Jialu Liu, Shumin Zhang, Xiaohui Li, Lin Sun, Fuyou Liu, Yu Liu, Li Xiao.
      Mitochondrial quality control (MQC) imbalance has been implicated in tubulointerstitial damage of diabetic kidney disease (DKD). The mitochondrial unfolded protein response (UPRmt) is a stress-adaptive transcriptional response required for MQC. Caseinolytic peptidase P (ClpP), the critical component of the UPRmt proteolytic system, plays an essential role in regulating mitochondrial function with both beneficial and detrimental outcomes. Still, its effects on kidney pathobiology remain unclear. Here, we observed that ClpP was distributed in renal tubules and was significantly increased in the kidneys of DKD patients and db/db mice, accompanied by increased expression of the UPRmt-related molecular chaperones heat shock protein 60 (HSP60), heat shock protein 10 (HSP10) and activating transcription factor 5 (ATF5) and positively correlated with renal oxidative stress, cell apoptosis and tubulointerstitial fibrosis. ClpP shRNA alleviated tubular cell apoptosis, oxidative damage and tubulointerstitial injury in diabetic mice. The expression of HSP60, HSP10 and ATF5 was inhibited, indicating that lowering ClpP suppressed UPRmt activation. In vitro, ClpP was localized in the mitochondria of HK-2 cells. High glucose (HG) treatment upregulated ClpP expression and UPRmt-related proteins, concurrent with enhanced mitochondrial reactive oxygen species (mtROS), fibrosis markers and apoptosis. These alterations were reduced by ClpP siRNA. Instead, ClpP overexpression further exacerbated these abnormalities in HK-2 cells, while these facilitation effects were partially reversed by UPRmt suppression. Our results indicated that ClpP deficiency ameliorated renal oxidative stress and tubulointerstitial injury in DKD by inhibiting excessive UPRmt activation. These results suggest that ClpP is a valuable therapeutic target for DKD.
    Keywords:  Apoptosis; ClpP; Diabetic kidney disease; Oxidative stress; Tubular epithelial cell; UPRmt
    DOI:  https://doi.org/10.1016/j.intimp.2025.115641
  12. Hepat Med. 2025 ;17 141-159
    Aldose Reductase Mediated Mitophagy Promotes Epithelial-Mesenchymal Transition of Hepatocytes.
    Jingjing Yan, Wenke Zhao, Haoyu Wang, Lutan Zhou, Xianwei Li, Guannan Wang.
       Background: Recent studies suggest that impaired mitophagy leading to epithelial-mesenchymal transition (EMT) in hepatocytes plays a major role in the progression of hepatic fibrosis (HF). The authors' previous study demonstrated that aldose reductase (AR) promotes radiation-induced EMT in alveolar epithelial cells. This study aims to examine whether AR influences EMT in hepatocytes by regulating defective mitophagy.
    Methods: Some histological techniques, including HE staining, Masson's trichrome staining, immunohistochemistry, and transmission electron microscopy, were employed to validate the model and examine mitochondrial injury. Subsequently, EMT was induced in hepatocytes through TGF-β1 treatment. Then experiments such as siRNA-mediated gene silencing, AR inhibition, and AR overexpression were performed. Finally, the activation status of AKT and mTOR, as well as the expression levels of proteins associated with mitophagy and EMT, were evaluated using RT-qPCR, immunofluorescence staining, and Western blotting.
    Results: AR knockout significantly reduced AKT and mTOR phosphorylation In vivo but increased the expression of Pink1 and Parkin in CCl4-exposed liver tissues. This was associated with an increased LC3 II/I expression ratio, decreased p62 expression, reduced mitochondrial damage, enhanced E-cadherin expression, and diminished Snail, α-SMA, and vimentin expression, which collectively alleviated HF. In vitro experiments revealed that AR knockdown significantly attenuated the activation of the TGF-β1-induced AKT/mTOR pathway, restored mitochondrial autophagy function, decreased ROS levels, increased mitochondrial membrane potential (MMP) and ATP production, and reversed EMT in hepatocytes via siRNA or pharmacological inhibition. Conversely, AR overexpression exacerbated the activation of the TGF-β1-induced AKT/mTOR pathway, impaired mitophagy efficiency, increased ROS levels, decreased MMP and ATP levels, and facilitated EMT process.
    Conclusion: The study findings demonstrated that AR facilitates EMT in hepatocytes and plays a major role in enhancing HF. This process may be linked to AR-induced activation of the AKT/mTOR. Consequently, this activation suppresses the expression of Pink1 and Parkin, ultimately reducing the risk of mitophagy in hepatocytes.
    Keywords:  aldose reductase; epithelial-mesenchymal transition; hepatic fibrosis; mitophagy
    DOI:  https://doi.org/10.2147/HMER.S546357
  13. Cell Mol Life Sci. 2025 Oct 07. 82(1): 349
    Ginkgolide a enhances the resistance to pathogen infection through mitochondrial unfolded protein response.
    Yingwen Cui, Rujia Wang, Xie Li, Guohui Bai, Yi Xiao.
      The normal function of mitochondria plays a key role in innate immunity. Normally, changes in the internal and external environment will lead to mitochondrial stress, and then the body will produce mitochondrial unfolded protein response (UPRmt) to maintain mitochondrial homeostasis. Ginkgolide A (GA) is a diterpenoid isolated from Ginkgo, which has many important biological activities such as anti-inflammatory, anticancer, anxiolytic-like, anti-antherosclerosis and anti-atherombosis. However, whether GA affects innate immune responses and the underlying molecular mechanisms are still unknown. In the present study, we show that 100 µM GA enhances the resistance to Gram-negative pathogens Pseudomonas aeruginosa, Salmonella enterica and Gram-positive pathogens Staphylococcus aureus, Enterococcus faecalis in Caenorhabditis elegans by clearance intestinal bacterial loads. We also find that GA enhances innate immunity through a homeodomain transcriptional regulator DVE-1, which activates the UPRmt. Because DVE-1 encodes a homeodomain transcription regulator that is homologous to the mammalian SATB2 transcription factor. Furthermore, we demonstrate that this function was conserved, because GA also manifested protective function in lung epithelial cell and mice during P. aeruginosa infection via the homeodomain transcription factor SATB2. Hence, our research suggests that GA has the potential therapeutic compound to protect patients from pathogen infection.
    Keywords:  DVE-1/SATB2; Ginkgolide a; Innate immunity; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1007/s00018-025-05869-5
  14. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122
    STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis
    DOI:  https://doi.org/10.1073/pnas.2508809122
  15. Front Endocrinol (Lausanne). 2025 ;16 1620004
    Ischemic postconditioning ameliorates diabetic cerebral ischemia via activating the brain-derived neurotrophic factor-tropomyosin receptor kinase B-hypoxia-inducible factor 1α-Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 pathway to induce microglial mitophagy and suppress A1 astrocyte-mediated neuroinflammation.
    Ling Zhao, Yuanyuan Han, Ying Wang, Tingyu Ke, Shiying Huang.
       Aim: Diabetes mellitus exacerbates cerebral ischemic injury. However, effective interventions remain limited. Ischemic postconditioning (IPOC) is a potential neuroprotective strategy; however, its efficacy and mechanisms in diabetes remain poorly understood. This study aimed to explore the therapeutic effects and underlying mechanisms of IPOC in diabetes complicated by cerebral ischemia.
    Methods: Tree shrews with diabetes complicated by cerebral ischemia were used as the study subjects and were subjected to a standardized IPOC intervention protocol.
    Results: The results showed that compared with the control group, the cerebral infarction volume of tree shrews in the cerebral ischemia (IS) group and the diabetes complicated with cerebral ischemia (DMIS) group was significantly higher, the neurons were severely damaged, A1 astrocytes were activated, the levels of inflammatory factors interleukin (IL)-1β and IL-6 increased, and mitochondrial autophagy was inhibited. In contrast, in the DMIS + IPOC group, cerebral infarction volume was significantly reduced, neuronal damage was improved, activation of A1 astrocytes and release of inflammatory factors were inhibited, and mitochondrial autophagy was increased. Mechanistically, IPOC activated the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway and upregulated hypoxia-inducible factor 1α (HIF-1α) expression, which further promoted the expression of Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3).
    Conclusion: IPOC coordinates microglial mitochondrial autophagy and astrocyte inflammatory regulation through the BDNF-TrkB-HIF-1α-BNIP3 signaling cascade, providing a new target for precise intervention in diabetes combined with cerebral ischemia.
    Keywords:  BDNF-TrkB-HIF-1α-BNIP3; cerebral ischemia; diabetes; ischemic postconditioning; neuroprotective
    DOI:  https://doi.org/10.3389/fendo.2025.1620004
  16. Neuromolecular Med. 2025 Oct 08. 27(1): 67
    Sex-Dependent Regional Vulnerability and Recovery Mechanisms in a Mouse Model of Transient Global Cerebral Ischemia.
    Debiprasad Sinha, Roli Kushwaha, Shashikant Patel, Sainath Sunil Dhaygude, Mydhili Radhakrishnan, Papia Basuthakur, Arvind Kumar, Sumana Chakravarty.
      This study investigates the influence of sex on region-specific neural vulnerability following global cerebral ischemia using a Bilateral Common Carotid Artery Occlusion (BCCAo) mouse model that mimics severe ischemic brain stroke condition in humans. Comprehensive behavioral assessments, neuropathological analyses, and molecular profiling were conducted across multiple time points post-ischemia in male and female CD1 mice. Both sexes exhibited early motor deficits, cortical-striatal mitochondrial dysfunction, inflammation, and cell death at day 1, with gradual behavioral recovery. However, the hippocampus demonstrated a clear sex-specific divergence: males exhibited delayed yet prolonged inflammation, apoptotic cell death, and increased autophagy/mitophagy activity, while females were largely protected despite hypoxic and inflammatory gene expression. Molecular assays revealed prolonged upregulation of hypoxia-inducible factor 1α (HIF-1α), IL-1β, IL-6, TNF-α, and apoptotic markers in males, especially in the hippocampus, alongside increased expression of autophagy (Beclin-1, LC3-II, ATG7) and mitophagy (PINK1, BNIP3L) regulators and a shift in mitochondrial dynamics favoring fission.
