bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–07–13
fifty-two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Single-cell transcriptome atlas reveals mitophagy dynamics in acute chemical injury model and the role of MSCs transplantation.
  2. Age and sex-specific changes in mitochondrial quality control in skeletal and cardiac muscle.
  3. FAdV-4 infection induces selective mitochondrial autophagy.
  4. Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.
  5. Critical role of mitochondrial dynamics in chronic respiratory diseases and new therapeutic directions.
  6. VMP1 attenuates ferroptosis and mitochondrial dysfunction in nucleus pulposus cells through the PINK1/Parkin-mediated mitophagy pathway.
  7. A murine model of gestational diabetes reveals MASLD risk and alterations in markers of hepatic mitochondrial metabolism.
  8. Exploration and validation of the prognostic value of mitophagy and mitochondrial dynamics-related genes in cervical cancer.
  9. Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
  10. Bibliometric and visualized analysis of mitophagy in liver cancer from 1998 to 2024.
  11. Patient-derived induced pluripotent stem cell models reveal mechanistic links between aberrant mitochondrial dynamics and cardiomyopathy.
  12. Anthracyclines as diagnostic stressors: mitophagy signaling and hidden cardiac vulnerability.
  13. Enhancing Sirt1-mediated deacetylation of p62 with a self-assembling nanopeptide and resveratrol hydrogel to mitigate sepsis-induced inflammation.
  14. PINK1 Loss of Function Selectively Alters the Mitochondrial-Derived Vesicle Pathway.
  15. Targeting mitophagy in diabetic retinopathy: novel insights into SQSTM1/BNIP3L pathway regulated by luteolin.
  16. Correction to "The P2X7-Mediated Mitochondrial ROS as an Emerging Core Target of Tuftsin Nanoparticles in Severe Acute Pancreatitis Therapy via Regulating Mitophagy".
  17. Modulation of mitochondrial quality control through autophagic pathway in familial Alzheimer's disease.
  18. Promotion of pathological cardiac remodeling by excessive mitochondrial fission in physical inactivity and myocardial infarction.
  19. Modulation of mitochondrial dysfunction: Mechanisms and strategies for the use of natural products to treat stroke.
  20. Long noncoding RNA GCH1 mediates mitophagy via the PTEN-induced kinase 1/Parkin pathway to drive chondrocyte dysfunction and cartilage degeneration in osteoarthritis.
  21. Vps34 knockdown attenuated AlNPs-induced neurodevelopmental toxicity in zebrafish larvae and adults by inhibiting mitophagy.
  22. Reciprocal c-Abl-GPx1 regulation controls CA1 neuronal viability to oxidative stress via ERK1/2-DRP1-mediated mitochondrial dynamics.
  23. Mitochondrial dysfunction and mitophagy as a driver of chronic kidney disease; An area for future exploration in feline chronic kidney disease?
  24. The Role of Estrogen in Mitochondrial Disease.
  25. Targeting Dio3 to enhance mitophagy and ameliorate skeletal muscle wasting in sepsis.
  26. Nrf2-activated mitophagy and ferroptosis suppression synergistically mediate tangeretin's protection against hepatic ischemia-reperfusion injury.
  27. HDAC3-YY1-RAB5A axis remodels AML-supportive niche by modulating mitochondrial homeostasis in bone marrow stromal cells.
  28. Altered endothelial mitochondrial Opa1-related fusion in mouse accelerates age-associated vascular and kidney damage.
  29. Dexmedetomidine preserves neuronal function by promoting mitochondrial biogenesis through the AMPK/PGC-1α pathway.
  30. [Impact of tyrosine phosphorylation site mutation in FUNDC1 protein on mitophagy in H9c2 cardiomyocytes].
  31. Drp1 Proteins Released from Hydrolysis-Driven Scaffold Disassembly Trigger Nucleotide-Dependent Membrane Remodeling to Promote Scission.
  32. Silencing ATF3 mediates mitochondrial homeostasis and improves ischemic stroke through regulating the MAPK signaling pathway.
  33. Crosstalk between mitochondrial quality control and novel programmed cell death in pulmonary diseases.
  34. Regulation of Mitochondrial Metabolism by Mfn1 Gene Encoding Mitofusin Affects Cellular Proliferation and Histone Modification.
