bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–07–20
sixty-two papers selected by
Gavin McStay, Liverpool John Moores University
  1. The Role of Mitochondrial Dynamics in Doxorubicin-Induced Disease: Implications for Therapy.
  2. Mechanism of ruxolitinib enhancing mitophagy against renal fibrosis via PINK1/Parkin pathway.
  3. Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.
  4. m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.
  5. Piperine Enhances Mitochondrial Biogenesis to Mitigate Stress in SH-SY5Y Neuroblastoma Cells.
  6. Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging.
  7. Promoting ubiquitin-dependent Drp1 degradation contributes to the protective effect of Astragalin against diabetic renal fibrosis.
  8. Restricting intracellular Salmonella proliferation by coordinating p-TBK1 mediated mitophagy and xenophagy.
  9. Nutrient-Responsive Formation of Mitochondrial-Derived Structures in Caenorhabditis elegans.
  10. Luteolin Regulates Mitophagy to Alleviate Myocardial Ischemia-Reperfusion Injury via Sirt3/Foxo3a Pathway.
  11. Astaxanthin Prevented Acute Alcoholic Cardiomyopathy by Maintenance of Mitophagy-Mediated Mitochondrial Homeostasis.
  12. The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications.
  13. Amyloid-β protein precursor modulates mitophagy and mitochondrial function through its cellular localization.
  14. Laminar Shear Stress Increases the Cytosolic Pool of PINK1 in Endothelial Cells and Enhances Mitophagic Sensitivity Toward Dysfunctional Mitochondria.
  15. Baicalin and its nanoliposome ameliorate diquat-induced liver injury by promoting PINK1/Parkin-dependent mitophagy.
  16. The PGC-1α/SIRT3 pathway mediates the effect of DON on mitochondrial autophagy and liver injury in mice.
  17. Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging.
  18. Cadmium-induced apoptosis of granulosa cells is mediated by excessive activation of mitophagy and ROS-mediated mitochondrial dysfunction.
  19. MitoQ alleviates prion-induced neurodegeneration by modulating DRP1- and OPA1-mediated mitochondrial dynamics.
  20. STAT6 Activation Exacerbates Ferroptosis in Airway Epithelium by Inhibiting PRKN-Mediated Mitophagy in Pulmonary Fibrosis.
  21. Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
  22. Blueberry anthocyanins ameliorate arsenic-induced cognitive impairment in rats: mitigating mitochondrial damage and dysregulation.
  23. Palmatine Ameliorates High-Temperature and High-Humidity-Induced Enteritis Via Mitophagy and NLRP3 Inflammasome Degradation.
  24. Gipc3 Mutation Might Cause Sensorineural Hearing Loss by Inhibiting Mitophagy in Inner Ear Hair Cells.
  25. Beyond the Pseudogene: p17/PERMIT as a Mitochondrial Trafficking Protein Linking Aging and Neurodegeneration.
  26. Mitochondrial dysfunction in fibrotic diseases: Research progress and MSC-exos therapy.
  27. Mitochondrial Quality Control in Bovine Oocyte Maturation: Mechanisms, Challenges, and Prospects for Enhancing Reproductive Efficiency.
  28. Identification of mitophagy-related biomarkers in human rheumatoid arthritis using machine learning models.
  29. Nickel exposure induced endoplasmic reticulum stress by disturbing calcium homeostasis and triggered mitochondrial autophagy in domestic animal oocytes.
  30. Jianpi Qushi Heluo Formula ameliorates podocytes injury related with ROS-mediated NLRP3 inflammasome activation in membranous nephropathy by promoting PINK1-dependent mitophagy.
  31. Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
  32. Mitochondria from huntington´s disease striatal astrocytes are hypermetabolic and compromise neuronal branching.
  33. Sulfide Quinone Oxidoreductase Alleviates Acute Ulcerative Colitis by Regulating Mitochondrial Dysfunction.
  34. Mechanism and regulation of mitophagy in liver diseases: a review.
  35. CRISPRa-Mediated Increase of OPA1 Expression in Dominant Optic Atrophy.
  36. Hearing the call of mitochondria: Insight into its role in sensorineural hearing loss.
  37. ANGPTL4 promoted the cognitive impairment in vascular dementia via increasing integrin/p-Syk signalings induced mitochondrial autophagy and apoptosis in the hippocampus.
  38. POLR1A inhibits ferroptosis by regulating TFAM-mediated mitophagy and iron homeostasis.
  39. Regulation of NR4A1 by Taohong Siwu Decoction Inhibits Endothelial Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury.
  40. Resveratrol restores insulin signaling and balances mitochondrial biogenesis and autophagy in streptozotocin-induced neurodegeneration in vitro.
  41. A biomimetic multimodal nanoplatform combining neutrophil-coated two-dimensional metalloporphyrinic framework nanosheet and exendin-4 to treat obesity-related osteoporosis.
  42. Modulation of peripheral energy metabolism through central leucine administration in rainbow trout (Oncorhynchus mykiss).
  43. Gut microbiota derived butyrate enhances ferroptosis sensitivity in endometriosis through FFAR2/PPAR-γ/PINK1/Parkin mediated mitophagy.
  44. The crucial function of IDO1 in pulmonary fibrosis: From the perspective of mitochondrial fusion in lung fibroblasts and targeted molecular inhibition.
  45. Casein Kinase 2α Ablation Confers Protection Against Metabolic Dysfunction-Associated Steatotic Liver Disease: Role of FUN14 Domain Containing 1-Dependent Regulation of Mitophagy and Ferroptosis.
  46. Identification of Critical Gut Metabolites Mediating the Protective Effects of Lacticaseibacillus paracasei on Myocardial Injury in Mice.
  47. Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
  48. Wnt5a-AS knockdown alleviates sevoflurane-induced depression by promoting hippocampal neurogenesis and mitochondrial fusion in adolescent rats.
  49. Organelle regulation of SUMOylation: regulatory mechanisms and therapeutic application.
  50. AMPK impairment caused by gelatin disturbs mitochondrial dynamics leading to enhanced phagocytosis of bacteria in PMA-stimulated U937 cells.
  51. Mitochondrial Fragmentation and Long Noncoding RNA MALAT1 in Diabetic Retinopathy.
  52. DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
  53. Drp1-Dependent Mitochondrial Fission is Involved in Adriamycin Resistance in Gastric Cancer Cells: A Perspective from the BATF2/p53/ERK Regulatory Axis.
  54. m5C-modified circRREB1 promotes lung cancer progression by inducing mitophagy.
  55. The mitochondrial unfolded protein response and metabolic reprogramming promote PASMC proliferation in response to sphingosine kinase-1/sphingosine-1-phosphate signaling.
  56. Cross-regulation between adipose tissue innervation and metaflammation: a potential therapeutic target for obesity.
  57. Polystyrene nanoplastics promote muscle cell senescence through microtubule hyper-stabilization-mediated mitophagy dysfunction and cGAS-Sting activation.
  58. Mitochondrial homeostasis: Exploring their impact on skin disease pathogenesis.
  59. PHB2 protects against pressure overload-induced myocardial remodeling in mice via stabilizing TOMM40 and regulating mitochondrial morphofunctional homeostasis.
  60. Tang Bi formula alleviates diabetic sciatic neuropathy via AMPK/PGC-1α/MFN2 pathway activation.
  61. (ID-ICPMB05) Running on Empty: Mitochondria Without DNA Exhibit Differential Motility and Connectivity.
  62. The therapeutic effects of genistein in rats with epilepsy by influencing mitochondrial biogenesis and regulating apoptosis in brain tissue.
  1. J Cell Physiol. 2025 Jul;240(7): e70064
    The Role of Mitochondrial Dynamics in Doxorubicin-Induced Disease: Implications for Therapy.
    Huan Yue, Yousheng Chen, Junxiao Feng, Weiying Yue, Xingjuan Shi.
      As an anthracycline chemotherapy drug, doxorubicin (Dox) is generally prescribed to treat a variety of malignant tumors. Nevertheless, Dox exhibited toxicity at a high dosage, which might eventually lead to injury of the body. Mitochondrial dynamics, including mitochondrial fission and fusion, regulates mitochondrial homeostasis and cellular function. Mounting evidence has demonstrated that imbalance in mitochondrial dynamics, manifested by increased mitochondrial fission or decreased mitochondrial fusion, is associated with the development of Dox-induced diseases. In this paper, we will elaborate the role of mitochondrial dynamics in Dox-induced diseases, and discuss the regulatory mechanism of mitochondrial dynamics in Dox-induced diseases, including apoptosis, fibrosis, myocardial atrophy and inflammation. Elucidating these issues may provide important value in the diagnosis and potential therapeutic strategies for Dox-induced diseases through regulation of mitochondria dynamics.
    Keywords:  Dox‐induced diseases; apoptosis; fibrosis; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1002/jcp.70064
  2. Biochim Biophys Acta Mol Basis Dis. 2025 Jul 09. pii: S0925-4439(25)00326-6. [Epub ahead of print]1871(7): 167978
    Mechanism of ruxolitinib enhancing mitophagy against renal fibrosis via PINK1/Parkin pathway.
    He Li, Peipei Meng, Yuhang Meng, Yige Yang, Wensheng Zheng, Hongdong Huang, Zhigang Zhao.
      Renal fibrosis represents a critical pathological hallmark in progressive chronic kidney disease (CKD), yet effective therapeutic strategies remain elusive. Emerging evidence suggests that impaired mitophagy contributes to its pathogenesis. This study investigated whether ruxolitinib alleviates renal fibrosis by enhancing PINK1/Parkin-mediated mitophagy. Network pharmacology was employed to explore the potential regulatory mechanisms of ruxolitinib in renal fibrosis treatment, revealing that ruxolitinib might exert therapeutic effects through modulation of inflammation, oxidative stress and mitophagy. Subsequent in vivo and in vitro studies demonstrated that ruxolitinib treatment not only attenuated renal fibrosis progression but also reduced inflammatory responses and oxidative stress while enhancing mitophagic activity. Mechanistically, the enhancement of mitochondrial autophagy and the amelioration of renal fibrosis by ruxolitinib might be mediated via the PINK1/Parkin pathway. These results suggest that ruxolitinib may ameliorate renal fibrosis by activating PINK1/Parkin-mediated mitophagy, providing new perspectives for CKD therapeutic development.
    Keywords:  Inflammation; Mitophagy; PINK1/Parkin pathway; Renal fibrosis; Ruxolitinib
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167978
  3. bioRxiv. 2025 Jul 11. pii: 2025.07.10.663832. [Epub ahead of print]
    Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.
    Hoda Ahmed, Mack B Reynolds, Gary Kasof, Gerald S Shadel, Reuben Shaw.
      Mitophagy is a selective autophagic process that eliminates damaged mitochondria via lysosomal degradation, playing a crucial role in maintaining cellular metabolic balance. Mitophagy can occur through two pathways: ubiquitin-dependent and ubiquitin-independent. Recently, we and others have shown that, upon mitochondrial stress, AMP-activated protein kinase (AMPK) contributes to Parkin-mediated, ubiquitin-dependent mitophagy. The ubiquitin-independent pathway involves multiple outer mitochondrial membrane (OMM) "mitophagy receptors" that contain LC3-interacting region (LIR) motifs, including BNIP3, NIX/ BNIP3L, FUNDC1, and BCL2L13. LIR motifs bind Atg8/LC3 family proteins, facilitating the recruitment of the autophagosome membrane to target damaged mitochondria for degradation. The kinase Unc-51 Like autophagy activating kinase 1 (ULK1) phosphorylates the serine preceding the LIR motif in BNIP3, NIX, and FUNDC1, enhancing their binding to LC3 and promoting mitophagy. However, while BCL2L13 has been identified as a ULK1 binding partner, its regulation by phosphorylation remains unclear. We utilized mass spectrometry (MS) to map phosphorylation sites in BCL2L13 following mitochondrial stress and developed phospho-specific antibodies against two sites, Ser261 and Ser275, which were induced after exposure to the mitochondrial uncoupler, CCCP. Endogenous BCL2L13 Ser261 and Ser275 were both phosphorylated in an AMPK-dependent manner in cells and tissues. As neither site matches the established AMPK substrate consensus motif, we sought to identify which kinases directly mediate their phosphorylation downstream of AMPK. Surprisingly, genetic studies revealed that ULK1 is not regulating either site, but instead, TBK1 is controlling Ser275. This work reveals that BCL2L13 is unique amongst mitophagy receptors in being activated by mitochondrial stress and innate immune stimuli in an AMPK- and TBK1-dependent manner.
    DOI:  https://doi.org/10.1101/2025.07.10.663832
  4. Am J Med Genet B Neuropsychiatr Genet. 2025 Jul 17. e33048
    m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.
    Di An, Yuhao Wu, Jingzhe Han, Pingping Fang, Yi Bu, Guang Ji, Jinliang Deng, Xueqin Song.
      We investigate the role of m6A RNA methylation in regulating transcription factor EB (TFEB) and its contribution to mitochondrial autophagy (mitophagy) dysfunction in amyotrophic lateral sclerosis (ALS). ALS cell models were used to analyse mitophagy markers and TFEB expression under METTL3 and TFEB modulation, using RT-qPCR, Western blot, MeRIP, RIP, and immunofluorescence. Elevated m6A methylation and reduced TFEB expression were observed in hSOD1-G93A models. METTL3 overexpression suppressed TFEB expression, leading to impaired mitophagy, while METTL3 knockdown alleviated these effects. MeRIP assays confirmed increased m6A modifications on TFEB mRNA, and RIP assays demonstrated direct interaction between METTL3 and TFEB mRNA. Notably, TFEB overexpression rescued mitophagy dysfunction, whereas TFEB knockdown exacerbated the impairment. METTL3-mediated m6A methylation inhibits mitophagy by downregulating TFEB expression, revealing the m6A-TFEB pathway as a promising therapeutic target for ALS.
    Keywords:  METTL3; amyotrophic lateral sclerosis; m6A methylation; mitochondrial autophagy; transcription factor EB (TFEB)
    DOI:  https://doi.org/10.1002/ajmg.b.33048
  5. Food Sci Nutr. 2025 Jul;13(7): e70637
    Piperine Enhances Mitochondrial Biogenesis to Mitigate Stress in SH-SY5Y Neuroblastoma Cells.
    Nongluk Saikachain, Pawitchaya Charoensawat, Oramon Tuntoolavest, Napak Vejsureeyakul, Teeranart Kunpittaya, Wanangkan Poolsri, Titiwat Sungkaworn, Rungnapha Saeeng, Chatchai Muanprasat, Nithi Asavapanumas.
      Mitochondrial dysfunction plays a crucial role in neurodegenerative disorders. Enhancing mitochondrial biogenesis is a promising therapeutic strategy for mitigating mitochondrial damage. Piperine, a bioactive alkaloid from black pepper, the fruit of Piper nigrum L. in the family Piperaceae, has demonstrated neuroprotective effects against mitochondrial stress. However, its effects on mitochondrial health remain unclear. This study investigated the effects of piperine on mitochondrial dynamics in SH-SY5Y neuronal cells. Our findings suggest that piperine enhances mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) mRNA and translocase of outer mitochondrial membrane 20 (TOM20) protein expression. Additionally, piperine improves Ca2+ transport within mitochondria and boosts mitochondrial metabolic activity without significantly altering mitochondrial morphology. Furthermore, piperine prevents 6-hydroxydopamine (6-OHDA)-induced cellular stress by alleviating the activation of Homo sapiens heat shock protein family A member 5 (HSPA5) and DNA damage inducible transcript 3 (DDIT3) mRNA expression and inhibiting the apoptotic Bcl-2-associated X protein (BAX) to B-cell lymphoma 2 (Bcl-2) pathway. Notably, this neuroprotective effect occurs independently of its antioxidative activity. Taken together, our results reveal a previously unexplored aspect of piperine's neuroprotective mechanism, highlighting its ability to enhance mitochondrial biogenesis and prevent mitochondrial stress in neuronal cells. Further studies, including in vivo investigations and long-term assessments, are warranted to explore the therapeutic potential for mitochondrial dysfunction in the central nervous system.
    Keywords:  mitochondria; mitochondrial dynamic; neurodegeneration; neuron; piperine
    DOI:  https://doi.org/10.1002/fsn3.70637
  6. Stem Cell Res Ther. 2025 Jul 15. 16(1): 365
    Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging.
    Yihao Wang, Wanxing Liao, Yiping Wang, Junlin Liao, Nian Chen, Chiyu Jia, Li Zeng.