    Keywords:  Autophagy; Hippocampus; Ischemia; Motor function; Neuroinflammation
    DOI:  https://doi.org/10.1007/s12017-025-08887-5
  17. J Nanobiotechnology. 2025 Oct 10. 23(1): 635
    Porphyromonas gingivalis extracellular vesicles exacerbated osteoporosis by disrupting osteoblast mitochondrial dynamics and inhibiting Cpt2-regulated fatty acid oxidation.
    Qiujing Qiu, Xiaoyuan Yan, Zeying Zhang, Xiyue Zhang, Jiawei Ma, Wenqing Gao, Na An, Lihong Qiu, Jiajie Guo.
       BACKGROUND: Recent studies have implicated periodontitis (PD) as a potential risk factor for osteoporosis; however, the precise mechanisms remain unclear. Porphyromonas gingivalis (Pg), a key pathogen associated with PD, can secrete extracellular vesicles (EVs). However, whether Pg EVs can be transported to the bone marrow and influence osteoporosis-related osteoblast differentiation warrants exploration. This study compares Pg EVs with EVs from Porphyromonas endodontalis (Pe), which is a less virulent congener but the evidence for its pathogenicity in PD is weak.
    RESULTS: Pg EVs can be translocated into the marrow of mice and be internalized by osteoblasts through clathrin- and lipid raft-mediated endocytosis, thereby exacerbating osteoporosis. Pg EVs promote mitochondrial fission and inhibit mitochondrial fusion, leading to mitochondrial fragmentation, impaired mitochondrial activity and suppressed osteogenic differentiation. Furthermore, Pg EVs downregulate the protein level of carnitine palmitoyl transferase 2 (Cpt2) and inhibit fatty acid oxidation (FAO) by disrupting mitochondrial dynamics, which impairs osteoblast ATP production and exacerbates osteoporosis. The effects of Pe EVs are similar but weaker than those of Pg EVs.
    CONCLUSIONS: This study elucidates that Pg EVs exacerbate osteoporosis by disrupting osteoblast mitochondrial dynamics and suppressing Cpt2-regulated FAO. This study contributes to understanding of the etiological mechanisms through which Pg contributes to the progression of osteoporosis and highlights the pivotal role of EVs in the association between periodontal disease and systemic diseases.
    Keywords:   Porphyromonas gingivalis ; Carnitine palmitoyl transferase 2; Extracellular vesicles; Fatty acid oxidation; Mitochondrial dynamics; Osteoblast
    DOI:  https://doi.org/10.1186/s12951-025-03717-z
  18. Autophagy. 2025 Oct 08.
    PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis.
    Ningning Li, Hongyu Hou, Dan Su, Bojun Yang, Rui Ni, Guoqiang Ma, Shan Sun, Qilian Ma, Qiang Peng, Siqian Chen, Kin Yip Tam, Hongfeng Wang, Zheng Ying.
      Atg8-family proteins are autophagosome-associated proteins and play important roles in macroautophagy/autophagy, a conserved process for degrading defective or excessive cellular components. Post-translational modifications of mammalian Atg8-family proteins, including phosphorylation, regulate multiple steps in the autophagic process. In this context, several Atg8-family protein-associated kinases have been found to regulate autophagy, yet the phosphatases in the dephosphorylation of Atg8-family proteins remain unknown. Here, we report that the heterotrimeric PPP2/PP2A (protein phosphatase 2) is a novel regulator in modulating LC3B dephosphorylation. Mechanistically, we find that PPP2-mediated LC3B dephosphorylation reduces the interaction between LC3B and the mitophagy receptor OPTN, thereby impeding the mitochondrial recruitment of phagophores during PINK1-PRKN/Parkin-mediated mitophagy. Interestingly, we find that overexpression of the β2 isoform of PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta; PPP2R2Bβ2), which mimics the spinocerebellar ataxia type 12 (SCA12) pathological condition, harms neuronal survival by enhancing PPP2-mediated LC3B dephosphorylation and reducing mitochondrial recruitment of phagophores upon mitochondrial damage. Importantly, pharmacological induction of mitophagy by the small molecule compound deferiprone (DFP) relieves PPP2R2Bβ2-mediated neuronal toxicity. Overall, our results not only uncover a mechanism by which protein dephosphorylation negatively regulates mitophagy but also provide insights into the pathogenesis of PPP2R2Bβ2-mediated SCA12.
    Keywords:  LC3B; PINK1-PRKN/Parkin-mediated mitophagy; PPP2/PP2A; PPP2R2Bβ2; dephosphorylation; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2025.2572528
  19. Medicine (Baltimore). 2025 Oct 03. 104(40): e44923
    Identification of key mitophagy-related genes in osteomyelitis: Insights from differential gene expression and machine learning models.
    Sirui Zhou, Fan Bai, Shiqiang Wang, Yangyang Zhou, Peibei Yao, Qiang Zheng.
      Osteomyelitis, a severe skeletal infection, involves complex pathogenic mechanisms. Mitophagy (mitophagy) is crucial for cellular homeostasis and has been linked to various diseases, including osteomyelitis. This study explores the genetic basis of mitophagy in osteomyelitis, identifying differentially expressed genes related to mitophagy and their potential as biomarkers and therapeutic targets. Using the GSE30119 dataset from GEO, mRNA expression profiles from 49 osteomyelitis patients and 44 healthy individuals were analyzed. Differential gene expression analysis identified 2876 differentially expressed genes with a threshold of |log FC| > 0.5 and P < .05. Mitophagy-related genes were sourced from GeneCards, with 25 overlapping genes identified. Functional enrichment analyses, including gene ontology and Kyoto encyclopedia of genes and genomes, were conducted. Four machine learning models (generalized linear model, random forest, support vector machine, and extreme gradient boosting) identified 9 key genes for a diagnostic model. Gene set enrichment analysis and immune cell infiltration analysis using CIBERSORT were performed. Furthermore, RT-qPCR was performed to experimentally validate the expression patterns of the identified key genes in an inflammatory cellular model. Twenty-five intersecting genes were identified, with gene ontology and Kyoto encyclopedia of genes and genomes analyses highlighting their roles in autophagy and mitochondrial functions. The random forest model identified 9 key genes: BMP2KL, ALPK1, PGAM5, PINK1, TP53, GPC1, ITPKC, PEX3, and P2RX5, validated with an area under the receiver operating characteristic curve of 0.905. Gene set enrichment analysis indicated their involvement in metabolic and signaling pathways. Immune infiltration analysis revealed significant differences between patients and healthy individuals. RT-qPCR validation confirmed significant expression changes of the 9 key genes under inflammatory conditions, consistent with bioinformatics predictions. This study identifies key mitophagy genes and targets in osteomyelitis, providing a basis for future research and therapies.
    Keywords:  biomarkers; differential gene expression; machine learning classification; mitophagy; osteomyelitis
    DOI:  https://doi.org/10.1097/MD.0000000000044923
  20. Environ Pollut. 2025 Oct 08. pii: S0269-7491(25)01605-7. [Epub ahead of print] 127231
    Increased S-adenosyl methionine strengthens the suppression in mitochondrial unfolded protein response induced by 6-PPD quinone at environmentally relevant concentrations in Caenorhabditis elegans.
    Yuxing Wang, Guocheng Hu, Dayong Wang.
      Exposure to 6-PPD quinone (6-PPDQ) caused mitochondrial dysfunction; however, underlying mechanisms remain largely unclear. In cells, S-adenosylmethionine (SAM) can be generated from methionine. In nematodes, 6-PPDQ (0.1-10 μg/L) reduced methionine content by decreasing expression of msra-1 encoding methionine sulfoxide reductase. 6-PPDQ further increased SAM content by enhancing expressions of sams-1 and sams-5 encoding methionine adenosyltransferases, which activated expressions of mitochondrial slc-25A26 encoding SAM transporter and trmt-10C.2 encoding tRNA methyltransferase. The 6-PPDQ induced mitochondrial dysfunction was inhibited by slc-25A26 and trmt-10C.2 RNAi. Additionally, slc-25A26 and trmt-10C.2 RNAi inhibited 6-PPDQ caused suppression in mitochondrial unfolded protein response (mt UPR) by increasing expressions of haf-1 and clpp-1, two mitochondrial genes governing mt UPR. Moreover, after treatment with methionine to reduce SAM content, 6-PPDQ induced mitochondrial dysfunction and suppression in mt UPR were inhibited. Therefore, 6-PPDQ caused increase in SAM could strengthen mitochondrial dysfunction by enhancing mt UPR suppression, which suggested a metabolic regulatory mechanism of 6-PPDQ toxicity on mitochondrial function.
    Keywords:  Methionine; Mitochondrial UPR; Mitochondrial function; SAM
    DOI:  https://doi.org/10.1016/j.envpol.2025.127231
  21. Stroke. 2025 Oct 09.
    Expression of Concern for: "Mitophagy Reduces Oxidative Stress Via Keap1 (Kelch-Like Epichlorohydrin-Associated Protein 1)/Nrf2 (Nuclear Factor-E2-Related Factor 2)/PHB2 (Prohibitin 2) Pathway After Subarachnoid Hemorrhage in Rats".
      
    DOI:  https://doi.org/10.1161/STR.0000000000000504
  22. Front Mol Biosci. 2025 ;12 1643829
    Transformation of acute kidney injury to chronic kidney disease: the interaction between mitophagy and NLRP3 inflammasome.
    Yixin Zhu, Chenxi Lv, Yanheng Qiao, Hanqi Yang, Wentong Lin, Xuchen Wang, Yueqi Zhang, Bo Yang.
      Acute kidney injury (AKI) and chronic kidney disease (CKD) are closely interrelated renal disorders, where AKI frequently progresses to CKD, resulting in irreversible loss of renal function. In recent years, the roles of the NLRP3 inflammasome and mitophagy in the AKI-to-CKD transition have attracted significant attention. As a crucial component of the innate immune system, the NLRP3 inflammasome promotes AKI-to-CKD progression by mediating inflammatory responses and cellular pyroptosis during renal injury. Conversely, mitophagy exerts renoprotective effects through the selective removal of damaged mitochondria, maintenance of cellular homeostasis, and alleviation of inflammation and oxidative stress. Studies demonstrate that NLRP3 activation is closely associated with mitochondrial dysfunction, while mitophagy can suppress NLRP3 activation by clearing damaged mitochondria, establishing a negative feedback regulatory mechanism. During the AKI phase, mitochondrial damage and excessive NLRP3 activation exacerbate renal tubular epithelial cell injury and inflammatory responses. Concurrently, persistent NLRP3 activation and impaired mitophagy lead to chronic inflammation and fibrosis, accelerating the transition from AKI to CKD. Therefore, targeting the NLRP3 inflammasome and modulating mitophagy may emerge as novel therapeutic strategies for AKI-to-CKD transition. This review focuses on elucidating the molecular mechanisms between mitophagy and the NLRP3 inflammasome, along with related targeted therapies, to provide new insights for preventing AKI progression to CKD.