  35. Adipose Mesenchymal Stem Cells Derived Exosomes Ameliorates KOA Cartilage Damage and Inflammation by Activation of PINK1-Mediated Mitochondrial Autophagy.
  36. Dynamin-like Proteins Combine Mechano-constriction and Membrane Remodeling to Enable Two-Step Mitochondrial Fission via a "Snap-through" Instability.
  37. PEDV Nsp14 induces mitophagy-mediated degradation of MAVS to antagonize host innate immunity and facilitate viral proliferation.
  38. Targeting ROCK1/YAP1 Axis Ameliorates Inflammation-Induced Prostatic Hyperplasia via Stabilising SIRT1-Dependent Mitochondrial Dynamics.
  39. Hesperidin mitigates copper nanoparticle exposure-induced mitochondrial unfolded protein response through the SIRT3-FOXO3A signaling pathway.
  40. Activation of endogenous PRKN by structural derepression is linked to increased turnover of the E3 ubiquitin ligase.
  41. Extremely low-frequency electromagnetic field (ELF-EMF) enhances mitochondrial energy production in NARP cybrids.
  42. A narrative review on bridging the gap between periodontitis and cardiovascular disease: exploring the cellular and molecular mechanisms of periodontitis-driven atherosclerosis.
  43. Mitochondrial homeostasis restoring peptide-drug conjugates with ROS-responsive NO releasing ability for targeted therapy of myocardial infarction.
  44. Chronic exposure to bisphenol S impairs hepatic mitochondrial dynamics, induces endoplasmic reticulum stress, and worsens metabolism in high-fat diet fed mice.
  45. Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis.
  46. A review of mitochondrial dysfunction in diabetic sarcopenia: Mechanisms, diagnosis, and treatment approaches.
  47. Mitochondrial homeostasis and their impact on gastric carcinoma.
  48. Downregulation of Mfn2 Contributes to Chronic Postsurgical Pain via Inducing the Pyroptosis of GABAergic Neurons in the Spinal Cord.
  49. MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
  50. DPSCs modulate synovial macrophage polarization and efferocytosis via PINK1/Parkin-dependent mitophagy.
  51. Soyasapogenol B prevents sarcopenia by increasing skeletal muscle mass and function through the Sirt1/PGC-1α and PI3K pathway.
  52. USP10 protects against pressure overload-induced mitochondrial morphofunctional defects and pathological cardiac hypertrophy through stabilizing cytoplasmic Mfn2.
  1. Stem Cell Res Ther. 2025 Jul 06. 16(1): 350
    Single-cell transcriptome atlas reveals mitophagy dynamics in acute chemical injury model and the role of MSCs transplantation.
    Sang Luo, Fang Wu, Xiaojun Yang.
       BACKGROUND AND PURPOSE: Mitochondrial autophagy, also referred to as mitophagy, clears damaged mitochondria and has dual functions in disease development and liver homeostasis in response to liver pathologies. Mesenchymal stem/stromal cells (MSCs) are most commonly used to treat liver failure because they are easy to obtain and present no ethical problems. However, the molecular mechanisms by which MSCs promote liver failure progression are not fully understood. This study explored the distinct mitophagy states in hepatocytes and macrophages during MSCs therapy.
    EXPERIMENTAL APPROACH: To investigate tissue-specific mitophagy in acute liver failure (ALF), we generated a single-cell transcriptome (scRNA-seq) atlas of liver tissue from healthy mice, ALF mice and human umbilical cord mesenchymal stem/stromal cell (hUC-MSC)-transplanted mice.
    KEY RESULTS: The data revealed the complex cellular landscape of liver tissue during ALF progression, revealing alterations in metabolic fluxes and mitophagy activation. Through the intersection of single-cell sequencing data with mitophagy-related genes (MRGs), a total of 24 differentially expressed MRGs were identified. Gene Ontology (GO) analysis further revealed that the ubiquitinating enzyme Arih1 was significantly upregulated after MSC transplantation, whereas the mitophagy genes Bnip3L/NIX and Beciln1 were significantly downregulated in mononuclear phagocytes(MPs).