       BACKGROUD: Mitochondrial DNA (mtDNA) deletion and oxidative stress are key contributors to skin photoaging. Mitophagy helps mitigate oxidative stress. Human adipose-derived stem cell exosomes (hADSC-Exos) have been shown to counteract skin photoaging. This study aimed to explore the role and mechanism of hADSC-Exos in addressing skin photoaging.
    METHODS: hADSC-Exos were isolated, and their surface markers were identified. Human dermal fibroblasts (HDFs) and nude mice were exposed to ultraviolet-B (UVB) irradiation, and treated with hADSC-Exos. Oxidative stress and photoaging were assessed through SA-β-gal staining, p21 expression, mtDNA deletion, reactive oxygen species (ROS) levels, and histological analysis. The PINK1, Parkin, LC3b, and p62 protein levels were measured to evaluate mitophagy. The PINK1 small-interfering RNA (siPINK1) was then used in HDFs to investigate the role of hADSC-Exos in mitophagy.
    RESULTS: In UVB-exposed HDFs and nude mice, the number of SA-β-gal-positive cells, along with levels of p21, ROS, and mtDNA deletion, were significantly increased, but these effects were reduced by hADSC-Exos. Moreover, hADSC-Exos treatment significantly elevated PINK1 and Parkin levels, as well as the LC3bII/I ratio, while reducing p62 expression. In photoaged HDFs treated with hADSC-Exos, PINK1 knockout using siRNA decreased the LC3bII/I ratio and levels of PINK1 and Parkin, while increasing p62, ROS, and mtDNA deletion compared to the negative control (NC) group.
    CONCLUSION: hADSC-Exos can mitigate skin photoaging by promoting PINK1/Parkin-mediated mitophagy, thereby reducing mtDNA deletion and oxidative stress.
    Keywords:  Exosomes; Human adipose-derived stem cell; Mitophagy; Oxidative stress; Photoaging; mtdna common deletion
    DOI:  https://doi.org/10.1186/s13287-025-04475-3
  7. Biochem Pharmacol. 2025 Jul 12. pii: S0006-2952(25)00423-X. [Epub ahead of print] 117158
    Promoting ubiquitin-dependent Drp1 degradation contributes to the protective effect of Astragalin against diabetic renal fibrosis.
    Ruotong Yin, Yalin Wang, Peng Zhang, Mengyao Sun, Zijie Jin, Shihao Ma, Qingyu Huang, Hongbo Weng.
      Diabetic kidney disease (DKD) is a severe complication of diabetes. Fibrosis is an irreversible pathological change closely associated with the development of disease. Disrupted mitochondrial dynamics involved in the progression of fibrosis. Astragalin (AG) exhibits therapeutic potential for DKD. However, the effects of AG on renal fibrosis, as well as precise target and underlying mechanisms, remain largely unexplored. Here, we report the alleviation of diabetes-induced renal fibrosis by AG and the mechanism of regulating dynamin-related protein1 (Drp1)-mediated mitochondrial dynamics. A diabetic mouse model was induced by streptozotocin and treated with AG for 8 weeks. In vitro, HK2 cells were treated with high glucose and lipids. Mitochondrial morphology and function were assessed to explore the mechanisms. The results demonstrated that AG significantly alleviated renal fibrosis, mitochondrial damage and inhibited renal tubular cell apoptosis in diabetic mice. In vitro, AG reduced Drp1 protein levels, inhibited excessive mitochondrial fission and restored mitochondrial function. Mechanistically, knockdown of Drp1 with siRNA and Drp1 overexpression further verified the effects of AG. Additionally, Cellular thermal shift assay (CETSA) and immunoprecipitation (IP) results confirmed the interaction between AG and Drp1. These findings suggested that Drp1 may serve as a key target for AG to exhibit the benefits. Furthermore, the proteasome inhibitor MG132 abolished the effects of AG, indicating that AG reduced Drp1 expression by enhancing its degradation via the ubiquitin-proteasome pathway. In conclusion, our data suggest that AG may be a potential therapeutic agent for diabetic renal fibrosis by inhibiting mitochondrial excessive fission through promoting ubiquitin-dependent Drp1 degradation.
    Keywords:  Astragalin; Diabetic kidney disease; Drp1; Kidney fibrosis; Mitochondrial dynamic
    DOI:  https://doi.org/10.1016/j.bcp.2025.117158
  8. Autophagy. 2025 Jul 14.
    Restricting intracellular Salmonella proliferation by coordinating p-TBK1 mediated mitophagy and xenophagy.
    Jun Li, Yang Yang, Yao Ge, Xinyu Zhang, Haozhen Liu, Yinfeng Chen, Ying Yang, Zhenlong Wu.
      Mitophagy is essential for eliminating dysfunctional mitochondria and is closely implicated in the immune evasion of several pathogens, including S. typhimurium. However, the specific mechanisms regarding the interaction between S. typhimurium and host cells in relation to mitophagy and xenophagy and their contribution to pathogen survival are unclear. Herein, using both in vitro and in vivo systems, we found that S. typhimurium escaped host innate immunity by repressing mitophagy and xenophagy to facilitate its intracellular replication. Moreover, we identified a novel xenophagy modulator, fisetin that could activate mitophagy to restrict intracellular S. typhimurium replication in RAW264.7 and bone marrow-derived macrophages, which was abolished by mitophagy inhibitor Mdivi-1. RNA-Seq transcriptome and metabolomics analysis demonstrated the effectiveness of fisetin in alleviating S. typhimurium infection. Confocal microscopy analysis revealed that fisetin-induced mitophagy promoted xenophagy, whereas inhibiting mitophagy repressed xenophagy and facilitated the survival of S. typhimurium. Our study further demonstrates that fisetin-induced mitophagy requires the recruitment of phosphorylation of TBK1 to mitochondria, which is a protein implicated in mitophagy and xenophagy. Additionally, fisetin improved the body weight loss, relative spleen, kidney, and liver weights, hepatic damage, and S. typhimurium load, all of which were abrogated by Mdivi-1 or Pink1 siRNA treatment in S. typhimurium-infected mice. Collectively, our results suggest that S. typhimurium induces mitochondrial damage whilst inhibiting mitophagy, while fisetin promotes xenophagy and restrains S. typhimurium survival by facilitating Pink1-Parkin mediated mitophagy and p-TBK1 mitochondrial recruitment. Fisetin proves effective as a xenophagy enhancer in reducing intracellular Salmonella burden.
    Keywords:  Immune escape; Mitophagy; Salmonella; TBK1; Xenophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2534298
  9. bioRxiv. 2025 Jun 26. pii: 2025.06.24.661357. [Epub ahead of print]
    Nutrient-Responsive Formation of Mitochondrial-Derived Structures in Caenorhabditis elegans.
    Miriam Valera-Alberni, Anne Lanjuin, Silvia Romero-Sanz, Kristopher Burkewitz, Adam L Hughes, William B Mair.
      Mitochondrial morphology is dynamically regulated through remodeling processes essential for maintaining mitochondrial function and ensuring cellular and metabolic homeostasis. While classical models of mitochondrial dynamics center on cycles of fragmentation and elongation, emerging evidence highlights additional membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and mitochondrial-derived compartments (MDCs). These mitochondrial-derived structures, however, have been predominantly characterized in cultured cells and unicellular organisms, leaving their relevance in multicellular systems largely unexplored. Here, we identify a previously uncharacterized class of mitochondrial-derived structures in Caenorhabditis elegans muscle cells that are induced in response to intermittent fasting. We show that these structures appear specifically during the refeeding phase- coinciding with mitochondrial elongation -and are absent during fasting. Consistent with MDCs, the structures, approximately 1 µm in size, are enriched in outer mitochondrial membrane markers such as TOMM-20 aa1-49 and TOMM-70, but notably lack components of the inner mitochondrial membrane. Their formation requires the microtubule-associated MIRO-1/2 proteins, and their size is modulated by the mitochondrial dynamics machinery. Together, our findings reveal a nutritionally regulated mitochondrial remodeling event in C. elegans muscle that may play a role in mitochondrial quality control and adaptation to metabolic cues.
    DOI:  https://doi.org/10.1101/2025.06.24.661357
  10. Adv Biol (Weinh). 2025 Jul 18. e00778
    Luteolin Regulates Mitophagy to Alleviate Myocardial Ischemia-Reperfusion Injury via Sirt3/Foxo3a Pathway.
    Li Yan, Lei Liang, Qiling Gou, Haoyu Wu, Mengya Dong, Hao Chen, Jiayu Diao.
      Luteolin (LUT) belongs to a kind of flavonoid, which has protective effects on myocardial ischemia/reperfusion (I/R) injury. Sirt3 is located in mitochondria and interacts with Foxo3a to protect mitochondrial function against stress. Mitophagy is an important form of mitochondrial quality control. However, whether LUT regulates mitophagy to alleviate myocardial I/R injury via the Sirt3/Foxo3a pathway is rarely reported. In this study, 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP) is used to inhibit the Sirt3/Foxo3a pathway. Male adult rats are divided into four groups: Sham group, I/R group, I/R+LUT group, and I/R+LUT+3-TYP group. The I/R rats model is established by ligating the left anterior descending coronary artery for 30 min, then releasing the ligature for 24 h. Indexes of left ventricular function, myocardial damage, oxidative stress, and mitophagy are detected. It is found that LUT treatment activated Sirt3/Foxo3a pathway, improves left ventricular function, decreases myocardial infarction size, inhibits myocardial apoptosis and oxidative stress, and initiates mitophagy in I/R rats. Moreover, these protective effects of LUT are weakened when Sirt3 is inhibited. Together, LUT regulates mitophagy to alleviate myocardial I/R injury via the Sirt3/Foxo3a pathway.
    Keywords:  Sirt3; inchemia reperfusion injury; luteloin; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1002/adbi.202400778
  11. J Cell Mol Med. 2025 Jul;29(13): e70714
    Astaxanthin Prevented Acute Alcoholic Cardiomyopathy by Maintenance of Mitophagy-Mediated Mitochondrial Homeostasis.
    Guoyong Fan, Tinghao Liu, Xuemei Chen, Yan Guo, Xuan Li, Yue He, Peng Hua, Xiufei Lin, Dini Lin, Xiaoqing Yan, Shicui Jiang, Chi Zhang.
      Acute alcoholism commonly targets the myocardium, triggering acute alcoholic cardiomyopathy (ACM). Strong evidence suggested that mitochondrial dysfunction-induced myocardial oxidative stress is involved in the subcellular pathogenesis of acute ACM. We investigated whether astaxanthin (AST), an antioxidant lutein carotenoid, prevents acute ACM and explored the underlying mechanisms. C57BL/6J mice were used to model ethanol-induced ACM and were treated with AST (100 mg/kg/day) alongside the autophagy inhibitor, 3-methyladenine (10 mg/kg/day). Cardiac function, heart pathology, cardiac hypertrophy, cardiomyocyte apoptosis, oxidative stress and mitochondrial function were evaluated, respectively in response to ethanol and/or AST. The in vivo study showed that ethanol-induced cardiac dysfunction, morphological injury, cardiomyocyte apoptosis and oxidative stress were mitigated by AST. AST's anti-apoptotic effects against ethanol were confirmed in vitro. Ethanol-induced cardiac apoptosis is closely associated with mitochondrial dysfunction which was attenuated by AST characterised by inhibiting fission and promoting fusion, as well as maintaining stable mitochondrial membrane potential, increased ATP production, enhanced biogenesis and restored mitophagy. Autophagy inhibition suppressed AST-induced myocardial protection, indicating that myocardial mitophagy mediates AST effects. The present study demonstrates that AST induces cardiac protection against acute ACM by improving cardiac function, reducing pathological changes, and inhibiting oxidative stress, inflammation and apoptosis through preserved myocardial mitophagy-mediated mitochondrial homeostasis.
    Keywords:  acute alcoholic cardiomyopathy; astaxanthin; mitochondrial homeostasis; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1111/jcmm.70714
  12. Open Life Sci. 2025 ;20(1): 20251086
    The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications.
    Lina Guan, Jing Chen, Hongqun Jiang.
      This study focuses on the critical role of HDAC11 in age-related hearing loss and its underlying mechanisms. Through cellular experiments, we deeply explored the effects of HDAC11 on the proliferation and senescence of HEI-OC1 cells. The results showed that HDAC11 overexpression significantly reduced the acetylation level of α-microtubule protein, which in turn affected the stability of microtubule structure and accelerated the apoptosis and senescence process of HEI-OC1 cells. In addition, the overexpression of HDAC11 inhibited the Pink1/Parkin signaling pathway, which impeded the mitochondrial autophagy process and ultimately led to mitochondrial dysfunction. In animal experiments, we further verified the ameliorative effect of HDAC11 overexpression on hearing loss in aged mice. The experimental results showed that HDAC11 overexpression not only attenuated the histopathological damage of the cochlea in aged mice but also effectively improved their hearing function. Notably, HDAC11 overexpression suppressed the expression of cellular autophagy-related proteins and Pink1 and Parkin proteins. In summary, the present study preliminarily revealed that HDAC11 may regulate mitochondrial autophagy by inhibiting the Pink1/Parkin pathway, thus providing a new theoretical basis for improving hearing loss in the elderly.
    Keywords:  HDAC11; Pink1/Parkin; Pink1/Parkin pathway; age-related hearing loss; apoptosis and senescence; mitophagy
    DOI:  https://doi.org/10.1515/biol-2025-1086
  13. J Alzheimers Dis. 2025 Jul 17. 13872877251360243
    Amyloid-β protein precursor modulates mitophagy and mitochondrial function through its cellular localization.
    Taylor A Strope, Benjamin Troutwine, Brittany M Hauger, Keith P Smith, Russell H Swerdlow, Heather M Wilkins.
      BackgroundAmyloid-β (Aβ) is generated from amyloid-β protein precursor (AβPP) via secretase enzymes. While AβPP processing and its localization are well understood, the function of AβPP is largely unknown. AβPP has been shown to localize to mitochondria, but the consequence of this is not understood.ObjectiveWe examined the consequences of modulating mitochondrial AβPP content on mitochondrial function.MethodsWe measured mitochondrial AβPP localization in postmortem human brain from non-demented and AD subjects. To understand the effects of mitochondrial localization of AβPP on mitochondria, we leveraged AβPP constructs with increased (D23A) or decreased (3 M) mitochondrial localization compared to a wild-type (WT) construct. We measured mitochondrial function including dynamics and mitophagy.ResultsWe observed increased AβPP mitochondrial localization in postmortem brain of sporadic AD subjects. Increased or decreased mitochondrial AβPP content led to reduced electron transport chain (ETC) activities, reduced ATP levels, increased mitochondrial superoxide production, hyperpolarized mitochondrial membrane potential, and increased mitochondrial calcium content. Reduced mitochondrial AβPP content reduced mitophagy flux, while increased mitochondrial AβPP content increased mitophagy flux. Increased or decreased mitochondrial AβPP content reduced mitochondrial biogenesis. We identified interactions between AβPP and mitophagy/autophagy proteins. We next examined if a specific motif in AβPP was responsible for alterations in mitochondrial function and mitophagy. Mitophagy flux was inhibited with expression of ΔCT AβPP, suggesting a role for the C-terminus of AβPP in mitophagy induction.ConclusionsOverall, these findings highlight a critical role of AβPP in mitochondrial physiology. Alterations to AβPP mitochondrial content can lead to mitochondrial dysfunction.
    Keywords:  Alzheimer's disease; amyloid-β; amyloid-β protein precursor; mitochondria; mitophagy
    DOI:  https://doi.org/10.1177/13872877251360243
  14. bioRxiv. 2025 Jun 26. pii: 2025.06.21.660867. [Epub ahead of print]
    Laminar Shear Stress Increases the Cytosolic Pool of PINK1 in Endothelial Cells and Enhances Mitophagic Sensitivity Toward Dysfunctional Mitochondria.
    Soon-Gook Hong, Junchul Shin, Jason Saredy, Soo Young Choi, Hong Wang, Joon-Young Park.
      Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) is an essential molecule in mitophagy process in mammalian cells. Mutation or deficiency of PINK1 has been closely related to several disease conditions. The purpose of this study was to determine PINK1 expression levels and subcellular localization under exercise-mimic laminar shear stress (LSS) condition in human aortic endothelial cells (HAECs) or in exercising mice, and its implication on endothelial homeostasis and cardiovascular disease (CVD) prevention. First, LSS significantly elevated both full-length PINK1 (FL-PINK1) mRNA and protein expressions in ECs. Mitochondrial fractionation assays and confocal microscopic analysis showed reduced FL-PINK1 accumulation on mitochondria with an increase in a cytosolic pool of FL-PINK1 under LSS. Mitophagy flux, determined by a mtKeima probe, decreased with intact mitochondrial morphology and membrane potential under LSS, suggesting that elevated cytosolic PINK1 is not utilized for immediate mitophagy inductions. However, increased cytosolic PINK1 seems to elevate mitophagic sensitivity toward dysfunctional mitochondria in pathological conditions. LSS-preconditioned ECs showed lower angiotensin II (AngII)-induced mtDNA lesions and displayed rapid Parkin recruitment and mitophagy induction in response to mitochondrial uncoupler (CCCP) treatment. Exercise-preconditioned mice, a physiological LSS-enhanced model, showed elevated PINK1 expression in ECs of the thoracic aorta compared to sedentary control. In addition, exercise enhanced AngII-induced mitophagy induction in ECs and reduced AngII-induced mtDNA lesion formation in the mouse aorta. Taken together, LSS increases a cytosolic pool of FL-PINK1, which may elevate the mitophagic sensitivity toward dysfunctional mitochondria in ECs.
    DOI:  https://doi.org/10.1101/2025.06.21.660867
  15. Hepatobiliary Pancreat Dis Int. 2025 Jul 01. pii: S1499-3872(25)00104-3. [Epub ahead of print]
    Baicalin and its nanoliposome ameliorate diquat-induced liver injury by promoting PINK1/Parkin-dependent mitophagy.
    Han-Ying Zhou, Ting Li, Yuan-Qiang Lu.
       BACKGROUND: Diquat, a commonly employed bipyridyl herbicide, is recognized for its hepatotoxic effects attributed to the generation of reactive oxygen species. Baicalin (BAI), a flavonoid derivative, has garnered significant research interest for its hepatoprotective properties. Nevertheless, the clinical application of BAI is constrained by its limited water solubility and poor bioavailability. To address these challenges, BAI-nanoliposome (BAI-NL) has emerged as a novel drug delivery platform aimed at enhancing therapeutic outcomes.
    METHODS: We used diquat-induced liver injury mouse model and AML12 hepatocytes to test the protective effect of BAI and BAI-NL on liver inflammation, oxidative stress, and mitochondrial function. The parameters included histological, biochemical, and molecular biological analyses.
    RESULTS: In the diquat-induced model, both BAI and BAI-NL exhibited effectiveness on attenuating liver inflammation. Ex vivo analyses further indicated that BAI-NL was superior to BAI in preserving mitochondrial membrane potential, reducing oxidative stress, and modulating the phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin RBR E3 ubiquitin-protein ligase (Parkin) signaling pathway. These findings enhanced mitophagy and facilitated the removal of damaged mitochondria.
    CONCLUSIONS: BAI-NL exhibited superior hepatoprotective effects compared to free BAI, possibly by reducing inflammation, preserving mitochondrial homeostasis, and reinstating autophagic balance through modulation of the PINK1/Parkin signaling pathway. These outcomes indicate a groundbreaking method for addressing liver diseases and underscore the potential of nanoliposome technology in augmenting the efficacy of natural compounds.
    Keywords:  Baicalin; Diquat; Liver injury; Mitophagy; Nanoliposome
    DOI:  https://doi.org/10.1016/j.hbpd.2025.06.008
  16. Mycotoxin Res. 2025 Jul 16.
    The PGC-1α/SIRT3 pathway mediates the effect of DON on mitochondrial autophagy and liver injury in mice.
    Yihan Wang, Jiali Fu, Danni Zhou, Zhihua Ren, Junliang Deng.
      Deoxynivalenol (DON)-induced liver injury is closely associated with mitochondrial dysfunction, yet it remains unclear whether this injury is mediated by mitochondrial autophagy via the PGC-1α/SIRT3 pathway. This study aimed to ascertain whether DON triggers mitochondrial autophagy, thereby causing liver injury in mice through the PGC-1α/SIRT3 pathway. Mice were orally administered DON at doses of 1.2 and 2.4 mg/kg once daily for 28 consecutive days. The results indicated that DON treatment significantly elevated the activity levels of two key liver enzymes and increased oxidative stress in the mouse liver. Additionally, DON upregulated several pivotal pro-inflammatory cytokines in the liver, leading to inflammation. The impact of DON on liver mitochondrial autophagy was assessed through histopathological analysis and observations of mitochondrial ultrastructure. These alterations were concurrent with activating the PGC-1α/SIRT3 signaling pathway in the liver following DON exposure. This research demonstrates that PGC-1α/SIRT3-regulated mitochondrial autophagy exacerbates DON-related hepatic damage, shedding light on the molecular mechanisms involved.
    Keywords:  DON; Liver; Mitochondrial autophagy; PGC-1α/SIRT3 pathway
    DOI:  https://doi.org/10.1007/s12550-025-00601-5
  17. Front Immunol. 2025 ;16 1621759
    Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging.
    Lillie Lewis, Deepa Valvi, Roberto Gedaly, Francesc Marti.
      Age-related conditions, such as neurodegenerative disease, cancer, and autoimmune disorders, are increasingly recognized as closely linked with the gradual deterioration of the immune system. Regulatory T cells (Tregs) are a small, specialized subset of T lymphocytes that play a critical role in maintaining immune homeostasis and self-tolerance. As individuals age, Treg cells demonstrate reduced capacity to suppress some autoreactive immune responses, although they largely retain their capacity to regulate effector antiviral and antitumor immunity. Unlike conventional effector T cells (Teff), which primarily derive energy from glycolysis, Tregs rely more on mitochondrial oxidative phosphorylation to fulfill their energy requirements. This metabolic profile renders them particularly sensitive to mitochondrial dysfunction, underpinning the critical role of mitochondrial protective pathways in preserving the functional integrity of Treg cells. The mitochondrial unfolded protein response (mitoUPR) is gaining special relevance among these protective mechanisms. In this review, we examine the complex interplay between immune aging and mitochondrial dynamics, with particular emphasis on the essential role of mitoUPR in supporting Treg function. We further discuss how targeting mitochondrial stress responses may offer novel therapeutic avenues for age-related diseases characterized by Treg dysfunction.
    Keywords:  aging; cell metabolism; cellular stress; immunosenescence; oxidative stress; regulatory T-cells; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2025.1621759
  18. Toxicol Appl Pharmacol. 2025 Jul 11. pii: S0041-008X(25)00238-8. [Epub ahead of print]503 117462
    Cadmium-induced apoptosis of granulosa cells is mediated by excessive activation of mitophagy and ROS-mediated mitochondrial dysfunction.
    Wenqian Li, Mengqi Wu, Haotian Shi, Muran He, Junyue Wang, Yichao Huang, Dexiang Xu, Jun Zhang.
      Cadmium (Cd), a pervasive environmental and occupational toxicant, has raised significant public health concerns due to its detrimental effects on human health. Emerging evidence highlights its capacity to impair the female reproductive system, notably through induction of follicular cell apoptosis. However, the underlying mechanism of Cd-induced apoptosis of granulosa cells remains unclear. In this study, thirty female mice were randomly allocated into three groups and exposed to CdCl₂ (0, 1.0, or 4.0 mg/kg) for 12 h, while 40 mice were divided into four groups and treated with CdCl₂ (4 mg/kg) for varying durations (0, 6, 12, or 24 h). Ovarian injury, apoptosis and mitophagy were observed in mice. To further elucidate the mechanism, human ovarian granulosa-like tumor cells (KGN cells) were treated with CdCl₂ (0-40 μM). Cd triggered apoptosis and excessive mitophagy in KGN cells, accompanied by reduced adenosine triphosphate (ATP) levels, diminished mitochondrial membrane potential (MMP), and elevated total reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Pharmacological inhibition of autophagy using 3-methyladenine (3-MA) attenuated Cd-induced apoptosis and mitochondrial dysfunction, whereas autophagy activation via rapamycin exacerbated these detrimental effects. Our findings demonstrate that Cd disrupts mitochondrial homeostasis by over activating mitophagy, which subsequently amplifies apoptotic signaling in ovarian granulosa cells. These results provide mechanistic insights into Cd-associated ovarian pathologies and highlight the therapeutic potential of targeting mitophagy to mitigate reproductive toxicity.
    Keywords:  Apoptosis; Cadmium; Granulosa cells; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.taap.2025.117462
  19. Free Radic Biol Med. 2025 Jul 10. pii: S0891-5849(25)00821-4. [Epub ahead of print]238 582-594
    MitoQ alleviates prion-induced neurodegeneration by modulating DRP1- and OPA1-mediated mitochondrial dynamics.
    Wei Wu, Xixi Zhang, Jia Xing, Siyu Kong, Mingyue Jiang, Meiyi Zhou, Yi Liao, Baojian Liao, Ning Ma.
      Prion diseases are a group of fatal neurodegenerative disorders with no effective treatments. MitoQ, a mitochondria-targeted antioxidant, has shown promise in treating mitochondrial redox-related diseases; however, its role in prion diseases remains unclear. In this study, we demonstrate that MitoQ significantly alleviates PrP106-126-induced oxidative stress, mitochondrial dysfunction, and apoptosis in mouse neuroblastoma N2a cells. Specifically, MitoQ reduces intracellular and mitochondrial reactive oxygen species (ROS) accumulation, enhances total antioxidant capacity (T-AOC) and the glutathione (GSH)/oxidized glutathione (GSSG) ratio, restores oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and intracellular ATP levels, and prevents cytochrome c release and caspase 3 activation. Mechanistically, MitoQ downregulates dynamin-related protein 1 (DRP1) phosphorylation at Ser616 and reduces mitochondrial DRP1 accumulation, while upregulating optic atrophy 1 (OPA1), thereby improving the mitochondrial dynamics imbalance induced by PrP106-126. Notably, DRP1 overexpression or OPA1 knockdown abolishes these protective effects, resulting in persistent oxidative stress, mitochondrial dysfunction, and apoptosis. These findings suggest that MitoQ alleviates prion-induced neurodegeneration by modulating DRP1- and OPA1-mediated mitochondrial dynamics, highlighting its therapeutic potential in prion diseases.
    Keywords:  DRP1 and OPA1; MitoQ; Mitochondrial dynamics; Mitochondrial dysfunction; Oxidative stress; Prion diseases
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.017
  20. Adv Sci (Weinh). 2025 Jul 17. e01718
    STAT6 Activation Exacerbates Ferroptosis in Airway Epithelium by Inhibiting PRKN-Mediated Mitophagy in Pulmonary Fibrosis.
    Youjing Yang, Guangbin Huang, Tao Zhang, Yi Ling, Junyu Jiang, Dingyuan Du, Yu Ma, Shasha Tao.
      Pulmonary fibrosis (PF) remains a clinically intractable condition with limited therapies. Ferroptosis has emerged as a critical driver of PF. The previous study demonstrates that increased secretion of tissue plasminogen activator from ferroptotic airway epithelial cells contributes to PF progression in a paracrine manner. Herein, the indispensable role of signal transducer and activator of transduction 6 (STAT6) is further elucidated in maintaining airway epithelial homeostasis during PF and uncovers a novel mechanism by which STAT6 regulates mitophagy to modulate ferroptosis. Specifically, mitophagy is induced during PF along with STAT6 activation, and deficiency of STAT6 significantly alleviates epithelial ferroptosis and PF. Mechanistically, STAT6 directly binds to the parkin RBR E3 ubiquitin protein ligase (PRKN) promoter region at the site (-990 to -976), inhibiting PRKN transcription and thereby impairing mitophagy. Consistently, lentivirus-mediated PRKN interference in both wild-type and STAT6 knockout mice aggravates ferroptosis and PF. Furthermore, virtual screening identifies rifabutin as a potential STAT6 inhibitor, that exhibits therapeutic effects against PF both in vivo and in vitro. Collectively, these findings reveal an unreported mechanism by which STAT6 promotes PF by inhibiting PRKN-mediated mitophagy in the airway epithelium. Rifabutin is further identified and validated as a promising STAT6 inhibitor to alleviate PF, offering new insights into therapy development.
    Keywords:  STAT6; ferroptosis; mitophagy; pulmonary fibrosis; rifabutin
    DOI:  https://doi.org/10.1002/advs.202501718
  21. bioRxiv. 2025 Jun 26. pii: 2025.06.26.661693. [Epub ahead of print]
    Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
    Xiaoxu Li, Weisha Li, Arwen W Gao, Yunyun Zhu, Elena Katsyuba, Katherine A Overmyer, Terytty Yang Li, Ziwen Wang, Luc Legon, Lucie Plantade, Laurent Mouchiroud, Matteo Cornaglia, Hao Li, Riekelt H Houtkooper, Joshua J Coon, Johan Auwerx.
      The mitochondrial unfolded protein response (UPR mt ) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPR mt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPR mt modulator, fipp-1 / FIP1L1 , which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, underscoring its translational relevance. Overall, our findings demonstrate a novel UPR mt modulator across species and provide insights into potential translational research.
    DOI:  https://doi.org/10.1101/2025.06.26.661693
  22. Phytomedicine. 2025 Jul 08. pii: S0944-7113(25)00701-9. [Epub ahead of print]145 157062
    Blueberry anthocyanins ameliorate arsenic-induced cognitive impairment in rats: mitigating mitochondrial damage and dysregulation.
    Xinbo Ma, Yang Liu, Bo Ding, Yanan Liu, Yuchen Zhang, Yuxi Wang, Liu Yang, Yanmei Yang, Xiaona Liu.
       BACKGROUND: Blueberry anthocyanin extract (BAE) is a natural antioxidant flavonoid found in blueberries that has the potential to alleviate oxidative stress-induced neurodegeneration. Previous studies have demonstrated the potential of BAE to mitigate arsenic-induced cognitive impairment; however, the underlying protective mechanisms remain elusive.
    PURPOSE: This study aimed to evaluate the effectiveness of BAE in reducing arsenic-induced cognitive impairment and explored whether BAE's neuroprotective effects are related to its antioxidant and mitochondrial protective effects.
    METHODS: Sixty male rats were exposed to sodium arsenite (NaAsO2, 10 mg/kg) with or without BAE (100 and 200 mg/kg) for 12 weeks. Spatial learning and memory were evaluated using the Morris water maze (MWM). Neuronal damage in rat hippocampi was evaluated using hematoxylin and eosin (H&E) staining, electron microscopy, and terminal deoxynucleotidyl transferase-mediated nick-end labelling (TUNEL) staining. Oxidative stress markers, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) were measured. Mitochondrial function was assessed by analysing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), deacetylase sirtuin 1 (SIRT1), and proteins related to mitochondrial biogenesis and mitochondrial dynamics.
    RESULTS: Arsenic exposure significantly impaired learning and memory in rats, as evidenced by reduced performance in the MWM, whereas BAE treatment ameliorated these deficits. Furthermore, BAE alleviated arsenic-induced hippocampal neuronal apoptosis, as well as alleviating increased oxidative stress, weakened antioxidant capacity, and imbalanced mitochondrial biogenesis and dynamics. In this study, we focused on the core of mitochondrial quality control mechanism - mitochondrial biogenesis, fusion and fission. We explored the protective mechanism of BAE against arsenic - induced nerve damage. Based on these, we proposed an innovative therapeutic strategy: using natural products to target and regulate mitochondrial quality control.
    CONCLUSION: This study indicated that BAE alleviates arsenic-induced neurotoxicity through its antioxidant and mitochondrial protective effects, effectively reducing arsenic-induced neurotoxicity and enhancing cognitive function.
    Keywords:  Anthocyanins; Arsenic; Mitochondrial biosynthesis; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.phymed.2025.157062
  23. Endocr Metab Immune Disord Drug Targets. 2025 Jul 15.
    Palmatine Ameliorates High-Temperature and High-Humidity-Induced Enteritis Via Mitophagy and NLRP3 Inflammasome Degradation.
    Xiaoying Mo, Tai Mi, Wanli Liu, Yao Wang, Yalan Wu, Xinhua Huang, Song Chen, Huanhuan Luo.
       BACKGROUND: Previous studies have shown that a High-Temperature- and High-Humidity (HTH) environment leads to mild enteritis, accompanied by impaired mitophagy and activated NLRP3-IL-1β, as found in Inflammatory Bowel Disease (IBD). Therefore, whether Palmatine (PAL), a candidate for treating IBD, ameliorates HTH-induced enteritis via mitophagy-associated mechanisms was examined. This study aimed to investigate the protective effects of PAL against HTH-induced enteritis in mice and determine the underlying mechanisms.