    Keywords:  AKI; CKD; NLRP3 inflammasome; mitophagy; targeted drugs
    DOI:  https://doi.org/10.3389/fmolb.2025.1643829
  23. Cell Death Dis. 2025 Oct 06. 16(1): 685
    P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and 125I brachytherapy sensitization in esophageal carcinoma.
    Xijuan Yao, Cheng Feng, Xing Huang, Songzhe Wu, Shuting Lu, Yang Gao, Tong Sun, Xiaxing Bai, Chenghui Li, Kaizhi Jia, Xue Han, Zhongkai Wang, Binda Chen, Xiaobin Wang, Jinhe Guo, Jian Lu.
      Interventional brachytherapy, such as iodine-125(125I), has improved the survival of obstructive late-stage esophageal cancer patients. However, most patients experience radioresistance after 125I brachytherapy. It is key to decipher the underlying mechanism of 125I radioresistance. In this study, we identified an endoplasmic reticulum-associated protein, P4HA2, which is upregulated and mediates resistance to 125I treatment. Mechanistically, P4HA2 enhances mitochondrial autophagy (mitophagy) via the PINK1/parkin pathway by binding to ATAD3A. Clinically, high expression of P4HA2 correlates with shorter overall survival and predicts poor prognosis with 125I brachytherapy. Moreover, the expression of P4HA2 is epigenetically increased by IGF2BP2 in an m6A-dependent manner. Notably, targeting P4HA2 with siRNA-based biocompatible nanomedicines significantly sensitizes ESCC to 125I brachytherapy. Collectively, our results show the molecular mechanism of mitophagy-mediated 125I radioresistance, which provides a potential therapeutic target and combinatorial strategy. Schematic diagram of the role of P4HA2 in 125I brachytherapy for tumors.
    DOI:  https://doi.org/10.1038/s41419-025-07864-x
  24. Blood Cancer J. 2025 Oct 06. 15(1): 156
    Cytoskeletal dynamics and mitochondrial rearrangements drive cell fate upon antibody-induced complement activation in DLBCL.
    Hilma J van der Horst, Tamás Csikós, Marjolein Quik, Jort J van der Schans, Klaas de Lint, Gonzalo Nuñez Moreno, Meijian Guan, Kubra Karagoz, Esther C W Breij, Kim C M Santegoets, Martine E D Chamuleau, M Guy Roukens, Marije B Overdijk, Tuna Mutis.
      Complement-dependent cytotoxicity (CDC) is an important effector function of various therapeutic antibodies. Cancer resistance to CDC is primarily attributed to extracellular factors. Using diffuse large B-cell lymphoma (DLBCL) models, we elucidated intracellular evasion mechanisms. By CRISPR-Cas9 library screening, we identified mitochondrial damage and reactive oxygen species as the key intracellular drivers of CDC. CDC resistance was linked to augmented mitochondrial mass, elongated mitochondria and reduced mitophagy, and decreased expression of actin-related genes. Actin downregulation in CDC-resistant cells occurred specifically within the mitochondria, connecting mitochondrial rearrangements and cytoskeletal dynamics with resistance. Stimulating actin polymerization could partially overcome CDC resistance. Of clinical significance, we observed a positive association between the cytoskeleton and antibody responses in DLBCL patient samples. In conclusion, our study unveils novel intracellular resistance mechanisms to antibody-induced CDC, highlighting the critical roles of mitochondrial rearrangements and cytoskeletal dynamics in CDC. We propose that decreased mitochondrial actin prevents overload of the mitophagy pathway, thereby reducing CDC.
    DOI:  https://doi.org/10.1038/s41408-025-01358-x
  25. Phytomedicine. 2025 Sep 28. pii: S0944-7113(25)00971-7. [Epub ahead of print]148 157333
    Prosapogenin CP4 exacerbates mitophagy to induce apoptosis via AMPK-mTOR and PINK1/Parkin pathways in A549 cells.
    Yiru Pan, Jing Wei, Dalian Qin, Xiaogang Zhou, Fei Gao, Lu Yu, Chi Feng, Jianing Mi, Jianming Wu, Betty Yuen Kwan Law, Vincent Kam Wai Wong, Hudan Pan, Bin Liao, Xuecong Ren, Fang Ren, Anguo Wu.
       BACKGROUND: Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality worldwide. While mitophagy, a process that selectively removes damaged mitochondria, typically promotes cell survival, its excessive activation can trigger apoptosis, offering a novel therapeutic avenue. In this study, we report for the first time the identification of prosapogenin CP4 (PCP4), a natural compound isolated from Anemone rivularis, which exerts its anticancer effects by exacerbating mitophagy-mediated apoptosis in A549 cells through dual modulation of the AMPK-mTOR and PINK1/Parkin pathways.
    METHODS: PCP4 was purified using activity-guided fractionation and structurally characterized via LC-MS and NMR. Antiproliferative activity was assessed through MTT and LDH assays, while migration and invasion were evaluated using wound healing and transwell assays. Mitochondrial integrity was assessed using confocal microscopy, 10-NAO, TMRM, and MitoSOX staining. Western blotting, GFP-LC3 puncta, tandem fluorescence-tagged LC3 (tf-LC3), and Mito-QC assays were employed to monitor mitophagy and autophagic flux. Apoptosis was analyzed via Annexin V-FITC/PI staining and caspase-3 activation. Antitumor efficacy was validated in vivo using an A549 xenograft model.
    RESULTS: PCP4 significantly inhibited proliferation, migration, and invasion of A549 and H1299 cells, while inducing mitochondrial fragmentation, depolarization, and oxidative stress. GO/KEGG analyses highlighted enrichment of PI3K-AKT, AMPK, and PINK1/Parkin pathways. Mechanistically, PCP4 enhanced autophagic flux and mitophagy via AMPK-mTOR and PINK1/Parkin signaling; blocking mitophagy partially abrogated its pro-apoptotic effects. Molecular docking confirmed the strong binding affinity of PCP4 to AMPK, PIK3R1, and PINK1. In vivo, PCP4 suppressed tumor growth without systemic toxicity and promoted mitophagy-associated apoptosis in tumor tissues.
    CONCLUSION: This study introduces PCP4 as a first-in-class mitophagy-exacerbating natural product that targets both the AMPK-mTOR and PINK1/Parkin axes to induce apoptosis in A549 cells. Its dual-pathway action, potent anticancer efficacy, and low toxicity profile underscore its therapeutic potential and mechanistic novelty compared to existing autophagy modulators.
    Keywords:  A549 cells; AMPK-mTOR; Apoptosis; Mitophagy; PINK1/Parkin; Prosapogenin CP4
    DOI:  https://doi.org/10.1016/j.phymed.2025.157333
  26. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  27. Neuroscience. 2025 Oct 05. pii: S0306-4522(25)00978-9. [Epub ahead of print]587 81-89
    The study of beneficial effect and mechanism of propofol on TNF-α-induced p-Tau increase in HT22 hippocampal neurons.
    Shuai Gao, Yifei Wang, Zhihong Xu, Minmin Zhu, Zhipeng Meng, Guanghui An, Jiawei Chen.
       BACKGROUND: Tau protein is a soluble microtubule-binding protein expressed in neurons. Abnormal post-translational modifications, such as hyperphosphorylation, are closely related to central nervous system inflammation and may lead to neuronal damage. Propofol has been shown to exert neuroprotective effects. In this study, we investigated the effects of propofol on TNF-α-induced p-Tau increase in hippocampal neurons and explored the underlying mechanisms.
    METHODS: HT22 hippocampal neurons were pretreated with propofol, and then stimulated with TNF-α. Cell viability was measured by cell counting kit-8 (CCK-8). The expression and phosphorylation of Tau, AMPK, AKT and the expression of SIRT3 were detected by Western blot. Mitophagy was detected through the mitophagy detection kit and confocal imaging of LC3B localization.
    RESULTS: TNF-α enhanced Tau phosphorylation in a time- and dose-dependent manner, and significant effects were observed at 10 ng/mL for 2 h. Pretreatment with 25 μM propofol for 1 h effectively reduced TNF-α-induced Tau phosphorylation. TNF-α activated the phosphorylation of AMPK and AKT, which was attenuated by propofol pretreatment and by AMPK inhibitor (Compound C) or AKT inhibitor (MK2206). Meanwhile, TNF-α promoted mitophagy and upregulated the expression of SIRT3, which was inhibited by propofol and by SIRT3 inhibitor (3-TYP).
    CONCLUSIONS: Propofol may attenuate TNF-α-induced p-Tau expression in HT22 cells through modulation of the AMPK/AKT signaling pathway, and may inhibit TNF-α-enhanced mitophagy by affecting the AMPK/SIRT3 signaling pathway.
    Keywords:  HT22 hippocampal neurons; Mitophagy; Propofol; TNF-α; p-Tau
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.09.048
  28. Neurosci Lett. 2025 Oct 06. pii: S0304-3940(25)00299-X. [Epub ahead of print]868 138410
    Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.
    Pallab Bhattacharya, Shailendra Saraf, Anirban Barik, Bijoyani Ghosh, Aishika Datta, Davendra Singh Malik.
      The crucial influence of mitochondria in ischemic stroke pathophysiology presents many unexplored yet promising avenues for therapeutic strategies and clinical outcomes. Post-stroke mitochondrial dysfunction contributes to aggravated levels of calcium overload and apoptosis. This dysfunction is signified by disruption of the mitochondrial lipids such as cardiolipin, along with mitochondrial DNA mutation, leading to an imbalance in mitophagy. Calcium overload-mediated calcineurin overexpression has been reported to exacerbate mitochondrial damage and further contribute to neuronal apoptosis. In our study, we explored the alterations in the mitochondrial function following inhibition of the calcium-mediated calcineurin levels in post-stroke condition. In a rodent model of middle cerebral artery occlusion (MCAo), we observed that the inhibition of the calcium channels in post-stroke condition led to restored neuronal histology and viability following upregulation of the antioxidant levels. At the mitochondrial level, calcium channel inhibition downregulated calcineurin activation and normalized cardiolipin concentration, mitochondrial membrane potential, and respiratory control ratio in post-stroke condition. This inhibition also balanced the mitochondrial dynamics proteins and mitophagy towards neuronal recovery following ischemic stress. Moreover, it also normalized the expression of TERT, a key marker of mitochondrial health and aging. These findings highlight the role of calcium-mediated calcineurin in influencing mitochondrial dysfunction and aging in ischemic stroke. Thus, calcium channel inhibition offers a promising therapeutic strategy by preserving mitochondrial integrity and promoting neuroprotection following stroke.