    CONCLUSIONS AND IMPLICATIONS: Our research demonstrated that during the development of ALF, mitophagy within hepatocytes is suppressed, whereas in MPs, mitophagy is excessively activated. MSCs are capable of alleviating disease progression by modulating the distinct mitophagy states of cells, providing an important resource for investigating mitophagy regulation in hepatic homeostasis and disease development.
    Keywords:  Liver failure; Mesenchymal stem/stromal cells; Mitophagy
    DOI:  https://doi.org/10.1186/s13287-025-04491-3
  2. Front Aging. 2025 ;6 1606110
    Age and sex-specific changes in mitochondrial quality control in skeletal and cardiac muscle.
    Catherine B Springer-Sapp, Olayinka Ogbara, Maria Canellas Da Silva, AbryAnna Henderson, Yuan Liu, Steven J Prior, Sarah Kuzmiak-Glancy.
       Introduction: Skeletal and cardiac muscle mitochondria exist in a dynamic reticulum that is maintained by a balance of mitochondrial biogenesis, fusion, fission, and mitophagy. This balance is crucial for adequate ATP production, and alterations in skeletal muscle mitochondria have been implicated in aging-associated declines in mitochondrial function.
    Methods: We sought to determine whether age and biological sex affect mitochondrial content [Complex IV (CIV)], biogenesis (PGC-1ɑ), fusion (MFN2, OPA1), fission (DRP1, FIS1), and mitophagy (Parkin, Pink1) markers in skeletal and cardiac muscle by assessing protein expression in tibialis anterior (TA) and ventricular tissue from 16 young (≤6 months) and 16 old (≥20 months) male and female Sprague-Dawley rats.
    Results: In the TA, CIV expression was 40% lower in old vs. young rats (p < 0.001), indicating lower mitochondrial content, and coincided with higher expression of Parkin (+4-fold, p < 0.001). Further, MFN2 expression was higher (+2-fold, p < 0.005) and DRP1 expression was lower (-40%, p = 0.014) in older rats. In cardiac muscle, mitochondrial content was maintained in old vs. young rats, and this occurred concomitantly with higher expression of both PGC-1ɑ and Parkin. MFN2 and OPA1 expression were also 1.2-5-fold higher in older rats (p < 0.05 for all). Largely, protein expression did not differ between male and female rats, with the exception of Pink1 and FIS1 expression in the TA.
    Discussion: Collectively, older skeletal and cardiac muscle demonstrated higher expression of fusion and mitophagy proteins, which indicates age alters the balance of biogenesis, fission, fusion, and mitophagy. This may, in turn, affect the ability to provide ATP to these metabolically active tissues.
    Keywords:  biological sex; fission; fusion; mitophagy; muscle health
    DOI:  https://doi.org/10.3389/fragi.2025.1606110
  3. Vet Microbiol. 2025 Jul 04. pii: S0378-1135(25)00266-4. [Epub ahead of print]308 110631
    FAdV-4 infection induces selective mitochondrial autophagy.
    Wenjing Dong, Peng Yang, Taiwei Ma, Yuting Liu, Yuehang Xu, Yongzhen Wang, Yunshu Li, Yujuan Niu.
      Fowl adenovirus serotype 4 (FAdV-4) is an infectious pathogen that poses a significant threat to the poultry industry. It is widely disseminated globally and is characterized by high infection and mortality rates. Mitochondria, as multifunctional dual membrane-enclosed eukaryotic organelles, maintain cellular homeostasis through various mechanisms. However, how FAdV-4 infection alters mitochondrial dynamics has not been previously established. In this study, transmission electron microscopy and immunofluorescence techniques were used to confirm that FAdV-4 infection can significantly alter mitochondrial morphology, disrupt mitochondrial fusion-fission homeostasis, and promote changes in the spatial distribution of mitochondria, causing them to gather around the nucleus. This leads to increased contact and interaction with other organelles. Preliminary analyses of the mechanistic basis for FAdV-4-mediated disruption of mitochondrial homeostasis revealed that the virus can induce selective mitophagy via the classical PINK1/Parkin signaling pathway and promote its own replication, which was confirmed by Western blotting. The novel findings regarding the ability of FAdV-4 to regulate mitochondrial morphology and function discussed in this study represent an important step forward, providing a foundation for further efforts to explore the underlying pathogenic mechanisms and to develop adjuvant approaches to preventing or managing FAdV-4 infection.