    METHODS: BALB/c mice were used to model HTH-induced enteritis. The mice were exposed to an HTH environment (33 ± 0.5°C, 85-90% humidity) for 28 days, with PAL or Cyclosporin A (CsA) administered daily. Mice were euthanized on days 7, 14, 28, or 35 to analyze the ileal tissues. Pathological examination, western blotting (Parkin, NLRP3, IL-1β), immunofluorescence (8-OHDG), and mtDNA quantification were performed to assess the therapeutic effects of the treatment.
    RESULTS: A total of 884 and 2,668 potential targeted genes were identified for PAL and IBD, respectively, including 183 overlapped genes, which were mainly involved in oxidative stress, inflammation, and autophagy. HTH induced weight loss and loose faeces, along with increased NLRP3, IL-1β, and 8-OHDG expressions, and decreased Parkin and mtDNA expressions in the ileum. These effects were ameliorated and exacerbated by PAL and CsA treatment, respectively.
    CONCLUSION: PAL ameliorated HTH-induced enteritis probably via augmenting mitophagy and inhibiting NLRP3 expression. The findings highlight the critical role of mitophagy in the pathogenesis of HTH-induced enteritis and support the potential use of PAL in treatment.
    Keywords:  Nod-like receptor family pyrin-domain-containing protein 3 (NLRP3); inflammatory bowel disease.; interleukin-1β (IL-1β); mitochondrial DNA (mtDNA) copies
    DOI:  https://doi.org/10.2174/0118715303348448250605071743
  24. Mol Neurobiol. 2025 Jul 14.
    Gipc3 Mutation Might Cause Sensorineural Hearing Loss by Inhibiting Mitophagy in Inner Ear Hair Cells.
    Xinxin Li, Jing Wang, Lin Shi, Liang Wang.
      Sensorineural hearing loss (SNHL) has a high degree of genetic heterogeneity, with numerous mutated genes that contribute to deafness. GIPC3 gene is one of the mutated genes that can cause congenital hearing loss, which has been identified in recent years; however, the exact mechanism behind this condition remains unclear. Mitophagy is the process of selectively encapsulating and lysing damaged or dysfunctional mitochondria in order to prevent the accumulation of damaged mitochondria from damaging the cells and is of great importance in the maintenance of homeostasis in the inner ear. This paper aims to investigate the potential mechanism of sensorineural hearing loss brought on by Gipc3 mutations by observing the impact of Gipc3 expression on mitochondrial metabolism and autophagy in inner ear hair cells. In this study, The House Ear Institute Organ of Corti 1(HEI-OC1) cells and cochlear explants were cultured to change the expression level of Gipc3 by transfection, and the knockdown efficiency was examined by quantitative polymerase chain reaction (qPCR) and Western blot. Knockdown of Gipc3 inhibited cell viability and its proliferation ability. When tert-butyl hydroperoxide (t-BHP) was used to induce oxidative stress injury and knockdown of Gipc3, inner ear hair cells had a weakened ability to resist oxidative stress injury, mitochondrial metabolism was altered, and there was an accumulation of reactive oxygen species (ROS) and a reduction of mitochondrial membrane potential. Immunofluorescence and Western blot techniques demonstrated autophagy abnormalities in the mitophagy-related proteins LC3B and p62. Early endosome-dependent mitophagy is mediated by a PH domain and leucine zipper motif 1 (APPL1), and mitophagy is hampered by APPL1 deletion. We discovered that there is probably co-localization between Gipc3 and APPL1 by confocal microscopy imaging and that their trends show a positive association. In summary, Gipc3 mutations may lead to decreased mitochondrial function by inhibiting the APPL1-mediated mitophagy process. This may lead to a reduction in oxidative metabolism in hair cells, which is one potential mechanism via which Gipc3 mutations suppress mitophagy.
    Keywords:   Gipc3 ; Hair cell; Mitophagy; Reactive oxygen species; Sensorineural hearing loss
    DOI:  https://doi.org/10.1007/s12035-025-05178-9
  25. Aging Cell. 2025 Jul 16. e70175
    Beyond the Pseudogene: p17/PERMIT as a Mitochondrial Trafficking Protein Linking Aging and Neurodegeneration.
    Onder Albayram, Natalia Oleinik, Besim Ogretmen.
      The misclassification of functional genomic loci as pseudogenes has long obscured critical regulators of cellular homeostasis, particularly in aging-related pathways. One such locus, originally annotated as RPL29P31, encodes a 17-kDa protein now redefined as PERMIT (Protein that Mediates ER-Mitochondria Trafficking). Through rigorous experimental validation-including antibody development, gene editing, lipidomics, and translational models-p17/PERMIT has emerged as a previously unrecognized mitochondrial trafficking chaperone. Under aging or injury-induced stress, p17 mediates the ER-to-mitochondria translocation of Ceramide Synthase 1 (CerS1), facilitating localized C18-ceramide synthesis and autophagosome recruitment to initiate mitophagy. Loss of p17 impairs mitochondrial quality control, accelerating neurodegeneration, and sensorimotor decline in both injury and aging models. This Perspective highlights p17 as a paradigm-shifting discovery at the intersection of lipid signaling, mitochondrial biology, and genome reannotation, and calls for a broader reassessment of the "noncoding" genome in aging research. We summarize a rigorous multi-platform validation pipeline-including gene editing, antibody generation, lipidomics, proteomics, and functional rescue assays-that reclassified p17 as a bona fide mitochondrial trafficking protein. Positioned at the intersection of lipid metabolism, organelle dynamics, and genome reannotation, p17 exemplifies a growing class of overlooked proteins emerging from loci historically labeled as pseudogenes, urging a systematic reevaluation of the "noncoding" genome in aging research.
    DOI:  https://doi.org/10.1111/acel.70175
  26. Exp Mol Pathol. 2025 Jul 10. pii: S0014-4800(25)00033-4. [Epub ahead of print]143 104983
    Mitochondrial dysfunction in fibrotic diseases: Research progress and MSC-exos therapy.
    Xiaoyun Zhang, Yingyu Wang, Xinyi Guo, Yu Xiao, Weiguo Wan, Hejian Zou, Xue Yang.
      Fibrosis is a common pathological feature of most chronic diseases progressing to the end stage, with its specific pathogenesis still unclear and lacking effective therapeutic approaches. Mitochondria are essential organelles responsible for energy production and the maintenance of cellular homeostasis. Increasing evidence indicates that mitochondrial dysfunction is closely associated with the onset and progression of fibrotic diseases. In this review, we explore the relationship between mitophagy, oxidative stress, mitochondrial dynamics, mtDNA release, and progression of fibrosis from the perspective of mitochondrial dysfunction. Furthermore, we summarized the latest research advances of mitochondrial dysfunction in lung, liver, kidney and skin fibrosis, and provided an overview of the potential therapeutic use of mesenchymal stem cell-derived exosomes in the treatment of fibrotic diseases by improving mitochondrial function, aiming to deepen the understanding of mitochondrial dysfunction in the pathogenesis of fibrotic diseases and provide new insights into targeting mitochondria in the treatment of fibrotic diseases.
    Keywords:  Fibrotic diseases; Mesenchymal stem cell-derived exosomes; Mitochondrial dysfunction; Review
    DOI:  https://doi.org/10.1016/j.yexmp.2025.104983
  27. Animals (Basel). 2025 Jul 07. pii: 2000. [Epub ahead of print]15(13):
    Mitochondrial Quality Control in Bovine Oocyte Maturation: Mechanisms, Challenges, and Prospects for Enhancing Reproductive Efficiency.
    Yi-Ran Zhang, De-Jun Xu.
      Oocyte maturation represents a fundamental biological process in bovine reproduction, establishing the physiological basis for fertilization and early embryonic development while critically determining the propagation of improved varieties and breeding efficiency. The roles of MQC in reproduction have gained substantial scientific attention. The proper maturation of oocytes fundamentally depends on adequate mitochondrial functionality. However, the intrinsic regulatory mechanisms governing MQC during bovine oocyte maturation remain incompletely characterized. Here, we discuss the most recent progress on the molecular mechanisms and roles of mitochondrial fission/fusion, biogenesis, and mitophagy in MQC. Building upon the mechanistic foundations of MQC in bovine oocyte maturation, this review identifies key mitochondrial-targeted supplements with potential applications in enhancing oocyte quality. Furthermore, we evaluate epigenetic influences on mitochondrial regulatory networks through mitochondrial-nuclear communication. Finally, we discuss the challenges in elucidating mitochondrial quality control mechanisms during oocyte maturation and propose corresponding strategies to address these obstacles. Integrating mechanistic insights, this review proposes strategies to enhance in vitro culture systems and identify oocyte quality markers, providing valuable insights for optimizing in vitro production (IVP) of bovine embryos and enhancing reproductive efficiency.
    Keywords:  epigenetics; maturation; mitochondrial quality control; oocyte
    DOI:  https://doi.org/10.3390/ani15132000
  28. Artif Cells Nanomed Biotechnol. 2025 Dec;53(1): 287-303
    Identification of mitophagy-related biomarkers in human rheumatoid arthritis using machine learning models.
    Jiayi Chen, Zuhai Huang, Chengyu Qin, Zixiang Pang, Yuanming Chen.
      Rheumatoid arthritis (RA) is a systemic immune-mediated disease characterized by synovitis and joint cartilage destruction. Although many studies have shown that mitophagy is crucial in the development of bone metabolism disorders, its exact function in rheumatoid arthritis (RA) is still not well understood. This study analysed the GSE77298 dataset from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) between rheumatoid arthritis (RA) patients and healthy controls. Mitophagy-related genes (MRGs) were extracted from the literature and screened using bioinformatics techniques, resulting in differentially expressed MRGs (DE-MRGs). The diagnostic value of these genes was assessed using receiver operating characteristic (ROC) curves, and an ANN model was constructed. In the GSE77298 dataset, 267 differentially expressed genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) identified 2191 key module genes, leading to 63 DE-MRGs. Two MRGs, TMEM45A and ZBTB25, were identified as hub genes with areas under the curve (AUC) of 0.991 and 0.911, respectively. The nomogram model demonstrated high diagnostic value. Mitophagy plays a critical role in the progression of rheumatoid arthritis (RA). Identifying two genes associated with mitophagy may aid in the early diagnosis, mechanistic understanding, and treatment of RA.
    Keywords:  Rheumatoid arthritis; WGCNA; machine learning; mitophagy; ssGSEA
    DOI:  https://doi.org/10.1080/21691401.2025.2533361
  29. Ecotoxicol Environ Saf. 2025 Jul 14. pii: S0147-6513(25)01013-9. [Epub ahead of print]302 118668
    Nickel exposure induced endoplasmic reticulum stress by disturbing calcium homeostasis and triggered mitochondrial autophagy in domestic animal oocytes.
    Chengkun Zhong, Shengkui Hou, Jing Guo, Jing Zhao, Jun Wang, Yi Fang, Hongyu Liu, He Ding, Xin Ma, Wenfa Lyu.
      Nickel, a heavy metal with industrial applications and as a feed additive for livestock, can adversely impact reproductive function and gamete quality when present in excessive amounts in the animal feed environment. In this study, the results indicate that nickel exposure hampers polar body extrusion and cumulus cell expansion, thereby diminishing oocyte quality and developmental competence. Furthermore, nickel exposure reduces glutathione (GSH) levels in oocytes, leading to excessive accumulation of reactive oxygen species (ROS), provoking oxidative stress and mitochondrial impairment. This cascade initiates mitochondrial autophagy, upregulates the expression of autophagy-related proteins Parkin and PINK1, promotes LC3 binding to autophagosomes. Nickel exposure disrupts calcium homeostasis and induces endoplasmic reticulum stress (ERS). Inhibiting ERS effectively alleviates the deterioration of oocytes quality caused by nickel exposure and inhibits mitochondrial autophagy. Proteomics further confirms nickel's exposure detrimental effects on mitochondria and ER, impacting cellular processes. Employing bovine oocytes as a model, consistent phenotypes were observed. These results indicate that nickel exposure disrupts intracellular calcium homeostasis, elicits ERS, disrupts cellular calcium homeostasis, diminishes the quality of pig oocytes, impairs oocyte maturation and developmental potential, and instigates mitochondrial autophagy.
    Keywords:  Autophagy; Calcium homeostasis; Endoplasmic reticulum; Mitochondria; Nickel; Oocyte
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118668
  30. J Ethnopharmacol. 2025 Jul 12. pii: S0378-8741(25)00981-X. [Epub ahead of print] 120291
    Jianpi Qushi Heluo Formula ameliorates podocytes injury related with ROS-mediated NLRP3 inflammasome activation in membranous nephropathy by promoting PINK1-dependent mitophagy.
    Lei Yan, Qin Zeng, Wenru Wang, Ying Liang, Rui Lang, Jingyi Zhan, Jiayi Yang, Renhuan Yu, Xinhui Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Qushi Heluo formula (JQHF) is an evidence-based herbal formula based on "Fangji Huangqi Decoction" in the classic of traditional Chinese medicine (TCM) synopsis of the Golden Chamber. Its effectiveness in reducing idiopathic membranous nephropathy (IMN) proteinuria, edema and other clinical symptoms and improving kidney injury has been confirmed by clinical trials and animal experiments. These results demonstrate the critical significance of reducing podocyte injury by regulating mitophagy through integrating ethnopharmacology.
    AIM OF THE STUDY: This study aimed to explore the protective effects of JQHF on podocyte injury in IMN, focusing on its role in promoting PINK1-dependent mitophagy to inhibit reactive oxygen species (ROS) mediated activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome.
    MATERIALS AND METHODS: The main components of JQHF were identified by ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MSE). Passive Heymann nephritis (PHN) was induced in rats using anti-Fx1A antiserum, while podocyte injury in vitro was stimulated with sublytic complement C5b-9 (sC5b-9). The PHN rats were treated with JQHF, and autophagy inhibitor 3-methyladenine (3-MA) combined with JQHF was used for pathway verification, and Benazepril served as a positive control. In vitro, podocytes were exposed to palmitic acid (PA, a ROS inducer) and N-acetylcysteine (NAC, a ROS scavenger). Further, we silenced the expression of PINK1 in podocytes model and intervened with JQHF-containing serum. Renal function was assessed through biochemical analyses and histopathology. Mitochondrial function was measured by detecting mitochondrial membrane potential (MMP), ROS levels as well as mitochondrial ultrastructure. The expression of podocyte structural proteins (desmin, nephrin, podocin) and inflammasome-related markers (NLRP3, caspase-1, IL-1β, IL-6) was analyzed to assess podocyte injury and inflammasome activation.
    RESULTS: (1) In vitro, in contrast to the control group, PA intervention caused increased ROS accumulation, reduced MMP, upregulated NLRP3 and caspase-1 expression, as well as elevated expression of inflammatory factors IL-1β and IL-6. The expression of nephrin and podocin was notably reduced. By contrast, NAC reversed these effects. (2) In vivo, JQHF effectively ameliorated mitochondrial damage, reduced NLRP3 expression and mitigated podocyte injury in PHN rats. The protective effects of JQHF were diminished by 3-MA, confirming the involvement of autophagy. (3) In vitro, JQHF-containing serum attenuated C5b-9-induced podocyte injury, improved mitochondrial dysfunction, and inhibited ROS-mediated activation of NLRP3 inflammasome. Silencing PINK1 significantly reversed these protective effects.
    CONCLUSION: JQHF can alleviate podocyte damage, that through inhibiting ROS-mediated NLRP3 inflammasome activation by improving PINK1-mediated mitophagy.
    Keywords:  Jianpi Qushi Heluo Formula; NLRP3 inflammatory corpuscles; membranous nephropathy; mitochondrial function; podocytes injury
    DOI:  https://doi.org/10.1016/j.jep.2025.120291
  31. bioRxiv. 2025 Jun 15. pii: 2025.06.14.659625. [Epub ahead of print]
    Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy are two major proteostatic systems, how these pathways intersect to regulate mitochondrial integrity in metabolically active tissues remains poorly understood. Here, using adipocyte-specific genetic mouse models combined with high-resolution 2D and 3D ultrastructural imaging technologies, we reveal an unexpected synergy between SEL1L-HRD1 ERAD and autophagy in maintaining mitochondrial structure and function in brown adipocytes. Loss of ERAD alone triggers compensatory autophagy, whereas combined deletion of both pathways (double knockout, DKO) results in severe mitochondrial abnormalities, including the accumulation of hyperfused megamitochondria penetrated by ER tubules, even under basal room temperature conditions. These phenotypes are absent in mice lacking either pathway individually or in SEL1L-IRE1α DKO, highlighting the pathway-specific coordination between ERAD and autophagy. Mechanistically, dual loss of ERAD and autophagy induces ER expansion, excessive ER-mitochondria contact, upregulation of mitochondria-associated membrane (MAM) tethering proteins, impaired calcium transfer, and defective mitochondrial turnover. As a result, DKO adipocytes accumulate dysfunctional mitochondria, exhibit respiratory deficits, and fail to sustain thermogenesis. Collectively, our study uncovers a cooperative and previously unrecognized mechanism of mitochondrial surveillance, emphasizing the critical role of ERAD-autophagy crosstalk in preserving mitochondrial integrity and thermogenic capacity in brown fat.