    Keywords:  Calcineurin; Calcium signaling; Cardiolipin; Mitochondrial aging; Stroke
    DOI:  https://doi.org/10.1016/j.neulet.2025.138410
  29. Life Sci. 2025 Oct 08. pii: S0024-3205(25)00650-2. [Epub ahead of print] 124014
    Linking GLP-1 activation with steroidogenesis, redox, endoplasmic reticulum stress, mitophagy, and the apoptotic regulatory network unlocks the emerging impacts of semaglutide on 5-fluorouracil-induced testicular toxicity.
    Noha F Hassan, Haneen Y Khidr, Rania Farag A Eltelbany, Mona M Abd El-Galil, Enji Reda, Nahla A El-Zohairy, Ayah M H Gowifel.
       AIMS: One of the recent growing complications of neoplastic chemotherapy that is considered a challenge in their therapeutic protocol is testicular dysfunction. The pathogenesis of testicular injury is multifactorial, involving various pathogenic mechanisms, including oxidative stress, endoplasmic reticulum stress (ERS), and mitochondrial dysfunction. Semaglutide (Sema), a GLP1 agonist, is repurposed nowadays in multiple conditions ascribed to its effectiveness in shielding against oxidative stress and ERS, along with boosting mitochondrial biogenesis. Accordingly, this study proposes to investigate the use of Sema as adjunctive therapy in a 5-fluorouracil (5-FU) treatment protocol to diminish its testicular dysfunction complications.
    MATERIALS AND METHODS: Rats were allocated into five groups. Group I: normal control group; Group II was injected with Sema (12 μg/kg, s.c.) once weekly for 30 days. Groups III (5-FU group), IV, and V were injected with 5-FU (20 mg/kg, every other day, i.p.) for 30 days. Group IV (Sema-treated group) was injected with Sema, while group V (Blocker group) was injected with exendin 9-39 (50 μg/kg, once weekly, I.V.).
    KEY FINDINGS: The results revealed that activation of GLP-1 attenuated 5-FU-induced testicular dysfunction by enhancing the PINK-1/Parkin axis and mitochondrial biogenesis, eliminating ERS-related proteins (PERK, ATF6, GRP78, and CHOP). Sema activated the Nrf2/HO-1 hub, improved steroidogenesis and spermatogenesis by elevating STAR/DAZL and serum FSH, LH, and testosterone levels.
    SIGNIFICANCE: This study highlighted the use of Sema as adjunctive therapy in the 5-FU treatment protocol to guard against the associated testicular dysfunction, via modulating oxidative stress, ERS, and mitochondrial dysfunction in the rat experimental model.
    Keywords:  Endoplasmic reticulum stress; GLP-1; Mitochondrial biogenesis; Nrf2/HO-1; Steroidogenesis; Testicular dysfunction
    DOI:  https://doi.org/10.1016/j.lfs.2025.124014
  30. J Inflamm Res. 2025 ;18 13689-13710
    Identification of Mitophagy-Related Genes and Analysis of Immune Infiltration in Atherosclerosis.
    Jiaqi Zhang, Xiting Wang, Xiahuan Chen, Meilin Liu.
       Background: Atherosclerosis is a chronic inflammatory disease involving mitophagy and immune dysregulation. Currently, there is no integrated diagnostic model for autophagy immune genes in mitochondria. This study aimed to identify potential diagnostic markers through integrated bioinformatics and experimental validation.
    Methods: Two atherosclerosis-related datasets (GSE43292 and GSE100927) were analyzed to identify differentially expressed mitophagy-related genes (MRGs), followed by enrichment analysis. Key genes were screened using LASSO, SVM-RFE, and random forest algorithms. A diagnostic nomogram was constructed and validated by ROC analysis. Immune infiltration was evaluated using CIBERSORT and ssGSEA. GSEA, GSVA, and unsupervised clustering were applied to explore biological pathways and molecular subtypes. qPCR validation was performed in ox-LDL-treated RAW264.7 and THP-1 cells.
    Results: Thirteen upregulated and six downregulated MRGs were identified. Five hub genes (MNDA, CD163L1, NEXN, TC2N, SLC22A3) demonstrated strong diagnostic performance (AUC > 0.85) and were closely associated with immune cell infiltration; two molecular subtypes with distinct immune profiles were identified; qPCR validation confirmed the differential expression of these genes under inflammatory stimulation.
    Conclusion: MNDA, CD163L1, NEXN, TC2N, and SLC22A3 may serve as diagnostic biomarkers for atherosclerosis. This five-gene model can stratify patient risk and guide personalized anti-inflammatory/autophagic therapy.
    Keywords:  atherosclerosis; bioinformatics; cardiovascular disease; immune infiltration; mitophagy
    DOI:  https://doi.org/10.2147/JIR.S544597
  31. Toxicol Appl Pharmacol. 2025 Oct 04. pii: S0041-008X(25)00366-7. [Epub ahead of print]505 117590
    PM2.5 enhances DRP1-mediated mitochondrial fission to induce ferroptosis and exacerbate asthma through the AHR-HSP90-PKM2 pathway.
    Simiao Qiao, Fanshu Li, Jia Huang, Xiaoqian Wu, Xiaoying Cao, Xifeng Zhang, Zhifeng Wei.
      This study was designed to clarify the reason for PM2.5 to induce the ferroptosis of bronchial epithelial cells and worsen asthma in detail, advancing the development of relevant drugs. Results displayed that PM2.5 mainly induced ferroptosis but not apoptosis of bronchial epithelial cells, indicating by the changes of lipid reactive oxygen species (ROS), iron, malondialdehyde, lactic dehydrogenase, nuclear receptor coactivator 4, glutathione and glutathione peroxidase 4 levels, and further confirmed by using in combination with the ferroptosis and apoptosis inhibitors. It also caused the mitochondrial disturbance, reduced the level of mitochondrial membrane potential, up-regulated the level of mitochondrial ROS, and mechanisms were subsequently ascribed to dynamin-related protein 1 (DRP1)-related mitochondrial fission. Furthermore, the up-regulation on ubiquitination of pyruvate kinase M2 (PKM2) but not macrophage stimulating 1 or interferon regulatory factor 1, the transcriptional regulators locating at the upstream of DRP1, was showed by PM2.5via controlling "aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90)" axis. In addition, isoliquiritigenin (ISL), the main active ingredients in licorice, was demonstrated to prevent the PM2.5-induced activation of AHR-PKM2-ferroptosis in asthma. In conclusion, PM2.5 activated "AHR-HSP90" axis to disturb DRP1-related mitochondrial fission, induced ferroptosis of bronchial epithelial cells, and worsened asthma. Conversely, ISL restored the above-mentioned signals, ferroptosis and asthma mediated by PM2.5, and was suggested as a potential compound to combat the exacerbation of asthma.
    Keywords:  Asthma; Ferroptosis; Isoliquiritigenin; Mitochondrial homeostasis; PM(2.5)
    DOI:  https://doi.org/10.1016/j.taap.2025.117590
  32. JCI Insight. 2025 Oct 08. pii: e188904. [Epub ahead of print]10(19):
    AI662270/GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction.
    Suling Ding, Wen Liu, Zhiwei Zhang, Xiyang Yang, Dili Sun, Jianfu Zhu, Xiaowei Zhu, Shijun Wang, Mengshi Xie, Hongyu Shi, Junbo Ge, Xiangdong Yang.
      The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, comprises distinct pathways orchestrated by conserved molecular sensors. Although several of these components have been suggested to protect cardiomyocytes from ischemic injury, their precise functions and mechanisms remain elusive. In this study, we observed a marked increase in glucose-regulated protein 94 (GRP94) expression at the border zone of cardiac infarct in a mouse model. GRP94 overexpression ameliorated post-infarction myocardial damage and reduced infarct size. Conversely, GRP94 deficiency exacerbated myocardial dysfunction and infarct size. Mechanistically, GRP94 alleviated hypoxia-induced mitochondrial fragmentation, whereas its depletion exacerbated this fragmentation. Molecular investigations revealed that GRP94 specifically facilitated the cleavage of Opa1 into L-Opa1, but not S-Opa1. The study further elucidated that under hypoxic conditions, the binding shift of Yy1 from lncRNA Oip5os1 to AI662270 promoted Yy1's binding on the GRP94 promoter, thereby enhancing GRP94 expression. AI662270 attenuated mitochondrial over-fragmentation and ischemic injury after myocardial infarction similarly to GRP94. Moreover, coimmunoprecipitation coupled with LC-MS/MS identified the interaction of GRP94 with Anxa2, which regulates Akt1 signaling to maintain L-Opa1 levels. Overall, these findings unveiled what we believe is a novel role for the AI662270/GRP94 axis in linking ER stress to mitochondrial dynamics regulation, proposing new therapeutic avenues for managing cardiovascular conditions through ER stress modulation.
    Keywords:  Cardiology; Cell biology; Cell stress; Hypoxia; Noncoding RNAs
    DOI:  https://doi.org/10.1172/jci.insight.188904
  33. J Ethnopharmacol. 2025 Oct 07. pii: S0378-8741(25)01413-8. [Epub ahead of print] 120721
    Kai-Xin-San improves aging and associated neuroinflammation through mitochondrial autophagy.
    Yu Gao, Jinxue Zhang, Xiaoqian Zhang, Chengjie Xing, Pengfei Xie, Zhenfei Zhou, Ting Zhan, Hanrui Zeng, Yang Wang, Yuanxu Liu, Caiyun Zhang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS), a historically used traditional Chinese prescription, calms the mind, invigorates Qi, removes dampness and turbidity. Certain components of KXS have demonstrated anti-aging and anti-neuroinflammatory properties, but the underlying mechanisms of KXS as a whole remain unclear.
    AIM OF THE STUDY: To investigate the mechanisms through which KXS alleviates aging and neuroinflammation.