    Keywords:  FAdV-4; Mitochondrial dynamics; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.vetmic.2025.110631
  4. J Biol Chem. 2025 Jul 08. pii: S0021-9258(25)02314-2. [Epub ahead of print] 110464
    Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.
    Meiheriayi Yasheng, Yanchun Ji, Yunfan He, Qiuzi Yi, Huanhuan Zhang, Wenqi Shan, Kai Wang, Juanjuan Zhang, Ya Li, Feilong Meng, Minglian Zhang, Jun Qin Mo, Shihui Wei, Min-Xin Guan.
      Leber's hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying LHON-linked mtDNA mutations, especially their impact on mitochondrial and cellular integrity, is not well understood. Recently, the ND1 3733G>C (p.E143Q) mutation was identified in three Chinese pedigrees with suggestively maternal inheritance of LHON. In this study, we investigated the pathogenic mechanism of m.3733G>C mutation using cybrids generated by fusing mtDNA-less ρ0 cells with enucleated cells from a Chinese patient carrying the m.3733G>C mutation and control subject. Molecular dynamics simulations showed that p.E143Q mutation destabilized these interactions between residues E143 and S110/Y114, or between S141 and W290 in the ND1. Its impact of ND1 structure and function was further evidenced by reduced levels of ND1 in mutant cells. The m.3733G>C mutation caused defective assembly and activity of complex I, respiratory deficiency, diminished mitochondrial ATP production, and increased production of mitochondrial ROS in the mutant cybrids carrying the m.3733G>C mutation. These mitochondrial dysfunctions regulated mitochondrial quality control via mitochondrial dynamics and mitophagy. The m.3733G>C mutation-induced dysfunction yielded elevating mitochondrial localization of DRP1, decreasing network connectivity and increasing fission with abnormal morphologies. Furthermore, the m.3733G>C mutation downregulated ubiquitin-dependent mitophagy pathway, evidenced by decreasing the levels of Parkin and Pink, but not ubiquitin-independent mitophagy pathway. The m.3733G>C mutation-induced deficiencies reshaped the cellular homeostasis via impairing autophagy process and promoting intrinsic apoptosis. Our findings provide new insights into pathophysiology of LHON arising from the m.3733G>C mutation-induced mitochondrial dysfunctions and reprograming organellular and cellular homeostasis.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110464
  5. Chin Med J (Engl). 2025 Jul 10.
    Critical role of mitochondrial dynamics in chronic respiratory diseases and new therapeutic directions.
    Xiaomei Wang, Ziming Zhu, Haocheng Jia, Xueyi Lu, Yingze Zhang, Yingxin Zhu, Jinzheng Wang, Yanfang Wang, Rubin Tan, Jinxiang Yuan.
       ABSTRACT: Chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) are both chronic progressive respiratory diseases that cannot be completely cured. COPD is characterized by irreversible airflow limitation, chronic airway inflammation, and gradual decline in lung function, whereas PH is characterized by pulmonary vasoconstriction, remodeling, and infiltration of inflammatory cells. These diseases have similar pathological features, such as vascular hyperplasia, arteriolar contraction, and inflammatory infiltration. Despite these well-documented observations, the exact mechanisms underlying the occurrence and development of COPD and PH remain unclear. Evidence that mitochondrial dynamics imbalance is one major factor in the development of COPD and PH. Mitochondrial dynamics is precisely regulated by mitochondrial fusion proteins and fission proteins. When mitochondrial dynamics equilibrium is disrupted, it causes mitochondrial and even cell morphological dysfunction. Mitochondrial dynamics participates in various pathological processes for heart and lung disease. Mitochondrial dynamics may be different in the early and late stages of COPD and PH. In the early stages of the disease, mitochondrial fusion increases, inhibiting fission, and thereby compensatorily increasing adenosine triphosphate (ATP) production. With the development of the disease, mitochondria decompensation, causes excessive fission. Mitochondrial dynamics is involved in the development of COPD and PH in a spatiotemporal manner. Based on this understanding, treatment strategies for mitochondrial dynamics abnormalities may be different at different stages of COPD and PH disease development. This article will provide new ideas for the potential treatment of related diseases.