    One-sentence summary: Our study uncovers a previously unrecognized synergy between SEL1L-HRD1 ERAD and autophagy that is essential for preserving mitochondrial integrity and thermogenic capacity in brown adipocytes, revealing new opportunities for targeting mitochondrial dysfunction in metabolic disease.
    DOI:  https://doi.org/10.1101/2025.06.14.659625
  32. Cell Commun Signal. 2025 Jul 16. 23(1): 341
    Mitochondria from huntington´s disease striatal astrocytes are hypermetabolic and compromise neuronal branching.
    Laura López-Molina, Alba Pereda-Velarde, Nadia di Franco, Imme Aerts, Elisa Sebastià, Laura Valls-Roca, Mariona Guitart-Mampel, Gloria Garrabou, Silvia Gines.
       BACKGROUND: Deficits in mitochondrial bioenergetics and dynamics are strongly implicated in the selective vulnerability of striatal neurons in Huntington´s disease. Beyond these neuron-intrinsic factor, increasing evidence suggest that non-neuronal mechanisms, particularly astrocytic dysfunction involving disrupted homeostasis and metabolic support also contribute to disease progression. These findings underscore the critical role of metabolic crosstalk between neurons and astrocytes in maintaining striatal integrity. However, it remains unclear whether this impaired communication affects the transfer of mitochondria from astrocytes to striatal neurons, a potential metabolic support mechanism that may be compromised in Huntington´s Disease.
    METHODS: Primary striatal astrocytes were obtained from wild-type and R6/1 mice to investigate mitochondrial dynamics. Expression levels of key mitochondrial fusion and fission proteins were quantified by Western blotting and RT-PCR. Mitochondria morphology, oxidative stress and membrane potential were assessed using confocal microscopy following staining with mitochondria-specific dyes. Mitochondrial respiration was measured using the Oxygraph-2k respirometer system (Oroboros Instruments). Transmitophagy was evaluated by confocal imaging after labeling astrocytic mitochondria with Mitotracker dyes. To assess the functional impact of mitochondrial transfer on neurons, Sholl analysis, neuronal death and oxidative stress levels were quantified using specific fluorogenic probes.
    RESULTS: Striatal astrocytes from HD mice exhibited a significant increase in mitochondrial fission, and mitochondrial oxidative stress, mirroring alterations previously reported in striatal neurons. Analysis of mitochondrial oxygen consumption rate (OCR) revealed elevated respiration activity and enhanced ATP-linked respiration, indicative of a hypermetabolic state. Concurrently, increased lactate production suggested a shift toward dysregulated astrocytic energy metabolism. These mitochondrial alterations were functionally detrimental: astrocytic mitochondria derived from HD mice when taken up by striatal neurons via transmitophagy, led to reduced neuronal branching and disrupted oxidative homeostasis.
    CONCLUSIONS: Our findings demonstrate that striatal astrocytes from HD mice exhibit a hypermetabolic phenotype, characterized by increased mitochondrial respiration, disrupted mitochondrial dynamics, and elevated mitochondrial oxidative stress. Importantly, we identify a novel mechanism of astrocyte-neuron interaction involving the transfer of dysfunctional mitochondria from astrocytes to neurons. The uptake of these compromised mitochondria by striatal neurons results in reduced neuronal branching and increased reactive oxygen species (ROS) production. Collectively, these results highlight the pathological relevance of impaired astrocyte-to-neuron mitochondrial transfer and emphasize the contributory role of astrocytic dysfunction in Huntington´s disease progression.
    Keywords:  Astrocytes; Huntingtin; Mitochondria transfer; Neuroglial communication; R6/1 mice; Striatum
    DOI:  https://doi.org/10.1186/s12964-025-02341-6
  33. MedComm (2020). 2025 Jul;6(7): e70285
    Sulfide Quinone Oxidoreductase Alleviates Acute Ulcerative Colitis by Regulating Mitochondrial Dysfunction.
    Hailin Ma, Shuilian Fu, Chujun Huang, Na Han, Fangfang Cai, Dangran Li, Jian Cheng, Hongqin Zhuang, Zi-Chun Hua.
      Alteration in mitochondrial function within intestinal epithelial cells were closely related to inflammatory bowel disease (IBD) progression. Sulfide quinone oxidoreductase (SQOR), located in the inner mitochondria membrane, is a crucial enzyme in sulfide metabolism. Here, we observed that SQOR was downregulated during colitis. Intestinal epithelial cells specific knockout of SQOR (Sqor CKO) mice were more susceptible to acute ulcerative colitis (UC) with lower hydrogen sulfide (H2S) levels, and the absence of SQOR caused a breakdown of the epithelial barrier through disruption of the tight junction proteins. Furthermore, analysis of the mitochondrial morphology and functions revealed increased mitochondrial damage when SQOR deficiency. Mechanistically, it is observed that SQOR knockout increased lipid peroxidation, malondialdehyde (MDA) levels and ferroptosis. Further results demonstrated that SQOR may rely on inhibiting excessive mitochondrial division and promoting mitochondrial biogenesis to regulate reaction oxygen species (ROS) levels in intestinal epithelial cells. Treatment with ROS scavengers (NAC) showed significant reduced colonic inflammation symptoms observed in DSS-treated Sqor CKO mice. Collectively, these findings demonstrate the protective role of SQOR in intestinal epithelial cells in maintaining mitochondrial homeostasis by regulating ROS and providing novel insight into UC.
    Keywords:  ROS; intestinal epithelial cells; mitochondrial dynamics; sulfide quinone oxidoreductase; ulcerative colitis
    DOI:  https://doi.org/10.1002/mco2.70285
  34. Front Cell Dev Biol. 2025 ;13 1614940
    Mechanism and regulation of mitophagy in liver diseases: a review.
    Sen Liu, Libo Wang, Liuyang Zhu, Tianyu Zhao, Pinsheng Han, Fengying Yan, Xiaoliang Wang, Chunli Li, Ze Wang, Bao-Feng Yang.
      Mitochondria are vital for the proper operation of healthy eukaryotic cells. Mitophagy, a specialized form of autophagy that targets damaged or surplus mitochondria, plays a key role in both the normal functioning and disease-related processes within the liver. This review aims to explore the main mechanisms underlying the initiation of mitophagy and its importance in various liver conditions, such as alcoholic liver disease, drug-induced liver injury, non-alcoholic fatty liver disease, viral hepatitis, and cancer. Gaining insight into these mechanisms can help overcome the obstacles related to harnessing mitophagy as a therapeutic strategy in clinical practice.
    Keywords:  DILI; NAFLD; liver disease; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2025.1614940
  35. Int J Mol Sci. 2025 Jul 02. pii: 6364. [Epub ahead of print]26(13):
    CRISPRa-Mediated Increase of OPA1 Expression in Dominant Optic Atrophy.
    Giada Becchi, Michael Whitehead, Joshua P Harvey, Paul E Sladen, Mohammed Dushti, J Paul Chapple, Patrick Yu-Wai-Man, Michael E Cheetham.
      Dominant Optic Atrophy (DOA) is the most common inherited optic neuropathy and presents as gradual visual loss caused by the loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a mitochondrial GTPase essential in mitochondrial fusion. Currently, there are no treatments for DOA. Here, we tested the therapeutic potential of an approach to DOA using CRISPR activation (CRISPRa). Homology directed repair was used to introduce a common OPA1 pathogenic variant (c.2708_2711TTAGdel) into HEK293T cells as an in vitro model of DOA. Heterozygous c.2708_2711TTAGdel cells had reduced levels of OPA1 mRNA transcript, OPA1 protein, and mitochondrial network alterations. The effect of inactivated Cas9 fused to an activator (dCas9-VPR) was tested with a range of guide RNAs (gRNA) targeted to the promotor region of OPA1. gRNA3 and dCas9-VPR increased OPA1 expression at the RNA and protein level towards control levels. Importantly, the correct ratio of OPA1 isoform transcripts was maintained by CRISPRa. CRISPRa-treated cells showed an improvement in mitochondrial networks compared to untreated cells, indicating partial rescue of a disease-associated phenotype. Collectively, these data support the potential application of CRISPRa as a therapeutic intervention in DOA.
    Keywords:  CRISPR; CRISPR activation; OPA1; alternative splicing; gene editing; gene expression; mitochondria; mitochondrial fusion; optic atrophy; retinal ganglion cell
    DOI:  https://doi.org/10.3390/ijms26136364
  36. Neurobiol Dis. 2025 Jul 11. pii: S0969-9961(25)00246-3. [Epub ahead of print]213 107030
    Hearing the call of mitochondria: Insight into its role in sensorineural hearing loss.
    Haojia He, Zhuoxue Han, Shuai Cheng, You Zhou.
      Sensorineural hearing loss (SNHL) is a prevalent and complex auditory disorder with a multifactorial pathogenesis, in which mitochondrial dysfunction plays a pivotal role. Mitochondria are abundantly localized in critical structures of the inner ear, where they not only provide the substantial energy required for auditory transduction but also regulate key cellular processes. Growing evidence suggests that mitochondrial impairment, characterized by excessive reactive oxygen species (ROS) generation, dysregulated inflammatory responses, disrupted apoptosis, and mitochondrial DNA (mtDNA) mutations, is closely linked to the onset and progression of SNHL. Recent advances in mitochondria-targeted therapeutic strategies, such as antioxidant delivery, promotion of mitochondrial biogenesis, and mitochondrial gene therapy, have shown promising preclinical results. However, significant challenges remain in translating these approaches into clinical practice, particularly in terms of targeted delivery, long-term efficacy, and potential side effects. This comprehensive review systematically examines the molecular mechanisms underlying mitochondrial involvement in SNHL pathogenesis, evaluates recent progress in mitochondria-targeted interventions, and discusses current limitations and future directions in this rapidly evolving field. By integrating current knowledge and identifying key research gaps, this review aims to provide a solid theoretical foundation and fresh perspectives for the development of effective therapeutic strategies for SNHL.
    Keywords:  Mitochondria; Mitophagy; Oxidative stress; Sensorineural hearing loss; Therapy
    DOI:  https://doi.org/10.1016/j.nbd.2025.107030
  37. Sci Rep. 2025 Jul 13. 15(1): 25312
    ANGPTL4 promoted the cognitive impairment in vascular dementia via increasing integrin/p-Syk signalings induced mitochondrial autophagy and apoptosis in the hippocampus.
    Chunhong Yao, Jinfeng Wang.
      The aim of this study was to investigate the effects and mechanisms of ANGPTL4 on cognitive impairment in vascular dementia rats. 36 SD rats were randomly divided into Sham(n= 9), VaD(n= 9), VaD + ANGPTL4 OE(n= 9), and VaD + ANGPTL4 KD(n= 9). A bilateral carotid artery ligation (2-VO) rat VaD was established to study the effects of ANGPTL4. Spatial memory was tested in rats using the Morris water maze. Morphological changes of neurons were detected in the CA1 region of the hippocampus by hematoxylin-eosin staining. The expression of ANGPTL4, p-Syk in the cells of hippocampal CA1 area was also detected by immunohistochemistry. Afterwards, protein expression of ANGPTL4, p-Syk, p-JNK, BNIP3 was detected by Western blot (WB). Afterwards, the mechanism of ANGPTL4 effect on cognitive impairment in vascular dementia rats was further explored by ANGPTL4 OE hippocampal cells 1%O2 low-serum low-glucose stimulation with Syk inhibitor, JNK inhibitor. ANGPTL4 OE aggravated cognitive dysfunction in 2VO rats. ANGPTL4 KD treatment improved the memory performance of 2VO rats.Hippocampal tissue damage was obvious in the VaD group.Hippocampal tissue damage was aggravated in the ANGPTL4 OE group (P < 0.001).ANGPTL4 KD group Pathological features were significantly improved(P < 0.001). WB assay showed that the expression of ANGPTL4, p-Syk, p-JNK, and BNIP3 proteins was increased in 2VO rats(P < 0.05), which was further up-regulated by ANGPTL4 OE treatment, and significantly inhibited by ANGPTL4 KD treatment in 2VO rats(P < 0.05). In vitro cellular experiments revealed that ANGPTL4 OE treatment again up-regulated ANGPTL4, integrin, p-Syk, and p-JNK protein expression consistent with the in vivo results(P < 0.05), where the Syk inhibitor suppressed both p-Syk, and p-JNK protein expression(P < 0.05). It is also worth noting that the mitochondrial autophagy-related proteins BNIP3, PINK1, Parkin and JC-1 mitochondrial membrane potential assayed by wb revealed that ANGPTL4 OE treatment exacerbated mitochondrial stress(P < 0.05) and apoptosis(P < 0.05) in hippocampal cells, and that Syk inhibitor, and JNK inhibitor significantly inhibited the modulation of ANGPTL4 OE(P < 0.05). ANGPTL4 promotes mitochondrial autophagy and apoptosis in the hippocampal CA1 region by activating the integrin/p-Syk signalling pathway, thus aggravating cognitive impairment in vascular dementia rats.
    Keywords:  ANGPTL4; Mitochondrial autophagy; Vascular dementia; p-JNK; p-Syk
    DOI:  https://doi.org/10.1038/s41598-025-07811-y
  38. Redox Biol. 2025 Jul 08. pii: S2213-2317(25)00271-X. [Epub ahead of print]85 103758
    POLR1A inhibits ferroptosis by regulating TFAM-mediated mitophagy and iron homeostasis.
    Tuo Zhang, Yanyun Gao, Marcell Harhai, Alexis A Jourdain, Thomas M Marti, Erik Vassella, Zhang Yang, Qinghua Zhou, Patrick Dorn, Ren-Wang Peng.
      Evasion of programmed cell death (PCD) is a hallmark of cancer, yet the mechanisms underlying resistance to ferroptosis - an iron-dependent form of PCD triggered by excessive lipid peroxidation - remain incompletely understood. Here, we identify a previously unrecognized nucleolar-mitochondrial signaling axis that promotes ferroptosis resistance in pleural mesothelioma (PM) and potentially other cancers. This pathway involves RNA polymerase I (PolI) catalytic subunit A (POLR1A) and mitochondrial transcription factor A (TFAM), which together regulate mitophagy and intracellular iron metabolism to suppress ferroptosis. Mechanistically, POLR1A controls TFAM expression via the transcription factor ATF4, and this POLR1A-ATF4-TFAM axis inhibits mitophagy and limit mitophagy-dependent labile Fe2+ release, thereby preventing Fe2+-driven lipid peroxidation. Disruption of this pathway through POLR1A or TFAM inhibition leads to Fe2+ accumulation and increased sensitivity to ferroptosis inducers (FINs). Notably, CX-5461, a first-in-class RNA PolI inhibitor currently in clinical trials, synergizes with GPX4 blockade to induce ferroptotic cell death both in vitro and in vivo. This therapeutic synergy extends beyond PM, suggesting broader relevance in ferroptosis-resistant cancers. Together, our findings reveal a novel mechanism of ferroptosis evasion and establish a promising combinatorial strategy to overcome therapy resistance in cancer.
    Keywords:  ATF4; Ferroptosis; Iron metabolism; POLR1A; TFAM; mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2025.103758
  39. J Ethnopharmacol. 2025 Jul 11. pii: S0378-8741(25)00975-4. [Epub ahead of print] 120285
    Regulation of NR4A1 by Taohong Siwu Decoction Inhibits Endothelial Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury.
    Shuangping Li, Jingjing Li, Yumeng Li, Qingping Ye, Ruru Wang, Xinyao Liu, Huining Li, Daiyin Peng, Xianchun Duan.
       ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (THSWD), a classic prescription, is commonly used to treat ischemic stroke. However, the effects of THSWD on endothelial cells (ECs) in cerebral ischemia-reperfusion injury (IRI) are unclear.
    AIM OF THE STUDY: This study investigated whether THSWD can protect ECs from cerebral IRI by regulating NR4A1 to mitigate mitochondrial fission and reduce cell apoptosis.