    MATERIALS AND METHODS: Potential targets and signaling pathways of KXS in promoting mitochondrial autophagy and anti-aging were predicted using network pharmacology and molecular docking. In animal experiments, spatial learning memory and neuroinflammation in aging mice following KXS treatment were evaluated through behavioral tests and measurement of biochemical markers. Additionally, histopathological changes in the brain tissue of aged mice, along with mitochondrial autophagy levels, were examined using Hematoxylin and Eosin staining, Nissl staining, immunofluorescence labelling, and transmission electron microscopy (TEM). In cell experiments, the regulatory effect of KXS on mitochondrial autophagy was assessed using TEM and immunofluorescence techniques. Western blotting analyzed aging, inflammatory, and mitochondrial autophagy-related proteins in both models.
    RESULTS: Network pharmacology analysis identified 142 potential targets associated with aging and autophagy. Molecular docking suggested there was strong binding affinity between main components of KXS and relevant targets. In vivo, KXS significantly improved learning memory, biochemical indicators, and neuronal damage, immunofluorescence confirmed that it reduced the expression of the aging marker p21. In vitro, KXS-medicated serum increased mitochondrial autophagy. Moreover, TEM showed that KXS improved mitochondrial damage in aging mice and BV2 cells. Notably, KXS down-regulated the expression aging-related and inflammation-related proteins, then increased the expression mitochondrial autophagy proteins. Importantly, the therapeutic effects of KXS were diminished upon administration of chloroquine (CQ), a mitochondrial autophagy inhibitor.
    CONCLUSION: KXS could promote in vivo and in vitro mitochondrial autophagy and significantly ameliorate aging and associated neuroinflammation.
    Keywords:  Kai-Xin-San; aging; cognitive impairment; mitochondrial autophagy; network pharmacology; neuroinflammation
    DOI:  https://doi.org/10.1016/j.jep.2025.120721
  34. Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01192-1. [Epub ahead of print]44(10): 116421
    Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
    Lin Li, Yulan Chen, Yuanzhi Wang, Yuhui Dong, Haoran Wang, Ziyi Liu, Xin Ge, Puxiu Shen, Yue Li, Dingpu Liu, Xiangmei Zhou.
      Hexokinases (HKs) are essential enzymes in sugar metabolism, but their mitochondrial release also reflects cellular status in disease. Mycobacterium bovis (M. bovis), the causative agent of bovine and human tuberculosis, infects macrophages and induces mitophagy, yet the role of HKs in this process remains unclear. We find that M. bovis infection induces the release of HK2 from mitochondria, where it dissociates from voltage-dependent anion channel (VDAC). This dissociation promotes VDAC oligomerization, pore formation in the outer mitochondrial membrane, and mitochondrial damage. Damaged mitochondria subsequently undergo mitophagy, which enhances the intracellular survival of M. bovis. Consistent with this mechanism, we show that ESAT6-mediated phagosome membrane rupture is critical for HK2 release and subsequent mitochondrial events. Our study identifies a pathway by which M. bovis manipulates host cell processes to promote survival, providing insights into the host-pathogen interaction and potential avenues for tuberculosis prevention and therapy.
    Keywords:  CP: Microbiology; Mycobacterium bovis; VDAC; autophagy; hexokinase; macrophage; mitochondria; mitophagy; tuberculosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116421
  35. Ecotoxicol Environ Saf. 2025 Oct 09. pii: S0147-6513(25)01535-0. [Epub ahead of print]305 119190
    Prenatal exposure to cadmium induces multigenerational inheritance of male testicular damage and mitochondrial biogenesis abnormalities.
    Xueming Xu, Xiushuai Du, Chenyun Zhang, Yiqin Chen, Yi Sun, Liqin Zhan, Xuebin Lin, Lingfeng Luo, Wenxiang Wang, Jianlin Zhu, Jin Liu, Yuchen Li.
      Male fertility decline has become a global public health problem, for which environmental pollutants are important risk factors; meanwhile, the intergenerational genetic effects of environmental pollutants that induce reproductive toxicity have also received increasing attention. Cadmium has been recognized by WHO as one of the 10 pollutants causing significant public health concerns, and its reproductive toxicity has been demonstrated, but the intergenerational genetic effects of cadmium-induced reproductive toxicity remain to be further explored. In this study, we established a maternal genetic animal model and found that cadmium exposure during pregnancy resulted in testicular tissue damage and abnormal mitochondrial biogenesis in male offspring, and exhibited genetic effects. TFAM may be a key gene regulating abnormal mitochondrial biogenesis. The imprinted gene H19 may interfere with protein translation of TFAM by affecting 4EBP1 phosphorylation and plays an important role in the intergenerational effects of cadmium exposure during pregnancy leading to testicular damage. This study reveals for the first time the epigenetic mechanism of mitochondrial biogenesis disorder in testicular injury induced by cadmium exposure during pregnancy, providing important clues for further study of its intergenerational genetic effect regulation mechanism, and providing new ideas for the intervention of cadmium-induced health damage in the population.
    Keywords:  Cadmium; Gestational exposure; Intergenerational genetic effects; Mitochondrial biogenesis; Testicular injury
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119190
  36. Zhonghua Jie He He Hu Xi Za Zhi. 2025 Oct 12. 48(10): 970-978
    [The mechanism of mitochondrial damage in chronic obstructive pulmonary disease induced by cigarette smoke and its therapeutic implications].
    Y Zhao, Q L Qi, M J Hu, M L Zhang, H H Shi, W Y Liu.
      Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disorder characterized by persistent and progressive airflow limitation. Cigarette smoking is recognized as the primary risk factor. There is emerging evidence that mitochondrial dysfunction is a key pathological mechanism in smoking-induced COPD. Reactive oxygen species and other toxic components found in tobacco smoke can directly damage mitochondrial DNA, impair the function of the electron transport chain, decrease ATP production, and promote the excessive generation of reactive oxygen species, resulting in a self-perpetuating cycle of oxidative damage. Furthermore, disturbances in mitochondrial dynamics, including imbalances in fusion and fission processes, defective mitophagy, and heightened oxidative stress, contribute to increased airway epithelial cell apoptosis, persistent inflammatory responses, and impaired tissue repair. Mitochondria-derived damage-associated molecular patterns (DAMPs) have also been shown to activate the NLRP3 inflammasome, exacerbating pulmonary inflammation. Targeting mitochondrial dysfunction represents a promising therapeutic avenue for the prevention and treatment of COPD. Accordingly, this review summarized recent advances in understanding the role of tobacco-induced mitochondrial damage in COPD pathogenesis and highlighted its potential as a novel intervention target.
    DOI:  https://doi.org/10.3760/cma.j.cn112147-20250603-00298
  37. Regen Biomater. 2025 ;12 rbaf092
    L-arginine-loaded microneedle patch enhances diabetic wound healing by regulating macrophage polarisation and mitochondrial homeostasis.
    Hong Wang, Shun Yao, Qingyun Mo, Mingyue Chen, Danfeng He, Lingfeng Yan, Chang Wang, Tao Zou, Gaoxing Luo, Jun Deng.
      Excessive oxidative stress and dysregulated macrophage polarization-characterized by M1/M2 imbalance-drive chronic, persistent inflammation and represent key pathological mechanisms underlying impaired tissue repair in diabetic wounds; however, therapeutic strategies targeting both these processes remain limited. L-arginine (L-Arg) shows therapeutic potential through its antioxidant properties and ability to promote M1 macrophage polarization. Nevertheless, the mechanisms by which L-Arg regulates mitochondrial homeostasis to exert antioxidant effects remain unclear. Moreover, its clinical translation is hindered by poor retention, inadequate tissue penetration and damage induced by hypertonicity, thereby necessitating the development of innovative delivery systems. To address these limitations, we developed an L-Arg-loaded microneedle (L-Arg-MN) patch for controlled delivery. Our findings demonstrate that L-Arg alleviated hydrogen peroxide (H2O2)-induced cellular damage through activation of the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1) pathway, boosting antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px)) and lowering malondialdehyde (MDA) levels. Mechanistically, L-Arg maintained mitochondrial homeostasis by upregulating peroxiredoxin 1 (PRDX1) expression, restoring mitochondrial membrane potential and enhancing adenosine triphosphate production. Furthermore, L-Arg suppressed M1 macrophage polarization and promoted M2 polarization through PRDX1-mediated mitochondrial metabolic pathways. In models of diabetic wounds, the L-Arg-MN patch markedly enhanced the wound healing process, accelerated wound closure, reduced concentration of reactive oxygen species (ROS), enhanced granulation tissue, collagen formation and increased M2 macrophage infiltration. This study elucidates how L-Arg reduces oxidative stress and enhances M2 macrophage polarization by regulating mitochondrial metabolism through the PRDX1 pathway. By integrating the metabolic and immunomodulatory properties of L-Arg with advanced drug delivery technology, the L-Arg-MN patch presents an innovative and efficient approach to treating diabetic wounds.
    Keywords:  L-arginine; macrophage polarization; microneedle; mitochondrial homeostasis; oxidative stress
    DOI:  https://doi.org/10.1093/rb/rbaf092
  38. Cell Commun Signal. 2025 Oct 09. 23(1): 423
    Taurine can restrict MtdsRNA mediated pyroptosis by enhancing mitophagy in nucleus pulposus cells.
    Zixuan Ou, Junyu Wei, Bide Tong, Jie Lei, Huaizhen Liang, Dingchao Zhu, Hongchuan Wang, Xingyu Zhou, Di Wu, Hanpeng Xu, Zhi Du, Yifan Du, Shuchang Peng, Xiaoguang Zhang, Huipeng Yin, Kun Wang, Cao Yang, Zhiwei Liao.
      
    Keywords:  Intervertebral disc degeneration; Mitophagy; MtdsRNA; Pyroptosis; Taurine
    DOI:  https://doi.org/10.1186/s12964-025-02431-5
  39. Arch Biochem Biophys. 2025 Oct 06. pii: S0003-9861(25)00350-9. [Epub ahead of print] 110636
    MITOCHONDRIAL REDOX IMBALANCE AND CoQ10 DEFICIENCY IN RETT SYNDROME: INSIGHTS FROM PATIENT-DERIVED FIBROBLASTS.
    Francesco Mengarelli, Valeria Cordone, Alessandra Pecorelli, Mascia Benedusi, Giuseppe Valacchi, Camilla Morresi, Tiziana Bacchetti, Patrick Orlando, Luca Tiano, Sonia Silvestri.