    Keywords:  Chronic obstructive pulmonary disease; Chronic respiratory system diseases; Mitochondrial dynamics; New therapeutic directions; Pulmonary hypertension
    DOI:  https://doi.org/10.1097/CM9.0000000000003704
  6. J Orthop Surg Res. 2025 Jul 08. 20(1): 630
    VMP1 attenuates ferroptosis and mitochondrial dysfunction in nucleus pulposus cells through the PINK1/Parkin-mediated mitophagy pathway.
    Yang Zhang, Yucheng Gao, Shuanggong Liu, Guowei Yang, Yijun Rong, Dongjin Wu, Zengxin Gao.
       BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifactorial disorder and a leading contributor to chronic low back pain (LBP), highlighting the need for novel therapeutic strategies. Recent studies indicate that ferroptosis, driven by oxidative stress, plays a key role in the loss of nucleus pulposus cells (NPCs) during IVDD. Vacuole membrane protein 1 (VMP1), a membrane-associated regulator of autophagy, is known to influence various cellular processes. However, its role in IVDD remains unclear. This study investigates the function of VMP1 in IVDD and the mechanisms involved.
    METHODS: We established a rat model of IVDD to investigate the correlation between VMP1 expression and ferroptosis during IVDD progression. In vitro, a ferroptosis model of NPCs was induced using tert-butyl hydroperoxide (TBHP) to examine the effects of VMP1 knockdown on NPC apoptosis, extracellular matrix (ECM) degradation, ferroptosis, PINK1/Parkin-dependent mitophagy, and mitochondrial function. Furthermore, cyclosporin A (CsA), a mitophagy inhibitor, was employed to explore the role and potential mechanisms of VMP1 overexpression in regulating PINK1/Parkin-mediated mitophagy, mitochondrial function, and ferroptosis.
    RESULTS: In this study, we observed a significant downregulation of VMP1 expression in a rat model of IVDD, which was accompanied by the occurrence of ferroptosis. Subsequent experiments revealed that VMP1 knockdown aggravated apoptosis and ECM degradation in NPCs. Furthermore, we demonstrated that VMP1 silencing promoted ferroptosis, inhibited PINK1/Parkin-dependent mitophagy, and impaired mitochondrial function in NPCs. In contrast, VMP1 overexpression enhanced PINK1/Parkin-mediated mitophagy, mitigated mitochondrial dysfunction, and suppressed ferroptosis. Notably, these protective effects were abolished by treatment with CsA.
    CONCLUSIONS: This study demonstrates that VMP1 alleviates IVDD by inhibiting ferroptosis and mitochondrial dysfunction in NPCs, a protective effect mediated through the promotion of PINK1/Parkin-dependent mitophagy. Our study underscores the pivotal role of VMP1 in coordinating mitophagy and ferroptosis during IVDD pathogenesis, identifying VMP1 as a potential therapeutic target for IVDD treatment.
    Keywords:  Ferroptosis; IVDD; Mitochondrial dysfunction; Mitophagy; VMP1
    DOI:  https://doi.org/10.1186/s13018-025-06033-2
  7. Front Endocrinol (Lausanne). 2025 ;16 1498764
    A murine model of gestational diabetes reveals MASLD risk and alterations in markers of hepatic mitochondrial metabolism.
    Grace E Shryack, Alexa A Krause, Simone Hernandez Ruano, Laura C Schulz, Kathleen A Pennington, R Scott Rector.
       Introduction: Gestational Diabetes Mellitus (GDM) impacts roughly 1 in 7 pregnancies and results in metabolic dysfunction-associated steatotic liver disease (MASLD) in 30% of these women. Nonetheless, there exists a dearth of investigation into the relationship between GDM and MASLD. Here, we sought to investigate the potential role of hepatic mitochondrial function in GDM and MASLD.
    Methods: One week prior to conception and throughout pregnancy, mice were fed either a low-fat control diet (CD) or a high-fat, high-sucrose (HFHS) diet to induce an established model of GDM. Maternal livers were collected at day 0, 6.5, 13.5 and 17.5 of pregnancy. Hepatic markers (via mRNA and western blot analyses) of mitochondrial biogenesis, autophagy, mitophagy, activity, and function were assessed, as well as markers of inflammation and antioxidant status were evaluated.