    METHODS: We established the rat MCAO model and the OGD/R injury model of human BMECs cells. Observation of the protective effect of THSWD against IRI using Zea-Longa score, TTC staining, and HE staining; ELISA to detect ET-1, eNOS level; immunofluorescence to detect vWF, claudin-5, occludin in brain tissue; CCK8 to detect cell viability; transmission electron microscopy to observe mitochondrial morphology; Expression of mitochondrial division and apoptosis-related proteins and mRNAs detected by WB and RTqPCR; immunohistochemistry to detect the expression of NR4A1 and Caspase9, ROS content was detected by flow cytometry; mitochondrial membrane permeability colorimetric assay kit was used to observe the degree of mitochondrial mPTP opening; and endothelial cell permeability was measured by FITC-dextran; Meanwhile, public database data analysis, chromatin immunoprecipitation and luciferase gene reporter techniques were used to analyze and validate the NR4A1-Mff binding relationship, and molecular docking techniques and molecular dynamics simulations were used to validate the docking activity of NR4A1 with THSWD active ingredients.
    RESULTS: In the model group, vascular endothelial damage, mitochondrial structure impairment, increased opening of mPTP, elevated ROS levels, and upregulated NR4A1, Mff, and Drp1 expression at both the mRNA and protein levels, as well as increased apoptosis-related protein expression. After THSWD administration, vascular endothelial damage was improved. Mitochondrial damage was alleviated, degree of mPTP opening was reduced, ROS content was decreased, and NR4A1, Mff, and Drp1 expression at both the mRNA and protein levels was downregulated, along with a reduction in the expression of apoptosis-related proteins. NR4A1 was able to bind specifically to the R2 region of the Mff gene promoter. In microvascular endothelial cells with high expression of NR4A1, the transcriptional activity of the promoter region of the Mff gene was significantly enhanced, whereas THSWD-containing serum inhibited the activation of the Mff gene promoter region by NR4A1. Quercetin and kaempferol had a strong binding capacity to NR4A1, and the complexes remained stable during molecular dynamics simulations.
    CONCLUSION: During cerebral IRI, NR4A1 promotes excessive mitochondrial fission in vascular ECs, leading to apoptosis. THSWD can protect vascular ECs by inhibiting NR4A1, reducing excessive mitochondrial fission, and suppressing cell apoptosis.
    Keywords:  Apoptosis; Cerebral Ischemia-Reperfusion; Mitochondrial Fission; Taohong Siwu Decoction
    DOI:  https://doi.org/10.1016/j.jep.2025.120285
  40. Eur J Pharm Sci. 2025 Jul 11. pii: S0928-0987(25)00201-5. [Epub ahead of print]212 107202
    Resveratrol restores insulin signaling and balances mitochondrial biogenesis and autophagy in streptozotocin-induced neurodegeneration in vitro.
    Kamilla Varga, Noémi Sikur, Alexandra Paszternák, Anna-Lena Friesenhahn, Florian Emanuel Zymela, Fruzsina Bagaméry, Tamás Tábi, Stefan Wölfl.
      Resveratrol, a natural phytoalexin, has been suggested to have beneficial effects in age-related diseases, including Alzheimer's disease. Studies indicate that it may delay memory decline and exert neuroprotective properties in vitro and in vivo. However, the precise mechanisms underlying these effects remain unclear, and the impact of resveratrol on central insulin resistance-a key feature of neurodegenerative disorders-remains insufficiently explored. Given the potential therapeutic significance of targeting insulin sensitivity in neurodegeneration, further investigation into the role of resveratrol in modulating these pathways is warranted. Our aim was to investigate the effects of resveratrol on insulin signaling and mitochondrial function in a previously established streptozotocin-induced in vitro neurodegeneration model. The phosphorylation status of key insulin signaling proteins and regulators of insulin resistance and autophagy markers were analyzed via Western blot and an ELISA-based microarray technique. The effects of resveratrol on mitochondrial biogenesis were evaluated through Mitotracker staining and quantification of mitochondrial mRNA and protein expression. Resveratrol augmented the cytoprotective effect of insulin in a concentration-dependent manner. It reduced the Ser(312) phosphorylation of IRS1, which is commonly linked to insulin resistance, and lowered the IC50 value for Tyr(895) phosphorylation required for activation. Similar insulin-sensitizing effects were observed in downstream signaling components. Resveratrol treatment exerted a caloric restriction mimetic activity through activating the AMPK/PGC1α/SIRT1 pathway and upregulated the expression of mitochondrial transcription factor TFAM and ATP synthase subunit (ATP5B). Despite the activation of mitochondrial biogenesis, the number of mitochondria was not altered, because it simultaneously induced autophagy marked by ULK1 phoshorylation and LC3 lipidation. Our findings indicate that resveratrol can enhance insulin signaling, even at the initial step of IRS1 phosphorylation. Its insulin-sensitizing effects extend beyond metabolic regulation to include survival responses. Resveratrol as a caloric restriction mimetic exerted a balanced effect on mitochondrial biogenesis and autophagy therefore improving mitochondrial quality control.
    Keywords:  Alzheimer’s disease; Autophagy; Caloric restriction mimetic; Insulin resistance; Mitochondrial biogenesis; Resveratrol
    DOI:  https://doi.org/10.1016/j.ejps.2025.107202
  41. Mater Today Bio. 2025 Aug;33 102009
    A biomimetic multimodal nanoplatform combining neutrophil-coated two-dimensional metalloporphyrinic framework nanosheet and exendin-4 to treat obesity-related osteoporosis.
    Qifan Yang, Jing Liu, Yanwei Liu, Shun Liu, Xiaokang Wei, Yilin Yang, Weijie Zhang, Shuqi Zhang, Maosheng Zhang, Bin Liu, Xinyu Wang, Dong Zhu.
       Background: Obesity-induced osteoporosis is a prevalent complication among obese individuals. Conventional anti-osteoporosis medications often lack therapeutic specificity and may exacerbate lipid metabolism disorders. Consequently, identifying suitable pharmacological interventions for obesity-induced osteoporosis, elucidating its underlying biological mechanisms, and developing nanodrug delivery systems with enhanced biocompatibility and targeted delivery remain significant challenges.
    Methods: This study reveals that the pathogenesis of obesity-induced osteoporosis is primarily driven by excessive mitophagy. Notably, Exendin-4 (Ex-4) has been shown to ameliorate mitophagy and mitigate obesity-induced osteoporosis. The nanocomposite DSPE-PEG-ALN (DPA)@Neutrophil membrane (NM)@Cu-TCPP(Zn)/Ex-4 (CTZE), characterized by high biocompatibility and reactive oxygen species (ROS) responsiveness, effectively targets bone tissue, reduces ROS levels, and regulates the release of Cu2+, Zn2+, Ex-4, and Alendronate (ALN). This composite interferes with B-cell lymphoma-2 (BCL2)- Beclin-1 (BECN1) binding via the tet methylcytosine dioxygenase 2 (TET2)/PTEN-induced putative kinase protein 1 (PINK1)/Parkin (E3 ubiquitin-protein ligase parkin) pathway, thereby promoting osteoblast differentiation and mineralization. The safety and efficacy of this nano-delivery platform were validated in a mouse model of obesity-induced osteoporosis.
    Conclusions: In summary, our study illustrates that excessive mitophagy plays a crucial role in obesity-induced osteoporosis. Furthermore, DPA@NM@CTZE exhibits significant potential for the precise treatment of obesity-induced osteoporosis, mitigating the side effects of Ex-4, and enhancing the bone microenvironment.
    Keywords:  Alendronate; Cu-TCPP(Zn); Exendin- 4; Mitophagy; Obesity-induced osteoporosis
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102009
  42. Am J Physiol Endocrinol Metab. 2025 Jul 12.
    Modulation of peripheral energy metabolism through central leucine administration in rainbow trout (Oncorhynchus mykiss).
    Sara Comesaña, Gabriel Pérez-Tierra, Jessica Calo, Cristina Velasco, Marta Conde-Sieira, José L Soengas.
      We aimed to evaluate the role of central leucine administration in the modulation of peripheral energy metabolism in fish. For this, rainbow trout (Oncorhynchus mykiss) were administered via intracerebroventricular 1 μL·100 g-1 body mass of saline solution alone (Control) or containing 10 μg·μL-1 of leucine. Samples of plasma, liver, adipose tissue, white muscle and red muscle were collected 1- and 3-hours post-injection. Firstly, metabolite levels were assessed in plasma and liver and a decrease in liver triglyceride at 1 h and an increase in plasma fatty acid at 3 h were observed. Metabolites levels were also assessed in white muscle, revealing decreased levels of α-amino acids and glycogen at 1h. Additionally, liver enzymatic activity and mRNA levels related to glucose, fatty acid, and amino acid metabolism showed no relevant changes. Then, energy metabolism in adipose tissue and muscle was assessed by examining the mRNA abundance of genes related to metabolism and oxidative capacity, thermogenesis, mitochondrial dynamics (mitochondrial fusion and fission), and other metabolic regulatory factors. Mitochondrial fusion were significantly influenced at 1 h post-injection in white muscle (upregulation of mfn1, mfn2, tfam and opa1), and to lesser extent in red muscle (upregulation of tfam). These findings differ from studies in mammals with leucine and in fish with other nutrients, in which liver metabolism is modulated. This also highlights the importance of leucine and its relationship with muscle and mitochondrial dynamics in controlling energy homeostasis in fish.
    Keywords:  adipose tissue; energy homeostasis; liver metabolism; mitochondrial fusion; muscle
    DOI:  https://doi.org/10.1152/ajpendo.00066.2025
  43. Free Radic Biol Med. 2025 Jul 14. pii: S0891-5849(25)00823-8. [Epub ahead of print]238 640-652
    Gut microbiota derived butyrate enhances ferroptosis sensitivity in endometriosis through FFAR2/PPAR-γ/PINK1/Parkin mediated mitophagy.
    Yanling Gou, Jin Ding, Honglin Wang, Ruru Bai, Hongli Wang, Beidi Wang, Yingying Cao, Jinming Liu, Jing Cui, Zongfeng Zhang.
      Endometriosis (EMs) is a chronic, estrogen-dependent disease defined by the presence of endometrial-like tissue outside the uterine cavity. Gut microbiota has emerged as potent inducer for chronic inflammatory disease, yet whether its mechanism in EMs remains elusive. In vivo EMs models were established using both microbiota-depleted (MD) and control mice to explore the role of gut microbiota in EMs. Stool samples were also collected from human patients with either endometriosis or benign ovarian cysts for 16S rRNA sequencing. CCK8, transmission electron microscopy, liperfluo, FerroOrange, MDA, GSH, JC-1, mitotracker, lysotracker, and mitoSOX assays were used to access the function of butyrate in endometriotic stromal cells (ESCs). Furthermore, westen blot was used to detect the signaling pathway involved in the process of butyrate. Results showed that depleting the gut microbiota in MD mice led to a significant increase in the volume and weight of endometriotic lesions. 16S rRNA sequencing revealed that patients with EMs had lower abundances of butyrate-producing microbiota compared to the control group. Butyrate supplementation in MD mice significantly reduced the growth of lesions. Mechanistically, butyrate was found to enhance the sensitivity of cells to erastin-induced ferroptosis. This effect was dependent on impaired mitophagy pathway. Further investigation showed that butyrate enhances ferroptosis sensitivity by impairing mitophagy through the FFAR2/PPAR-γ/PINK1/Parkin signaling pathway. The findings suggest that a deficiency in butyrate-producing gut microbiota contributes to the progression of endometriosis. Butyrate appears to counteract this by enhancing ferroptosis in ESCs via the FFAR2-mediated impairment of mitophagy. Therefore, butyrate shows potential as a therapeutic agent for the treatment of endometriosis.
    Keywords:  Butyrate; Endometriosis; Ferroptosis; Gut microbiota; Mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.019
  44. Acta Pharm Sin B. 2025 Jun;15(6): 3125-3148
    The crucial function of IDO1 in pulmonary fibrosis: From the perspective of mitochondrial fusion in lung fibroblasts and targeted molecular inhibition.
    Lei Wang, Shanchun Ge, Ye Zhang, Deqin Feng, Ting Zhu, Louqian Zhang, Chaofeng Zhang.
      The pathogenesis of pulmonary fibrosis (PF) is complex. It is characterized by myofibroblast hyperplasia and deposition of collagen protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is expressed in lung fibroblasts and epithelial cells, but its functions in lung homeostasis and diseases remain elusive. Here, we characterize the critical role of IDO1 in PF patients and bleomycin (BLM)-induced PF mouse models. We find that IDO1 is significantly upregulated in the fibrotic lungs of patients and mice, showing a positive correlation with genes characteristic of fibrosis. Functionally, IDO1 knockout inhibits lung fibroblast proliferation, differentiation, mitochondrial biogenesis, and mitochondrial oxidative phosphorylation. Conversely, IDO1 overexpression and accumulation of kynurenine (Kyn) exacerbate progressive lung fibrosis. Mechanistically, IDO1-deletion activated profound mitochondrial fusion-enhanced potentially the capacity for fatty acid oxidation, along with activation of de novo glycolytic serine/glycine synthesis pathways and mitochondrial one-carbon metabolism. Wedelolactone (WEL), a small molecule IKK inhibitor, is found to strongly bind to IDO1 and effectively protect mice from PF in an IDO1-dependent manner. Collectively, this study characterizes a promotor role for IDO1 in PF and suggests a potential avenue of targeting IDO1 to treat lung diseases.
    Keywords:  Indoleamine 2,3-dioxygenase 1; Lipid metabolism; Lung fibroblasts; Mitochondrial dynamics; Pulmonary fibrosis; Targets; Transcriptomics; Wedelolactone
    DOI:  https://doi.org/10.1016/j.apsb.2025.04.027
  45. MedComm (2020). 2025 Jul;6(7): e70277
    Casein Kinase 2α Ablation Confers Protection Against Metabolic Dysfunction-Associated Steatotic Liver Disease: Role of FUN14 Domain Containing 1-Dependent Regulation of Mitophagy and Ferroptosis.
    Ke He, Meixiao Zhan, Xuanming Luo, Ruibing Li, Ling Lin, Jie Lin, Liheng Li, Hongdong Chen, Gary D Lopaschuk, Hao Zhou, Fei Liu, Jun Ren.
      Mitochondrial dyshomeostasis provokes the onset of metabolic dysfunction-associated steatotic liver disease (MASLD) although its precise involvement in particular mitophagy in MASLD remains elusive. This work evaluated the role of casein kinase 2α (CK2α) and FUNDC1 in high-fat diet (HFD)-evoked MASLD. WT and CK2α deletion (CK2α -/- ) mice were subjected to low fat or HFD for 20 weeks. Global metabolism, AST, ALT, cholesterol, triglycerides, hepatic steatosis, fibrosis, inflammation, mitochondrial injury, mitophagy and ferroptosis were examined. Bioinformatics analysis enriched mitochondria-related pathways in MASLD. Hepatic CK2α and FUNDC1 were upregulated and downregulated, respectively, in MASLD patients and HFD-fed mice. HFD led to adiposity, hepatomegaly, hepatic steatosis, fibrosis, inflammation, ferroptosis, mitochondrial injury, elevated hepatic tissue Fe2+, FAS, CHREBP, SREBP1, PGC1α, PPARα, PPARγ, SCD1, PEPCK, G6Pase, and DGAT1 as well as downregulated FUNDC1, GPx4, SLC7A11 and NCOA4, the effects (except for NCOA4) were nullified by CK2α deletion. FUNDC1 deletion nullified CK2α deletion-evoked benefit on hepatic ferroptosis and lipid enzymes. In vitro study using palmitic acid indicated an obligatory role for CK2α, FUNDC1 and ferroptosis in hepatocyte steatosis. Collectively, our results demonstrated that CK2α activation by HFD serves as a trigger for mitochondrial damage, hepatic injury, and pathogenesis of MASLD through FUNDC1 disruption and ferroptosis.
    Keywords:  FUN14 domain containing 1; MASLD; casein kinase 2α; ferroptosis; steatosis
    DOI:  https://doi.org/10.1002/mco2.70277
  46. J Agric Food Chem. 2025 Jul 18.
    Identification of Critical Gut Metabolites Mediating the Protective Effects of Lacticaseibacillus paracasei on Myocardial Injury in Mice.
    Xiaolin Wu, Jing Yang, Jiayang Liao, Zsolt Zalán, Jianquan Kan, Huayi Suo, Yu Zhang, Jiajia Song.