      Rett syndrome (RTT), a neurodevelopmental disorder primarily affecting females, is characterized by mutations in the MECP2 gene, leading to systemic oxidative stress and mitochondrial dysfunction. This study investigates the role of Coenzyme Q10 (CoQ10), particularly its reduced form ubiquinol, in modulating oxidative stress and mitochondrial function in primary dermal fibroblasts derived from RTT patients with distinct MeCP2 mutations. Baseline assessments revealed significant CoQ10 deficiencies and elevated reactive oxygen species (ROS) levels, notably in fibroblasts with the T158M mutation. Ubiquinol supplementation effectively restored CoQ10 levels and improved redox balance in these cells. Additionally, treatment influenced mitochondrial dynamics, as evidenced by alterations in the expression of fission and fusion proteins and modulated the activity of paraoxonase 2 (PON2), an enzyme involved in cellular antioxidant defense. In conclusion, our data suggest that CoQ10 supplementation could mitigate oxidative damage and preserve mitochondrial integrity, but we are far from being able to claim that it can represents an effective therapeutic strategy to complement current pharmacological treatments in RTT patients. Further research is warranted to explore the potential of CoQ10 as an adjunctive treatment, particularly during the early stages of RTT.
    Keywords:  Coenzyme Q(10); Rett syndrome; mitochondrial dynamics; mitochondrial dysfunction; oxidative stress; paraoxonase 2; ubiquinol
    DOI:  https://doi.org/10.1016/j.abb.2025.110636
  40. Adv Sci (Weinh). 2025 Oct 06. e06107
    Onion-Mitochondria Inhibit Lipopolysaccharide-Induced Acute Lung Injury by Shaping Lung Macrophage Mitochondrial Function.
    Qingbo Xu, Yun Teng, Yinan Huang, Jingyao Mu, Lucy Teng, Hongjia Qian, Qiming Huang, Minmin Liu, Yi Zou, Lifeng Zhang, Michael L Merchant, Xiang Zhang, Jun Yan, Huang-Ge Zhang.
      Mitochondrial dysfunction contributes to various inflammatory-related diseases by triggering the release of inflammatory molecules. Targeting mitochondrial dysfunction is emerging as a promising avenue for treating inflammatory diseases. Here, it is demonstrated that dietary plant-derived mitochondria (P-Mit) are capable of rescuing the lung macrophage mitochondrial (M-Mit) dysfunction in lipopolysaccharide (LPS)-induced mouse acute lung injury (ALI). Specifically, oral administration of dietary onion-derived mitochondria (O-Mit) can travel from the gut to the lungs in ALI mice, where preferentially uptake by lung macrophage mediated by the interaction between O-Mit phosphatic acid (PA) and macrophage complement C3b/C4b receptor 1 Like (CR1L), followed by fusing with murine M-Mit and by reprograming the M-Mit energy metabolism in the lungs of ALI mice. Further evidence suggests that O-Mit enriches methyl 3,4-dihydroxybenzoate (MDHB) inhibits M-Mit NADH dehydrogenase subunit 1 (ND1) gene expression in the epigenetic process, which represses LPS-induced complex I-related oxidative stress activation and excessive mitochondrial fission via modulating dynamin-related protein 1 (DRP1) phosphorylation and cardiolipin peroxidation in M-Mit, eventually rescues the LPS-induced ALI. Given LPS-induced mouse model of ALI is widely used to study human ALI and acute respiratory distress syndrome, this finding provides a clinical potential for the treatment of human ALI via edible P-Mit.
    Keywords:  Cardiolipin peroxidation; Complex I subunits NADH dehydrogenase 1 (ND1); Dynamin‐related protein 1 (DRP1) phosphorylation; Mitochondrial dysfunction; Plant mitochondria‐animal mitochondria cross‐kingdom fusion
    DOI:  https://doi.org/10.1002/advs.202506107
  41. Exp Gerontol. 2025 Oct 05. pii: S0531-5565(25)00249-9. [Epub ahead of print]211 112920
    Compromised autophagy in the aging epididymis: Evidence and relevance to male fertility.
    Nabil Eid.
      Impaired autophagy and increased cellular senescence in the aging epididymis may lead to cellular stress, inflammation, and epithelial dysfunction. This reduction in autophagy can be identified using light and electron microscopy, as well as molecular biology techniques. Autophagy, which may be selective or non-selective, is tightly regulated by genes such as LC3 and LAMP-2. Decreased autophagic activity in the epididymis results in reduced sperm quality and male fertility. These findings highlight autophagy as a potential therapeutic target in age-related male reproductive decline.
    Keywords:  Autophagy; Epididymis; LC3-associated phagocytosis; Mitophagy; Senescence; Sperm
    DOI:  https://doi.org/10.1016/j.exger.2025.112920
  42. Cell Mol Life Sci. 2025 Oct 07. 82(1): 347
    Splicing factor Sf3b1 facilitates maintenance of neuronal dendrites by modulating mitochondrial health.
    Wei-Chia Tsao, Yi-Chun Huang, Hsin-Ho Sung, Chi-Hung Lin, Hwei-Jan Hsu, Hsiu-Fen Lin, Cheng-Ting Chien.
      The intricate process of dendritic arborization is essential for forming functional neural circuits, and many of the underlying molecular and cellular mechanisms have been uncovered. However, how they are linked to regulate dendritic arborization in neurons remains further exploration. Through genetic screening, we identify the splicing factor Sf3b1 as functioning cell-autonomously in neuronal dendrite growth and maintenance. Our transcriptomic analysis links Sf3b1-regulated alternative splicing to modulation of metabolic pathways, and we assess altered splicing patterns for several mitochondria-related genes. Importantly, Sf3b1 knockdown in neurons results in dramatic mitochondrial fragmentation and specific reductions in mitochondrial counts and ATP levels in dendrites, revealing a pivotal role for Sf3b1 in modulating the energy supply necessary for dendritic arborization. Additionally, a genetic rescue experiment uncovered mitophagy-modulating molecules that effectively restored the mitochondrial health and dendritic arborization of Sf3b1-depeted neurons. Our study establishes a previously unrecognized connection between RNA splicing and mitochondrial demand in differentiating neurons, providing insights into bioenergetic requirements for dendritic growth and maintenance.
    Keywords:  ATP levels; Alternative RNA processing; Metabolic regulation; Mitophagy; Transcriptomic analysis
    DOI:  https://doi.org/10.1007/s00018-025-05860-0
  43. Mol Biol Cell. 2025 Oct 08. mbcE25060302
    The biophysical mechanism of mitochondrial pearling.
    Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall.
      Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive, "beads-on-a-string" morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of "pearls" connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling, i) ionic flux producing internal osmotic pressure, ii) membrane packing lowering bending elasticity, and iii) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.
    DOI:  https://doi.org/10.1091/mbc.E25-06-0302
  44. Cell Commun Signal. 2025 Oct 08. 23(1): 420
    BMAL1 modulation alleviates inflammatory responses in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response in high-altitude hypoxia.
    Yi-Ling Ge, Jin Xu, Yue Cai, Bin Zhang, Si-Yuan He, Pei-Jie Li, Ying-Rui Bu, Lin Zhang, Zhi-Bin Yu, Heng Ma, Yong Liu, Xiong-Wen Chen, Man-Jiang Xie.
       BACKGROUND: Hypoxia-induced inflammation has been implicated in the progression of high-altitude illnesses. Mitochondria are key organelles for oxygen metabolism and inflammation that are controlled by circadian clocks. However, little is known regarding how circadian clocks sense hypoxic signals and trigger downstream mitochondrial responses.
    METHODS: Human participants and mice were exposed to a real or simulated high-altitude setting of 5500 m. Multichannel fluorescence intravital microscopy was used for in vivo molecular imaging of inflammation. Bioinformatics analysis, myeloid-specific knockout mice, and RAW 264.7 cells were used to investigate the underlying inflammatory mechanisms.
    RESULTS: We found that high-altitude hypoxia induced dynamic inflammatory activity in monocytes, characterized by significantly increased levels of cytokines (interleukin-6 [IL-6], IL-1β and monocyte chemoattractant protein-1) after acute (3-day) exposure, which returned to control levels after a prolonged (30-day) exposure. Bioinformatics analysis revealed that the core circadian transcription factor brain and muscle Arnt-like 1 (BMAL1) correlated positively with hypoxia-induced inflammation in monocytes. Mechanistically, BMAL1 induced NOD-like receptor protein 3 inflammasome activation in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response. Basic helix-loop-helix family member E40, a hypoxic stress-responsive transcription factor, directly promoted Bmal1 transcription and triggered inflammation in monocytes. In contrast, myeloid-specific deletion of BMAL1 alleviated the inflammatory activity of monocytes and circulating inflammation, both in vitro and in vivo, under high-altitude hypoxia.
    CONCLUSIONS: Our findings indicate that transcriptional activation of Bmal1 in monocytes can potentially serve as a novel biomarker of hypoxia-induced inflammation. Our findings also suggest a novel approach for modulating the intrinsic clock, which might render organisms less vulnerable to high-altitude hypoxia.
    Keywords:  BMAL1; High-altitude hypoxia; Inflammatory response; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1186/s12964-025-02420-8
  45. World J Urol. 2025 Oct 07. 43(1): 599
    Chronic prostatitis and male infertility: association mechanism and research progress.
    Zhang Qinyu, Shi Jitao, Xuan Yang, Duan Yue, Zhang Hao.
       OBJECTIVE: To systematically examine the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and male infertility, elucidate the pathophysiological mechanisms by which CP/CPPS impairs fertility, summarize current research advancements, and establish a foundation for targeted diagnosis and treatment strategies.
    METHOD: This study synthesizes clinical research, meta-analyses, and experimental model evidence to examine alterations in semen parameters (concentration, motility, morphology, DNA fragmentation rate) and seminal plasma biomarkers (PSA, cytokines, hormones). It explores the interactions across various systems, including neuro-immune-endocrine dysregulation, metabolic diseases, microcirculatory dysfunction, aberrant intestinal-prostate axis activity, and mitochondrial autophagy. The study assesses diagnostic frameworks such as NIH-CPSI and UPOINT, along with their therapeutic effectiveness.