    Results: Progressing gestation in both CD and GDM dams significantly decreased protein and mRNA markers of hepatic mitochondrial biogenesis (Pgc1-α, Tfam), autophagy (Atg5, Sqstm1), mitophagy (Pink1, Bnip3) and lipid handling (Ampk, pAMPK/AMPK, FAS, ACC, pACC, Mttp) with a main effect for time (P<0.05). HFHS-induced model of GDM lead to significant elevations in liver triglycerides and NAFLD Activity Score (NAS) (P<0.0001, P<0.0001) independent of body weight gain during gestation. MASLD development in the GDM mice occurred in conjunction with significant reductions in hepatic mitochondrial activity at day 6.5 (citrate synthase, p<0.01) and day 17.5 (β-HAD, citrate synthase, P<0.001) compared to CD mice. However, GDM lead to elevated protein and/or mRNA markers of mitochondrial biogenesis (Tfam), mitophagy (BNIP3, Bnip3, Sqstm1, Pink1), lipid handling (Mttp), inflammation (Il-1β, Tnf-α, Tgf-β) and antioxidant defense (Gxp1, Nfe2l2, Sod2) (P<0.05).
    Discussion: Pregnancy, independent of diet, decreased markers of liver mitochondrial biogenesis, autophagy, and mitophagy in dams. The GDM mouse model exhibited elevated hepatic TG and NAS, as well as decreased liver mitochondrial activity. These findings demonstrate that pregnancy and GDM significantly impact maternal liver mitochondrial metabolism and unveil new insight on the potential relationship between MASLD and GDM.
    Keywords:  GDM; MASLD; NAFLD; liver; mitochondria
    DOI:  https://doi.org/10.3389/fendo.2025.1498764
  8. Sci Rep. 2025 Jul 10. 15(1): 24950
    Exploration and validation of the prognostic value of mitophagy and mitochondrial dynamics-related genes in cervical cancer.
    Jiankui Li, Xi Chen, Juan Li.
      The mechanisms underlying mitophagy and mitochondrial dynamics (MD) in cervical cancer (CC), a disease with a high mortality rate, remain poorly understood. This study aimed to assess the prognostic significance of these processes in CC. Mendelian randomization (MR) and 101 machine learning models were employed to identify mitophagy- and MD-associated prognostic genes in CC. A subsequent risk model was developed to stratify patients by risk. Further analyses included functional pathway enrichment, immune infiltration, and single-cell RNA sequencing (scRNA-seq) analysis. The results identified PLOD3, SBK1, and SLC39A10 as prognostic genes for CC. Among these, PLOD3 and SLC39A10 were associated with poor prognosis, while SBK1 was protective. The risk model demonstrated high accuracy, with area under the curve (AUC) values exceeding 0.6. Following this, a prognostic nomogram was constructed incorporating risk score and pathological T stage, achieving high predictive accuracy. Gene Set Enrichment Analysis (GSEA) revealed significant enrichment in pathways such as ECM receptor interaction and olfactory transduction in high-risk groups. Additionally, SBK1 showed the strongest correlation with neutrophil infiltration. Expression pattern alterations of prognostic genes were observed in endothelial cells, T cells, and epithelial cells. In conclusion, a risk model based on mitophagy- and MD-related prognostic genes was established, offering a promising approach for the personalized management of patients with CC.
    Keywords:  Cervical cancer; Machine learning; Mendelian randomization; Mitochondrial dynamics; Mitophagy; Prognostic genes
    DOI:  https://doi.org/10.1038/s41598-025-09310-6
  9. Neurobiol Dis. 2025 Jul 04. pii: S0969-9961(25)00235-9. [Epub ahead of print]213 107019
    Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
    Li Zhang, Alireza Pouya, Janina Kopetzky, Sara Bitar, Christina Wolf, Federica Dal Bello, David Gomez-Zepeda, Stefan Tenzer, Axel Methner.
      Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to GDAP1 knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) - proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural Gdap1 knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of Gdap1 knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by GDAP1 loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.