      Heart failure is a leading cause of mortality worldwide, with myocardial injury as a major pathological contributor. Probiotics have shown cardioprotective effects, but their key gut metabolites remain unclear. In this study, Lacticaseibacillus paracasei DACN528, isolated from traditional fermented yak yogurt, significantly improved body weight (13.95% increase) and heart index (18.73% increase) and reduced serum cTnI and NT-proBNP levels by 54.96 and 22.05%, respectively, in a doxorubicin-induced mouse model of myocardial injury (all p < 0.05). Electrocardiographic abnormalities were attenuated, including reductions in QT interval (29.13%), PR interval (7.98%), and ST segment elevation (28.74%). Histological analyses revealed reduced myocardial fibrosis and apoptosis, with regulation of fibrosis- and apoptosis-related genes. DACN528 also modulated mitochondrial dynamics and autophagy by altering expression of Fis1, Drp1, Mfn2, and Parkin. Moreover, it reshaped gut microbiota composition by increasing beneficial taxa such as Lactobacillus and norank_f__Muribaculaceae while decreasing harmful ones such as Allobaculum. Metabolomic and correlation analyses identified seven microbial metabolites potentially involved in cardioprotection. Among them, 5-hydroxymethylfurfural showed protective effects in H9C2 cardiomyocytes. These findings provide mechanistic insights into probiotic-mediated myocardial protection and support DACN528 as a promising candidate for cardiovascular health interventions.
    Keywords:  Lacticaseibacillus paracasei; gut microbiota metabolites; mitochondrial homeostasis; myocardial injury
    DOI:  https://doi.org/10.1021/acs.jafc.5c08360
  47. bioRxiv. 2025 Jun 26. pii: 2025.06.23.660251. [Epub ahead of print]
    Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
    Prerona Bora, Mashiat Zaman, Samantha Oviedo, Sergei Kutseikin, Nicole Madrazo, Prakhyat Mathur, Meera Pannikkat, Sophia Krasny, Alan Chu, Kristen A Johnson, Danielle A Grotjahn, Timothy E Shutt, R Luke Wiseman.
      Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). These mutations disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR) - the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2 -deficient cells. These results demonstrate the potential for pharmacologic HRI activation as a viable strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.
    DOI:  https://doi.org/10.1101/2025.06.23.660251
  48. Eur J Pharmacol. 2025 Jul 09. pii: S0014-2999(25)00685-5. [Epub ahead of print]1003 177931
    Wnt5a-AS knockdown alleviates sevoflurane-induced depression by promoting hippocampal neurogenesis and mitochondrial fusion in adolescent rats.
    Guo-Lin Lu, Yi-Qing Zou, Min-Yi Lin, Hua-Lin Chen, Nan-Nan Shu, Li-Qun Chen, Tuan-Fang Fang.
       BACKGROUND: Early-life exposure to sevoflurane induces depressive-like behaviors and cognitive deficits in adolescent rodents (ELSDs) in adolescent rodents. Although hippocampal neurogenesis in the subgranular zone (SGZ) has been implicated in mental disorders, the role of Wnt5a-AS in onset of ELSDs remains unclear. We investigated whether Wnt5a-AS knockdown restores neurogenesis and mitochondrial dynamics to ameliorate ELSDs.
    METHODS: After exposure to sevoflurane or control gas early in life, adolescent rats were subjected to open field test, sucrose preference test, forced swim test, and Morris water maze test. Wnt5a-AS was knocked down with rAAV. Hippocampal neurogenesis was assessed by immunofluorescence. The levels of mitochondrial dynamics-associated proteins were assessed by western blotting. Mitochondrial reactive oxygen species (mtROS) levels were measured by flow cytometry, and mitochondria were labeled with Tom20.
    RESULTS: Rats that were exposed to sevoflurane in life exhibited depressive-like behaviors and a decline in cognition. Sevoflurane increased Wnt5a-AS expression, inhibited neurogenesis, and elevated mtROS production in the SGZ. In addition, sevoflurane increased the expression of Mitofusin1/2, Optic Atrophy 1, Drp1p-Ser637 and Drp1Ser616 but not Dynamin-related protein-1(Drp1). In the SGZ, Wnt5a-AS knockdown ameliorated ELSDs, promoted neurogenesis and mitochondrial fusion, decreased mtROS levels, and increased Drp1p-Ser637 and Drp1Ser616 levels.
    CONCLUSION: Collectively, these findings indicate that Wnt5a-AS knockdown alleviates ELSDs by restoring neurogenesis in the hippocampal SGZ by increasing mitochondrial fusion. These findings establish Wnt5a-AS as a potential therapeutic target for mitigating ELSDs-associated neurodevelopmental deficits in rodents, warranting further validation in higher species.
    Keywords:  Depressive-like behaviors; Early-life exposure; Mitochondria; Sevoflurane; Wnt5a-AS
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177931
  49. J Adv Res. 2025 Jul 15. pii: S2090-1232(25)00539-9. [Epub ahead of print]
    Organelle regulation of SUMOylation: regulatory mechanisms and therapeutic application.
    Menglin Gao, Xin Zhong, Kaisong Zhang, Huachao Jia, Saifei Zhu, Yuqiang Wu, Mingyan Liu, Minjie Wei.
       BACKGROUND: SUMOylation is a pivotal post-translational modification (PTM) that has been extensively investigated in nuclear processes. However, its role in regulating suborganelle homeostasis warrants further exploration. Recent studies have highlighted the significance of SUMOylation in modulating mitochondrial dynamics and endoplasmic reticulum stress (ERS), among other cellular processes, thereby offering novel insights into disease pathogenesis.
    AIM OF REVIEW: This review aims to systematically elucidate the roles and mechanisms of SUMOylation in regulating the homeostasis of various organelles. Furthermore, it integrates emerging evidence concerning the regulation of multi-organelle functions via SUMOylation and its associated PTM network. Additionally, it proposes noval therapeutic strategies targeting the SUMOylation pathway for diseases linked to these processes.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: SUMOylation plays a pivotal role in regulating fundamental cellular processes, including mitochondrial function, ER protein folding, intracellular vesicle transport and degradation, ribosome assembly, and lipid droplet formation. By serving as a bridge for inter-organelle signal communication, SUMOylation coordinates cross-organelle stress responses and acts as a central regulatory hub for maintaining organelle homeostasis. Moreover, the intricate network formed by SUMOylation in conjunction with other PTMs, such as ubiquitination and phosphorylation, collaboratively regulates organelle states and functions as a critical molecular switch for controlling cellular protein homeostasis. Currently, targeted intervention strategies focusing on the SUMOylation pathway have emerged as a promising translational medicine research direction for restoring organelle homeostasis and addressing tumors and metabolic diseases, demonstrating broad clinical application potential.
    Keywords:  ERS; Mitochondrial homeostasis; Organelle-specific regulation; PTM; SUMOylation
    DOI:  https://doi.org/10.1016/j.jare.2025.07.014
  50. Cell Signal. 2025 Jul 11. pii: S0898-6568(25)00400-0. [Epub ahead of print]135 111985
    AMPK impairment caused by gelatin disturbs mitochondrial dynamics leading to enhanced phagocytosis of bacteria in PMA-stimulated U937 cells.
    Kaihui Chen, Xiaoli Sun, Yue Feng, Shunuo Jiang, Hayashi Toshihiko, Itoh Kikuji, Mizuno Kazunori, Shunji Hattori, Hitomi Fujisaki, Weiwei Liu, Takashi Ikejima.
      In scenarios like burns or local infections, monocytes migrate from the circulatory system to the injured sites, which are rich in extracellular matrix (ECM) components, collagen and its derivative gelatin, to differentiate into macrophages. The roles of ECM components in the phagocytosis of macrophages raised our interest. We previously found that precoating the culture dishes with gelatin markedly enhances phagocytosis of bacteria in PMA-stimulated human lymphoma U937 cells which have macrophage-like properties. But type I collagen has no such effects. Here we reveal that AMPK pathway is impaired in gelatin-treated U937 cells, and this subsequently induces mitochondrial fission. Mitochondrial fission further leads to mitochondrial dysfunction and leakage of mitochondrial DNA into the cytoplasm, activating the STING pathway which is responsible for the enhanced phagocytosis. Additionally, mitochondrial dysfunction impairs aerobic respiration and this compensatively elevates glycolytic levels, contributing to the enhanced phagocytosis. In summary, our study comprehensively unveils that gelatin promotes bacteria phagocytosis via modulating an AMPK-mitochondrial fission axis, which leads to the STING activation and glycolytic reprogramming. Our findings offer new insights for the influence of gelatin on immune cells.
    Keywords:  AMPK; Gelatin; Glycolysis; Macrophages; Mitochondrial dynamics; Phagocytosis
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111985
  51. Int J Mol Sci. 2025 Jul 03. pii: 6429. [Epub ahead of print]26(13):
    Mitochondrial Fragmentation and Long Noncoding RNA MALAT1 in Diabetic Retinopathy.
    Renu A Kowluru, Jay Kumar.
      Mitochondria are dynamic in nature and depending on the energy demand they fuse and divide. This fusion-fission process is impaired in diabetic retinopathy and the promoter DNA of Mfn2, a fusion gene, is hypermethylated and its expression is downregulated. Long noncoding RNAs (RNAs with >200 nucleotides that do not encode proteins) can regulate gene expression by interacting with DNA, RNA, and proteins. Several LncRNAs are aberrantly expressed in diabetes, and among them, MALAT1 is upregulated in the retina, altering the expression of the genes associated with inflammation. Our aim was to investigate MALAT1's role in mitochondrial dynamics in diabetic retinopathy. Using MALAT1-siRNA-transfected human retinal endothelial cells (HRECs) and human retinal Muller cells (RMCs) incubated in 20 mM D-glucose, Mfn2 expression and activity and its promoter DNA methylation were quantified. Mitochondrial integrity was evaluated by analyzing their fragmentation, ultrastructure, membrane potential, and oxygen consumption rate. Compared to normal glucose, high glucose upregulated MALAT1 expression and downregulated Mfn2 expression and activity in both HRECs and RMCs. MALAT1-siRNA ameliorated the glucose-induced increase in Mfn2 promoter DNA hypermethylation and its activity. MALAT1-siRNA also protected against mitochondrial fragmentation, structural damage, and reductions in the oxygen consumption rate. In conclusion, the upregulation of MALAT1 in diabetes facilitates Mfn2 promoter DNA hypermethylation in retinal vascular and nonvascular cells, leading to its suppression and the accumulation of the fragmented/damaged mitochondria. Thus, the regulation of MALAT1 has the potential to protect mitochondria and provide a possible new target to inhibit/prevent the blinding disease in diabetic patients.
    Keywords:  DNA methylation; MALAT1; diabetic retinopathy; long noncoding RNA; mitochondria
    DOI:  https://doi.org/10.3390/ijms26136429
  52. bioRxiv. 2025 Jun 25. pii: 2025.06.25.661470. [Epub ahead of print]
    DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
    Natasha Kelly, Elliott Collins, Basel Abuaita, Juan J Martinez.
      Pathogenic Spotted Fever Group (SFG) Rickettsia species, including Rickettsia parkeri replicate in endothelial cells, monocytes, and macrophages in vitro and during infections in murine models of disease. We demonstrated that R. parkeri survives and proliferates within phagocytes and avoids intracellular killing within lysosomal compartments. We found that infection of human macrophage-like cells with a related SFG Rickettsia , R. conorii , resulted in a significant increase in mitochondria-associated proteins, suggesting that mitochondrial functions are involved in Rickettsia pathogenesis. Several intracellular bacterial pathogens manipulate host cell mitochondrial networks and stimulate mitochondrial fission mediated by a GTP-binding regulatory protein, DRP1/DMNL1, to promote intracellular replication. Here, we investigated the contribution of DRP1 in the growth of R. parkeri in macrophages. Murine immortalized bone marrow derived macrophages (iBMDMs) and primary human monocyte derived macrophages were infected with R. parkeri and mitochondrial dynamics (fission and network) were assessed by immunofluorescence microscopy. R. parkeri proliferated in macrophages, which coincided with a significant increase in mitochondria content and fission compared to uninfected cells. R. parkeri infection led to increases in host cell ATP production primarily due to mitochondrial respiration and bacteria were often found co-localized with mitochondrial fragments. Importantly, R. parkeri growth was significantly impacted in DRP1 deficient macrophages. These results suggest that the modulation of mitochondria content and dynamics are essential for replication and survival of pathogenic SFG Rickettsia species in macrophages and suggest that the metabolic requirements for obligate intracellular pathogens may differ from other pathogenic Gram-negative intracellular bacteria.
    DOI:  https://doi.org/10.1101/2025.06.25.661470
  53. Tohoku J Exp Med. 2025 Jul 17.
    Drp1-Dependent Mitochondrial Fission is Involved in Adriamycin Resistance in Gastric Cancer Cells: A Perspective from the BATF2/p53/ERK Regulatory Axis.
    Wei Yang, Rong Zeng, Jianlin Song, Ning Ma, Wenchuan Zhu, Tianyan Fu, Tingting Zhang, Fabi Li, Bian Wu.
      
    DOI:  https://doi.org/10.1620/tjem.2025.J091
  54. J Exp Clin Cancer Res. 2025 Jul 14. 44(1): 203
    m5C-modified circRREB1 promotes lung cancer progression by inducing mitophagy.
    Dunyu Cai, Xingcai Chen, Haotian Xu, Qingyun Zhao, Xiaodong Zhou, Jiaxi Wu, Shengyi Yuan, Yihong Gao, Deqing Li, Ruirui Zhang, Wenyi Peng, Gang Li, Aruo Nan.
       BACKGROUND: Lung cancer is the most common malignant tumour and the leading cause of cancer-related death. circular RNAs (circRNAs) have important biological functions and are closely related to tumour development. The 5-methylcytosine (m5C) modification can regulate the molecular fate of RNA molecules and thus influence disease development.
    METHODS: High-throughput RNA sequencing was used to construct the differential expression profiles of circRNAs. The m5C modification of circRREB1 was explored through methylated RNA immunoprecipitation (MeRIP) and crosslinking-immunoprecipitation (CLIP). RNA stability experiments, fluorescence in situ hybridization (FISH), and nuclear-cytoplasmic fractionation experiments were performed to explore the effects of the m5C modification on circRREB1. A system for the silencing and overexpression of circRREB1 was established, and in vitro and in vivo experiments were conducted to study the biological functions of circRREB1. Tagged RNA affinity purification (TRAP), RNA immunoprecipitation (RIP), and coimmunoprecipitation (Co-IP) experiments were conducted to reveal the molecular mechanisms of circRREB1.
    RESULTS: In this study, we found that circRREB1 is highly expressed in lung cancer tissues and cells and that patients with high circRREB1 expression have a poor prognosis. We discovered that circRREB1 undergoes the m5C modification mediated by the methyltransferase NSUN2. This modification facilitates its nuclear export via the m5C reader ALYREF. Functional studies demonstrated that circRREB1 promotes lung cancer progression both in vitro and in vivo. Mechanistically, circRREB1 directly binds to HSPA8 and stabilizes it by inhibiting ubiquitin-dependent degradation, thereby inducing mitophagy through the HSPA8/PINK1/Parkin signalling axis and ultimately promoting the development of lung cancer.
    CONCLUSIONS: This study revealed the presence of m5C modifications on circRREB1 and showed that m5C-modified circRREB1 can induce mitophagy, ultimately promoting lung cancer. These findings provide not only a theoretical basis for further exploration of the mechanisms underlying lung cancer development but also potential targets for lung cancer therapy.
    Keywords:  Lung cancer; Mitophagy; circRREB1; m5C modification
    DOI:  https://doi.org/10.1186/s13046-025-03460-1
  55. bioRxiv. 2025 Jun 11. pii: 2025.06.10.658872. [Epub ahead of print]
    The mitochondrial unfolded protein response and metabolic reprogramming promote PASMC proliferation in response to sphingosine kinase-1/sphingosine-1-phosphate signaling.
    Angelia D Lockett, Aaron Snow, Pontian Adogamhe, Justin Sysol, Manas Yadav, Tendo Mubuuke, Marta T Gomes, Todd Cook, Amanda Fisher, Micheala A Aldred, Roberto F Machado.