    RESULTS: CP/CPPS markedly decreased sperm concentration (SMD= - 14.12), forward motility (SMD= - 5.94), and normal morphology rate (SMD= - 8.26), while elevating DNA fragmentation rates (> 30%). Principal mechanisms comprise: (1) Pro-inflammatory cytokines (e.g., IL-6, TNF-α) impairing mitochondrial function and DNA integrity; (2) Neuroendocrine dysfunction inhibiting the hypothalamic-pituitary-testicular axis; (3) Metabolic syndrome comorbidity (OR = 2.10) inducing an energy crisis via mitochondrial dysfunction; (4) Gut microbiota dysbiosis diminishing anti-inflammatory short-chain fatty acids (SCFAs), intensifying systemic and reproductive tract inflammation; (5) Mitophagy impairments (e.g., PINK1 dysfunction) resulting in the accumulation of damaged sperm mitochondria. UPOINTs phenotype-guided multimodal therapy mitigates clinical symptoms, with 77.5% of patients attaining a reduction of at least 6 points in the NIH chronic prostatitis symptom index (NIH-CPSI) scores within 6 months.
    CONCLUSION: The intricate pathogenesis of male infertility in CP/CPPS encompasses a diverse array of pathways: inflammatory, autoimmune, neuroendocrine, metabolic, and mitochondrial. Future investigations should concentrate on the mechanisms of mitochondrial autophagy and the regulation of epigenetics. Clinical management may contemplate the implementation of multidisciplinary, collaborative, phenotype-oriented, comprehensive therapies to disrupt the "chronic pain-inflammation-infertility" vicious cycle and protect fertility health.
    Keywords:  Chronic prostatitis/chronic pelvic pain syndrome; Gut-prostate axis; Inflammatory cytokines; Male infertility; Mitochondrial autophagy; Mitochondrial dysfunction; Semen parameters; UPOINT phenotypic classification
    DOI:  https://doi.org/10.1007/s00345-025-05964-z
  46. Int J Biol Macromol. 2025 Oct 05. pii: S0141-8130(25)08664-7. [Epub ahead of print] 148107
    HRS sustains mitochondrial homeostasis by anchoring destabilized proteins during tumorigenesis.
    Bo-Lin Xiao, Jin-Bang Li, Zhuo-Kun Chen, Ze-Chen Zhao, Yi-Man Wang, Hai-Ming Liu, Hou-Fu Xia, Qiu-Yun Fu, Shao-Xin Huang, Jun Shang, Gang Chen, Wei Zhang.
      The role of the endosomal sorting complex required for transport (ESCRT) in tumorigenesis remains controversial and context-dependent, with its subunits often exhibiting opposing functions across cancer types. The ESCRT-0 component HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) has been linked to both tumor-suppressive and pro-oncogenic processes, yet its impact on tumor initiation and metabolic adaptation is poorly understood. Here, using a transgenic melanoma model, we demonstrate that melanocyte-specific deletion of HRS delays tumor onset, suppresses tumor growth, and prolongs survival. HRS-deficient tumor cells exhibit a shift toward glycolytic metabolism and impaired proliferation under energy stress. We further show that HRS loss leads to mitochondrial dysfunction, marked by disrupted morphology, reduced tricarboxylic acid (TCA) cycle metabolites, and decreased respiratory enzyme levels. Mechanistically, HRS deficiency disrupts the FYVE- and UIM domain-dependent endosomal clearance of ubiquitinated misfolded proteins, leading to their translocation into mitochondria. This aberrant accumulation triggers a mitochondrial unfolded protein response (mtUPR) and compromises mitochondrial function. Clearance of misfolded proteins from mitochondria rescues these defects. Our study reveals a non-canonical role for HRS in maintaining mitochondrial proteostasis and supporting tumor metabolic plasticity, highlighting HRS as a potential target for disrupting tumor metabolic adaptation.
    Keywords:  HRS; Mitochondrion; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148107
  47. iScience. 2025 Sep 19. 28(9): 113449
    Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.
    Marica Meroni, Erika Paolini, Miriam Longo, Michele Battistin, Daniele Dondossola, Michela Ripolone, Laura Napoli, Ettore Mosca, Stefania Corti, Paola Dongiovanni.
      Hepatic mitochondrial maladaptation features the transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to Steatohepatitis (MASH) up to fibrosis/cirrhosis. However, it is still unexplored whether mitochondrial alterations also affect adipose tissue, muscle and heart during disease progression. C57Bl/6 mice were fed an AMLN diet to recapitulate the human MASLD spectrum. In the liver, TEM depicted a progressive morphologic dysfunction of mitochondria, which appeared swollen in MASH, with disorganized cristae/matrix loss in MASH-fibrosis. The mitophagy pathway was reduced in MASH-fibrosis, thus explaining the accumulation of damaged mitochondria, whereas mitochondrial complexes activities alongside OXPHOS protein levels and ATP production were dampened across the disease in liver, adipose, muscle, and cardiac tissues. Finally, the release of cell-free circulating mitochondrial DNA into the bloodstream reflected tissue mitochondrial impairment. In sum, we demonstrated that alterations in mitochondrial morphology, life cycle, and activity feature all disease stages in the liver but also in other tissues engaged in MASLD evolution.
    Keywords:  Biochemistry; Systems biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113449
  48. Mol Med. 2025 Oct 06. 31(1): 308
    CAMKK2 restored mitochondrial dynamics homeostasis to alleviate pulmonary fibrosis via AMPK/PGC-1α signaling pathway in lung fibroblasts.
    Yanlin Zhou, Yuqi Wang, Mengyuan Wang, Bin Li, Kai Xu, Xiaoyue Pan, Zhongzheng Li, Qiwen Wang, Wanyu He, Jiaojiao Pang, Yingchun Guo, Yuqing Zhang, Koji Sakamoto, Juntang Yang, Lan Wang, Guoying Yu.
      
    Keywords:  CAMKK2; Energy metabolism; Fibroblasts; Mitochondrial dynamics; Pulmonary fibrosis
    DOI:  https://doi.org/10.1186/s10020-025-01373-5
  49. Artif Organs. 2025 Oct 09.
    Effect of Functional Electrical Stimulation Combined With Physical Exercise on Electron Transport Chain Activity in Peripheral Blood Cells of Stroke Patients.
    A Larrea, A Martín-Odriozola, E Astigarraga, C Rodríguez-de-Pablo, G Barreda-Gómez, M Torrecilla.
       BACKGROUND: Stroke is commonly accompanied by motor disorders secondary to the initial injury, and at the mitochondrial level, there is an increase in oxidative stress, causing tissue damage and relating to alteration in motor function. Functional electrical stimulation (FES) therapies can be useful in stroke patients aimed at restoring motor function and improving life quality. Several studies have recently proposed that electrical stimulation modulates mitochondrial biogenesis and physiology; however, the effect of FES on individual complexes comprising the mitochondrial electron transport chain (mETC) remains unknown.
    METHODS: To study the effect of FES therapy on the activity of the mETC, in vitro analyses were conducted using UV-spectrophotometry of the activity of the complexes (I, II, and IV), glycerol-3-phosphate dehydrogenase (G3PDH), and monoamine oxidase (MAO) in peripheral blood mononuclear cells (PBMCs) obtained from stroke patients. Patients' activity of complex II and MAO was also determined in platelets. Analyses were measured before and after 12 rehabilitation sessions based on FES therapy combined with physical exercises.
    RESULTS: The results showed that the activity of the mETC, G3PDH, and MAO was significantly reduced in pre-intervention stroke patients compared to healthy volunteers, both in PBMCs and platelets, except for complex II in platelets and MAO in PBMCs. Interestingly, FES intervention increased the mETC, G3PDH, and MAO activity in both cell types of stroke patients.
    CONCLUSIONS: This preliminary study indicates that intervention can restore motor function and mitochondrial activity, which are damaged in stroke patients. However, more research is needed to determine if changes in mitochondrial activity can be used as biomarkers of the pathology and/or the efficacy of intervention.
    Keywords:  functional electrical stimulation; mitochondrial electron transport chain; oxidative stress; rehabilitation; stroke
    DOI:  https://doi.org/10.1111/aor.70031
  50. J Respir Biol Transl Med. 2025 ;2(3):
    Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.
    Le Xu, Chunting Tan, Nicole Talaba, Andrew Sou, Yufeng Shen, Wendy K Chung, David J McCulley, Xin Sun.
      Congenital Diaphragmatic Hernia (CDH) is a rare neonatal disorder causing diaphragmatic defects and cardiopulmonary hypoplasia, traditionally attributed to mechanical compression from organ herniation. However, emerging evidence suggests genetic mutations may independently impair lung development, prompting debate over CDH etiology. Here, we investigated the requirement of mitochondrial function guarded by LON peptidase 1 (Lonp1), a CDH risk gene, in either diaphragm or lung development. Lonp1 loss in skeletal muscles of the diaphragm led to its thinning and membranization, recapitulating the pathology of sac-type CDH. On the other hand, lung-specific inactivation caused severe hypoplasia with defective branching morphogenesis, independent of diaphragm anomalies. Molecularly, Lonp1 disruption dysregulated key transcription factors and signaling pathways known to be critical for early lung development. Our findings here revealed that mitochondrial defects contribute to the pathogenesis of CDH in an organ and cell type specific manner, opening new avenues for drug and therapeutic development.
    Keywords:  CDH; Diaphragm; FGF10; LONP1; Lung; Mitochondria; SHH
    DOI:  https://doi.org/10.70322/jrbtm.2025.10008
  51. Front Biosci (Landmark Ed). 2025 Sep 26. 30(9): 45020
    PTDSS1 Drives Glycolysis and Malignant Progression of Lung Cancer Through Maintaining Nuclear-Mitochondrial Homeostatic Crosstalk.
    Hailun Wang, Qiao Wang, Yandu He, Xuelu Pu, Yajun Li.
       BACKGROUND: Phosphatidylserine synthase 1 (PTDSS1) is a crucial enzyme involved in phospholipid synthesis. However, its role in the metabolic regulation of lung cancer remains unclear. This study hypothesized that PTDSS1 promotes lung cancer progression by regulating metabolic reprogramming through nuclear-mitochondrial crosstalk.
    METHODS: PTDSS1's expression levels in lung cancer tissues and their correlation with patient prognosis were evaluated through bioinformatics analysis and immunohistochemistry. In vitro functional experiments, including cell proliferation, migration, invasion, and colony formation, were performed using PTDSS1-overexpressing lung cancer cell lines. Cellular glycolysis and mitochondrial oxidative phosphorylation levels were determined. PTDSS1's subcellular localization was investigated through cellular fractionation and immunofluorescence. Its regulatory interaction with pyruvate kinase M2 (PKM2) was examined. Expression levels of metabolism-related genes and mitochondrial dynamics markers were analyzed by qRT-PCR and Western blot.