      Proliferation and vasoconstriction of the intimal smooth muscle layer of the pulmonary artery are pathogenic characteristics of pulmonary arterial hypertension (PAH). Altered mitochondrial function, i.e. glycolysis, ROS generation and fission, are known potentiators of vascular remodeling. However, most current therapeutic interventions fail to effectively address the proliferation of the pulmonary artery smooth muscle cells (PASMCSs) lining the pulmonary vasculature and highlight the importance of identifying novel pathways to target for intervention. The Sphk1/S1P/S1P2 signaling axis is upregulated in PAH patients and is known to induce PASMC proliferation during hypoxia-mediated pulmonary hypertension (HPH). Interestingly, Sphk1 modulates mitochondrial function in that it regulates dynamics, cell growth and survival and in C. elegans , it induces activation of the unfolded protein response (UPR mt ). We aimed to investigate if the Sphk1/S1P/S1P2 signaling axis promotes vascular remodeling in PAH via activation of the UPR mt . PASMCs isolated from IPAH patients were subjected to RNAseq analysis. The effect of Sphk1 or S1P was interrogated in hPASMC cell lines and the HPH model was used to assess the effect of the UPR mt on PAH pathogenesis. RNAseq analysis revealed that pathways involved in mitochondrial respiration were among the top 20 most significantly regulated pathways. Furthermore, ATF-5, the transcription factor that mediates the UPR mt was significantly upregulated. In hPASMCs, Sphk1/S1P lead to decreased respiration, increased glycolysis, fission, ROS and UPR mt activation. Pharmacological inhibition of the UPR mt mediator, mtHSP70, mitigated the Sphk1 induced increase in hPASMC proliferation. Furthermore, mtHSP70 inhibition was protective in hypoxia-mediated pulmonary hypertension (HPH) as we observed a decrease in right ventricular systolic pressure, right ventricular hypertrophy and vascular remodeling. These data suggest that the UPR mt promotes vascular remodeling in PAH and may present a novel pathway to target for pharmaceutical intervention.
    DOI:  https://doi.org/10.1101/2025.06.10.658872
  56. Am J Transl Res. 2025 ;17(6): 4087-4100
    Cross-regulation between adipose tissue innervation and metaflammation: a potential therapeutic target for obesity.
    Weichang Shi, Huiwen Tan, Chenqian Liao, Zhenmei An.
      Obesity, marked by adipose tissue dysfunction and systemic metaflammation, poses a major global health burden. Emerging evidence underscores a critical interplay between neural regulation and immune-metabolic crosstalk in obesity pathogenesis. This review highlights the dynamic roles of sympathetic and sensory nerves in lipid metabolism, as well as metaflammation involving macrophage polarization, inflammatory cytokine cascades, and mitochondrial dysfunction. In obesity, decreased sympathetic nerve density and impaired adrenergic receptor signaling compromise lipolysis and thermogenesis, while sensory neuropeptides worsen metabolic dysregulation through immune cell interactions. Adipose tissue macrophages adopt pro-inflammatory phenotypes, releasing cytokines that inhibit insulin signaling - forming pathological crown-like structures. Mitochondrial dysfunction, characterized by excessive fission and reduced fusion, disrupts energy homeostasis and increases oxidative stress. Therapeutic approaches targeting neuropeptide signaling, inflammasome activation, and mitochondrial dynamics show promise in restoring metabolic balance. The neuro-immune-metabolic axis thus represents a novel therapeutic frontier for obesity, supporting integrated strategies targeting neural, inflammatory, and mitochondrial pathways.
    Keywords:  Adipose tissue innervation; metaflammation; mitochondrial dynamics; neuro-immune crosstalk; obesity
    DOI:  https://doi.org/10.62347/AIWS5429
  57. J Hazard Mater. 2025 Jul 12. pii: S0304-3894(25)02148-X. [Epub ahead of print]496 139232
    Polystyrene nanoplastics promote muscle cell senescence through microtubule hyper-stabilization-mediated mitophagy dysfunction and cGAS-Sting activation.
    Jie Cui, Xianlin Yue, Yajun Zhang, Bingjie Wang, Angela Mu, Shifeng Ren, Liwei Shao, Shanshan Zhu, Nan Zhang, Yu Lu, Hongjuan Cui, Dong Li, Xiaodong Mu.
      The detrimental effects of polystyrene nanoplastics (NPs) on human skeletal muscle cells and underlying mechanisms remain largely unclear. Here we exposed mice to NPs and observed significant NP uptake and damages in muscles. RNA sequencing result revealed that many cytoskeleton-related factors were markedly altered by NPs. With cultured human muscle cells, we demonstrate that internalized NPs profoundly changed the microtubule network by causing increased tubulin acetylation, enhanced stabilization, and reduced dynamics. These microtubule changes were accompanied by impaired microtubule-organizing center (MTOC) functionality, defective mechanotransduction capacity linked to YAP deactivation, and critically, compromised function as trafficking tracks for intracellular organelles like mitochondria and lysosomes, leading to accumulation of damaged mitochondria and dysfunctional mitophagy at MTOC location. mtDNA leakage from damaged mitochondria then led to cGAS-Sting activation and accelerated cellular senescence. Mechanistically, NP-induced microtubule hyper-stabilization was driven by deactivation of tubulin deacetylases Sirt2 and HDAC6, leading to α-tubulin hyperacetylation. Further, Sirt2 reactivation/overexpression in muscle cells effectively reduced NP-induced α-tubulin acetylation, mitochondrial damage, cGAS-Sting activation and cellular senescence, as well as the level of cytoplasmic NPs. Our findings unveil a novel mechanism by which NPs promote cellular senescence, highlighting microtubule dynamics as a key mediator of NP-induced damage and a promising therapeutic target.
    Keywords:  Cytoskeleton; Innate immune; Mechanical stress; Microplastics; Mitochondrial damage; Nanoplastics
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.139232
  58. Biomed Pharmacother. 2025 Jul 12. pii: S0753-3322(25)00543-8. [Epub ahead of print]189 118349
    Mitochondrial homeostasis: Exploring their impact on skin disease pathogenesis.
    Hajar Ahmad Jamil, Norwahidah Abdul Karim.
      Mitochondria play a vital impact in maintaining the well-being of the skin, by regulating key cellular activities and processes in various skin cell types, including keratinocytes, fibroblasts, and melanocytes. Understanding their activity and dysfunction is essential for comprehending the pathophysiology of skin diseases and establishing viable therapeutic approaches. This review synthesizes current knowledge on the role of mitochondria in skin cells and their impact on disease progression. In keratinocytes, mitochondria support differentiation and skin barrier formation. In fibroblasts, they are essential for collagen synthesis and maintaining redox balance. In melanocytes, mitochondria facilitate melanin synthesis and protect against UV-induced oxidative damage. Mitochondrial dysfunction, characterized by generation of reactive oxygen species (ROS), alterations in mitochondrial DNA (mtDNA), and changes in biogenesis and dynamics, has been linked to skin diseases such as psoriasis, atopic dermatitis, and vitiligo. These dysfunctions disrupt cellular energy metabolism and stress responses, compromising skin structure and function. Mitochondria are therefore integral not only to energy production and oxidative stress regulation but also to the overall biosynthetic and protective functions of the skin. Future research should aim to deepen our understanding of mitochondrial dysfunction in skin cells and explore targeted strategies to restore mitochondrial health in skin diseases.
    Keywords:  Atopic dermatitis; Fibroblasts; Keratinocytes; Melanocytes; Mitochondria; Mitochondrial dysfunction; Psoriasis; Vitiligo
    DOI:  https://doi.org/10.1016/j.biopha.2025.118349
  59. Acta Pharmacol Sin. 2025 Jul 14.
    PHB2 protects against pressure overload-induced myocardial remodeling in mice via stabilizing TOMM40 and regulating mitochondrial morphofunctional homeostasis.
    Dan Li, Jia-Hao Li, Ying-Ying Guo, Ya-Jie Chen, Meng Zhang, Fei-Xue Xu, Wan-Yi Li, Qi-Zhu Tang.
      Myocardial remodeling is critical pathological processes in various cardiovascular diseases, where redox imbalance and mitochondrial bioenergetic perturbations emerge as key determinants. Prohibitin 2 (PHB2), which resides in the mitochondrial inner membrane, serves as a critical regulator of mitochondrial homeostasis. In this study we investigated the protective role of PHB2 in transverse aortic constriction (TAC)-induced cardiac remodeling with a particular focus on its ability to safeguard the heart by improving mitochondrial function and alleviating oxidative stress. We revealed that PHB2 expression was significantly decreased in the heart of TAC mice and in Ang II (1 μM)-treated cardiomyocytes. Cardiac-specific PHB2 overexpression mitigated TAC-induced cardiac remodeling, improving cardiac function and attenuating hypertrophy. Additionally, PHB2 overexpression effectively suppressed oxidative stress in the hearts of TAC mice, while improving mitochondrial morphology and the integrity of inner membrane structure. Furthermore, PHB2 overexpression restored mitochondrial function in Ang II-treated cardiomyocytes evidenced by elevated ATP levels and enhanced oxidative phosphorylation capacity. IP-MS analysis revealed that PHB2 directly interacted with Transporter of Outer Mitochondrial Membrane 40 (TOMM40) to regulate mitochondrial function. Importantly, silencing TOMM40 abolished the protective effects of PHB2. We demonstrated that PHB2 preserves TOMM40 protein levels predominantly through inhibition of ubiquitin-dependent proteasomal degradation. Collectively, we discover a new function of PHB2 in safeguarding mitochondrial morphofunctional homeostasis in response to pathological stress through facilitating TOMM40 stabilization, suggesting PHB2 as a promising therapeutic target for potential interventions in heart diseases. Schematic illustration of PHB2's potential protective mechanism against cardiac hypertrophy. PHB2 protects against pressure overload-induced cardiac hypertrophy through preserving TOMM40 protein to maintain mitochondrial energetic homeostasis.
    Keywords:  Prohibitin 2; TOMM40; cardiac remodeling; mitochondria; pressure overload
    DOI:  https://doi.org/10.1038/s41401-025-01613-8
  60. Sci Rep. 2025 Jul 11. 15(1): 25069
    Tang Bi formula alleviates diabetic sciatic neuropathy via AMPK/PGC-1α/MFN2 pathway activation.
    Cunqing Yang, Honghai Yu, Linfeng Zhou, Hang Su, Xiangyan Li, Wenxiu Qi, Fengmei Lian.
      Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus, which affects various regions of the nervous system. Tang Bi formula (TBF) has been proven effective for DPN, while the underlying mechanism remains unclarified. This study aimed to clarifiy the neurprotective mechanism of TBF intervention in DPN through animal and cell models. UHPLC/QTOF-MS and network pharmacology analysis were utilized to identify the bioactive components and potential targets of TBF. DPN models were established in rats and Schwann cells to evaluate the therapeutic effects of TBF. In the DPN rats, body weight, fasting blood glucose, mechanical withdrawal threshold (MWT), paw withdrawal latency (PWL), sciatic motor nerve conduction velocity (MNCV), and sciatic nerve blood flow were measured. Pathological sections of the sciatic nerve (SN) were also examined. In vitro experiments, the Schwann cells (SCs) were cultured in a medium containing 30 mM glucose and treated with TBF for 48 h. Cell viability was assessed using the CCK-8 assay. The degree of apoptosis was evaluated by flow cytometry. The mitochondrial membrane potential was determined using JC-1 staining, and the generation of ROS was measured using DCFH-DA staining. Moreover, the expression levels of proteins related to the AMPK-PGC-1α-MFN2 pathway in the SN and SCs were detected. A total of 11 bioactive components of TBF were identified through UHPLC/QTOF-MS and network pharmacology analysis. In vivo experiments, MWT and PWL were decreased in DPN rats, which were restored after TBF administered daily for 12 weeks, TBF significantly attenuated thermal hyperalgesia and mechanical allodynia, and improved nerve conduction velocities. Further histopathological observations indicated that treatment with TBF promoted the regeneration of the myelin sheath of the SN, increased the density of intraepidermal nerve fibers, effectively improved distal microcirculation disorders, and alleviated demyelination and axonal degeneration. In vitro experiments were conducted to evaluate the protective effect of TBF on high-glucose-induced dysfunction of SCs. The data showed that treatment with TBF significantly inhibited the apoptosis of SCs. Meanwhile, TBF exhibited apparent antioxidant capacity, reducing the accumulation of intracellular ROS, and ameliorating mitochondrial dysfunction. Western blot analysis revealed that TBF activated the AMPK-PGC -1α-MFN2 pathway and upregulated the protein expressions of p-AMPK (Thr172), PGC-1α, and MFN2, suggesting that the neuroprotective effect of TBF was associated with the activation of this pathway. TBF ameliorated DPN by rectifying mitochondrial dynamic imbalance and modulating the activation of the AMPK-PGC-1α-MFN2 pathway. This, in turn, promoted neurogenesis and alleviated peripheral nerve lesions. Thus, this study demonstrated the therapeutic potential of TBF for DPN.
    Keywords:  1α; Diabetic peripheral neuropathy, UHPLC/QTOF; MFN2 pathway, Mitochondrial dynamics, Schwann cell; MS, AMPK; PGC
    DOI:  https://doi.org/10.1038/s41598-025-10513-0
  61. Physiol Plant. 2025 Jul-Aug;177(4):177(4): e70404
    (ID-ICPMB05) Running on Empty: Mitochondria Without DNA Exhibit Differential Motility and Connectivity.
    Joanna M Chustecki, Alora Q Schneider, Madeleine H Faber, Bara Altartouri, Alan C Christensen.
      Plant mitochondria are in continuous motion. While providing ATP to other cellular processes, they also constantly consume ATP to move rapidly within the cell. This movement is in part related to taking up, converting and delivering metabolites and energy to and from different parts of the cell. Plant mitochondria have varying amounts of DNA, even within a single cell, from none to the full mitochondrial genome. Because mitochondrial dynamics are altered in an Arabidopsis mutant with disrupted DNA maintenance, we hypothesised that exchanging DNA templates for repair is one of the functions of their movement and interactions. Here, we image mitochondrial DNA by two distinct methods while tracking mitochondrial position to investigate differences in the behaviour of mitochondria with and without DNA in Arabidopsis thaliana. In addition to staining mitochondrial DNA with SYBR Green, we have developed and implemented a fluorescent mitochondrial DNA binding protein that will enable future understanding of mitochondrial dynamics, genome maintenance and replication. We demonstrate that mitochondria without mtDNA have altered physical behaviour and lower immediate connectivity to the rest of the population, further supporting a link between the physical and genetic dynamics of these complex organelles.
    Keywords:  arabidopsis thaliana; fluorescence; mitochondrial DNA; mitochondrial dynamics; nucleoid binding protein
    DOI:  https://doi.org/10.1111/ppl.70404
  62. Physiol Int. 2025 Jul 15.
    The therapeutic effects of genistein in rats with epilepsy by influencing mitochondrial biogenesis and regulating apoptosis in brain tissue.
    Afnan S Almarwani, Shatha Al-Blowi, Maha Z Albalawi, Manahel Ab Alatawi, Sultan M Alanazi, Hanan M Hassan, Mohammed M H Al-Gayyar.
       Purpose: Epilepsy is a widespread, long-term neurological condition triggered by an overabundance of electrical activity from the neurons in the brain. Genistein, a natural isoflavone found in soybeans, can prevent chronic diseases such as cardiovascular disease and osteoporosis. We aimed to investigate the potential protective effects of genistein on epilepsy using rat models through behavior analysis and investigation of key pathways, including antioxidant activity (Nrf2 and HO-1), promoting mitochondrial biogenesis (TFAM), and reducing brain tissue apoptosis (BCL2, BAX, and caspases).
    Main methods: PTZ was used to induce epilepsy in rats, and then they were treated with genistein. The hippocampus sections were stained with Nissl stain, and others were stained with anti-TFAM antibodies. Furthermore, TFAM, Nrf2, HO-1, BCL2, BAX, and caspases-3/8/9 gene expression and protein levels were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and complementary biochemical/functional assays.
    Results: Rats treated with genistein displayed notable progress in their behavior during behavioral tests. Sections stained with Nissl revealed that genistein increased the staining intensity of Nissl granules in the cerebral cortex. Additionally, genistein increased the expression of TFAM, Nrf2, HO-1, and BCL2, which reduced levels of BAX and caspase-3/8/9.
    Conclusions: Genistein safeguards against epilepsy in rats by enhancing their behavior and reinstating normal neuron structure. Its protective benefits may stem from its potential to boost antioxidant activity and promote mitochondrial biogenesis, which in turn decreases cell apoptosis.
    Keywords:  B-cell lymphoma 2 (BCL2); BCL2-associated X (BAX); epilepsy; heme Oxygenase-1 (HO-1); mitochondrial transcription factor A (TFAM); nuclear factor erythroid 2-related factor-2 (Nrf2)
    DOI:  https://doi.org/10.1556/2060.2025.00641
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