    RESULTS: PTDSS1 was significantly overexpressed in lung cancer tissues. High PTDSS1 expression correlated with poor patient prognosis. PTDSS1 enhanced lung cancer cell proliferation, migration, and invasion capabilities. Metabolically, PTDSS1 promoted aerobic glycolysis. Mitochondrial oxidative phosphorylation was suppressed. Nuclear-localized PTDSS1 showed enhanced effectiveness in driving glycolysis and malignant progression. Mechanistically, PTDSS1 may accelerate glycolysis through PKM2 regulation. It may drive lung cancer progression through PKM2-mediated nuclear-mitochondrial homeostatic crosstalk.
    CONCLUSION: PTDSS1 functions as a multifunctional oncogene. It drives lung cancer progression through PKM2-mediated nuclear-mitochondrial homeostatic crosstalk. PTDSS1 represents a potential prognostic biomarker and therapeutic target.
    Keywords:  PKM2; PTDSS1; glycolysis; lung cancer; nuclear-mitochondrial crosstalk
    DOI:  https://doi.org/10.31083/FBL45020
  52. BMC Oral Health. 2025 Oct 06. 25(1): 1542
    Salivary mitofusin levels in periodontal disease: a cross-sectional case-control study.
    Ömer F Okumuş, Nezahat Kurt, Alpdoğan Kantarcı.
       BACKGROUND: Mitofusin (Mfn) is a mitochondrial fusion protein. It has two isoforms (Mfn1 and 2) and is critical in intracellular energy production, calcium transfer, and phospholipid metabolism. Based on previous evidence linking mitochondrial function with the pathophysiology of periodontal inflammation, we hypothesized that salivary Mfn1 and Mfn2 levels may differ across periodontal health, gingivitis, and periodontitis, and that these levels correlate with markers of inflammatory and oxidative stress. Although previous studies have suggested that Mfn2 plays a role in inflammatory and oxidative pathways, clinical evidence regarding its role in periodontal disease is lacking. The null hypothesis of this study was that salivary Mfn levels are not significantly altered with periodontal conditions and are not correlated with inflammation or oxidative stress markers in saliva.
    METHODS: A total of 81 participants were included in this cross-sectional case-control study, with 27 individuals per group. Periodontally healthy patients, patients with gingivitis, and patients with stage 3 or stage 4 grade C periodontitis were recruited for the study. Mfn-1 and Mfn-2 levels were measured. To identify their correlation with inflammatory mechanisms, interleukin-1β levels, total oxidative status (TOS), and total antioxidant status (TAS) were determined using enzyme-linked immunosorbent assay and colorimetric measurements. The oxidative stress index (OSİ) was calculated.
    RESULTS: Salivary Mfn1 levels were significantly higher in patients with periodontitis compared to healthy controls (36.54 ± 13.15 ng/mL, 24.67 ± 8.69 ng/mL, p < 0.001). No significant difference was observed between the groups in terms of Mfn2 levels (p > 0.05). While significant differences were found between Group P and Group H in TAS and OSI values (p < 0.05), TOS values ​​did not show any significant difference between the groups (p > 0.05). A positive correlation was found between Mfn1 and Mfn2 and IL-1β levels (p < 0.05). Mfn1 and Mfn2 did not have any significant correlation with TAS, TOS, or OSI values (p > 0.05).
    CONCLUSIONS: Elevated Mfn1 levels in the saliva of patients with periodontitis suggested that mitochondrial function was disrupted in severe periodontitis. Mitofusin levels showed no significant correlation with oxidative stress markers in this study.
    TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov under the number NCT06510608 on July 18, 2024.
    Keywords:  IL-1β; MFN1; MFN2; Mitochondria; Oxidative stress; Periodontitis
    DOI:  https://doi.org/10.1186/s12903-025-06932-0
  53. J Exp Pharmacol. 2025 ;17 687-705
    Neuroprotective Effects of Asiatic Acid on Autophagy and Mitochondrial Integrity in a Parkinson's Disease Cellular Model.
    Athinan Prommahom, Tatcha Balit, Sunisa Somkana, Satjapot Manprasong, Chonlakorn Panyasuppakun, Atipha Kijkraikul, Preawanit Thawornrungroaj, Pitchaya Thawornrungroaj, Permphan Dharmasaroja, Thanasup Gonmanee, Phisit Khemawoot, Kawinthra Khwanraj.
       Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. PD patients mostly exhibit mitochondrial dysfunction and autophagic impairment. Asiatic acid (AA) is a triterpenoid with the highest antioxidant activity used to treat oxidative stress. It has been found to have a neuroprotective effect against mitochondrial dysfunction in cellular models of PD; however, its effect on autophagy has not been investigated.
    Purpose: This study aimed to investigate whether AA affects autophagy in a cellular model of PD.
    Methods: SH-SY5Y cells were differentiated into dopaminergic neuron-like cells via retinoic acid administration. Differentiated cells were treated with AA for 24 h and then exposed to 1-methyl-4-phenylpyridinium (MPP+). Cell viability was assessed using a 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The expression of microtubule-associated protein 1 light chain 3 (LC3)-II/I, Beclin-1, sequestosome-1/ubiquitin-binding protein p62 (SQSTM1/p62), and tyrosine hydroxylase (TH) was analyzed via Western blot. Caspase-3/7 and LC3 expression was measured using immunofluorescence, as was the colocalization of LC3 and mitochondria. MitoTracker and JC-10 were used to assess the mitochondrial morphology and mitochondrial membrane potential (ΔΨm), respectively.
    Results: Pretreating cells with AA before MPP+ exposure resulted in significantly higher expression of LC3-II/I and Beclin-1, while the expression of SQSTM1/p62 was slightly lower compared to that in cells not pretreated with AA. Cells pretreated with AA exhibited significantly higher viability and TH expression, but significantly lower caspase-3/7 expression and numbers of apoptotic nuclei compared to cells treated with MPP+ alone. Notably, pretreatment with AA resulted in tubular mitochondria with considerably higher ΔΨm values. The colocalization of LC3 and mitochondria was also significantly higher in the cells pretreated with AA.
    Conclusion: AA protected dopaminergic neuron-like cells against MPP+-induced apoptosis via the induction of autophagy and the enhancement of mitochondrial function, suggesting that it could be developed as a therapeutic agent for PD.
    Keywords:  asiatic acid; autophagy; dopaminergic neuron-like cells; mitochondria; mitophagy
    DOI:  https://doi.org/10.2147/JEP.S536728
  54. Phytomedicine. 2025 Oct 02. pii: S0944-7113(25)00987-0. [Epub ahead of print]148 157349
    Spermidine enhances macrophages anti-inflammatory and regenerative functions by improving mitochondrial fitness.
    Rui Liu, Lijuan Cao, Yipeng Zhou, Yanan Li, Tingting Wang, Zhenzhen Meng, Tingting Yang, Chao Feng, Qian Yang, Xiaojie Liu, Yongjing Chen, Massimiliano Agostini, Peishan Li, Gerry Melino, Ying Wang, Changshun Shao, Yufang Shi.
       BACKGROUND: Liver fibrosis is an aberrant wound-healing process in response to chronic hepatic injury. Functional plasticity of macrophages is crucial in this pathological process. How the pro-fibrotic function of macrophages is sustained metabolically and whether it can be targeted for therapy remain to be explored.
    PURPOSE: This study investigates the impact of spermidine, a natural polyamine, on macrophage function and its potential in treating hepatic fibrosis.
    METHODS: Chronic liver disease datasets and single-cell RNA sequencing (scRNA-seq) data were analyzed for the characteristics of spermidine metabolism in hepatic macrophage function and liver fibrosis. Mice undergoing liver fibrosis caused by carbon tetrachloride (CCl4) were treated with spermidine through daily drinking water. Macrophage-specific PGC1α knockout mice were used to determine the requirement of mitochondrial fitness in the anti-fibrotic function of macrophages. Furthermore, spermidine-treated macrophages were adoptively transferred to mice with liver fibrosis to test their therapeutic potential.
    RESULTS: Analysis of chronic liver disease datasets revealed a dysregulated polyamine metabolism in diseased liver tissues, particularly in distinct subsets of macrophages. Spermidine supplementation protected mice from CCl4-induced liver fibrosis through endowing macrophages a persistent anti-inflammatory and pro-resolving function that is characterized by elevated matrix metalloproteinase expression and enhanced mitochondrial function. Spermidine-treated macrophages (SPDMs) exhibited increased mitochondrial mass, augmented oxidative phosphorylation, and altered fatty acid metabolism. The markers characteristic of tolerogenic and liver-regenerative macrophages were upregulated in SPDMs in a manner dependent on peroxisome proliferator-activated receptor-γ coactivator (PGC) -1α, a key regulator of mitochondrial homeostasis. Interestingly, oleate generated by stearoyl-CoA desaturase 1 (SCD1) was essential for SPDMs to acquire the increased mitochondrial fitness. Notably, adoptive transfer of SPDMs to fibrotic mice significantly attenuated disease progression. The anti-fibrotic effect was compromised in mice with myeloid cell-specific deletion of PGC1α, highlighting the importance of mitochondrial biogenesis in mediating macrophage phenotype plasticity.
    CONCLUSIONS: Our study implicates dysregulation of spermidine metabolism in hepatic macrophages in the development of chronic liver diseases. We demonstrated an anti-fibrotic function of spermidine that is attributed to its action on macrophages. PGC1α-mediated mitochondrial fitness is required for spermidine to confer macrophages an enhanced anti-inflammatory and anti-fibrotic capacity. Meanwhile, we provide novel insights into the role of fatty acid metabolism in modifying the biological function of macrophages. This study opens new avenues for treating fibrotic diseases by targeting macrophage plasticity through spermidine-mediated metabolic reprogramming and demonstrate the potential of spermidine-trained macrophages as approaches for inflammatory and fibrotic conditions.
    Keywords:  Liver fibrosis; Macrophages; Metabolism; Peroxisome proliferator-activated receptor-γ coactivator -1α; Spermidine; Stearoyl-coa desaturase 1
    DOI:  https://doi.org/10.1016/j.phymed.2025.157349
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