    Keywords:  BNIP3; Charcot-Marie-tooth (CMT) disease; Drosophila; GDAP1; Mitophagy
    DOI:  https://doi.org/10.1016/j.nbd.2025.107019
  10. Discov Oncol. 2025 Jul 06. 16(1): 1267
    Bibliometric and visualized analysis of mitophagy in liver cancer from 1998 to 2024.
    Shanshan Gong, Yuchang Fei.
       BACKGROUND: Mitophagy is crucial for maintaining mitochondrial homeostasis and the internal environment of the liver. It plays a dual role in the emergence and progression of liver cancer by removing damaged mitochondria and supplying energy. Additionally, mitophagy can influence the effectiveness of liver cancer treatments through various signaling pathways.
    AIM: This study aims to summarize the research status, hot spots, frontiers, and development trends of mitophagy in liver cancer based on bibliometrics and visual analysis.
    METHODS: Publications on mitophagy in liver cancer were searched in the Web of Science Core Collection (WoSCC) database as of December 11, 2024. Vosviewer, Co-Occurrence software, CiteSpace, and SCImago Graphica were utilized for bibliometric and visualized analysis.
    RESULTS: We collected 703 publications from WoSCC. Over the past 27 years, the number of publications on mitophagy in liver cancer has shown a consistent upward trend. China leads in the number of publications and total citations. Notable institutions contributing significantly to this field include Zhejiang University, the Chinese Academy of Sciences, and Sun Yat-sen University. Key journals for publishing research on mitophagy in liver cancer are the International Journal of Molecular Sciences, Frontiers in Oncology, and Autophagy. Major contributors to this area of study include Wang Bin and Li Yan. In recent years, the mechanisms associated with mitophagy and liver cancer have remained a hot spot, including ferroptosis, aerobic glycolysis, transcription factor EB, mitochondrial dysfunction, and oxidative stress. In addition, combining sorafenib with melatonin may present a promising therapeutic option for advanced liver cancer.
    CONCLUSION: This is the first comprehensive and in-depth bibliometric study of trends and developments of mitophagy in liver cancer. It provides researchers with panoramic knowledge of this field, as well as research hotspots and future directions.
    Keywords:  Bibliometrics; Liver cancer; Mitophagy; Visualization
    DOI:  https://doi.org/10.1007/s12672-025-03098-7
  11. Pediatr Res. 2025 Jul 09.
    Patient-derived induced pluripotent stem cell models reveal mechanistic links between aberrant mitochondrial dynamics and cardiomyopathy.
    Chrishan J Ramachandra.
       IMPACT: DNM1L mutations impair mitochondrial fission, leading to cardiomyocyte energy deficits and contractile dysfunction, and reveal a cardiac role for DNM1L beyond neurological disease. iPSC-cardiomyocytes derived from patients with DNM1L mutations demonstrate mitochondrial defects and cardiomyopathy phenotypes, offering a robust model to dissect disease mechanisms and identify personalised therapies. Disrupted mitochondrial dynamics directly lead to calcium mishandling and contractile dysfunction, positioning fission/fusion pathways as promising therapeutic targets in cardiomyopathy treatment.
    DOI:  https://doi.org/10.1038/s41390-025-04278-5
  12. Pharmacol Rep. 2025 Jul 11.
    Anthracyclines as diagnostic stressors: mitophagy signaling and hidden cardiac vulnerability.
    Natalia Kulicka, Artur Dziewierz.
      Anthracyclines are cornerstone agents in oncology, yet their cardiotoxic effects may do more than inflict damage-they may uncover latent cardiac vulnerabilities. This mini-review examines anthracycline-induced mitochondrial stress as a potential diagnostic stressor that exposes subclinical impairments in cardiomyocyte energetics and quality control. We focus on receptor-mediated mitophagy, particularly the TRDMT1-BNIP3 epitranscriptomic axis, which enables organelle clearance independently of membrane depolarization, and the canonical PINK1-Parkin pathway, highlighting their distinct and sometimes context-dependent roles. Unlike the canonical PINK1-Parkin pathway, which is typically activated by mitochondrial depolarization, the TRDMT1-BNIP3 axis may better reflect early adaptive responses to specific cellular stresses. We summarize emerging evidence from iPSC-derived cardiomyocytes, animal models, and molecular imaging studies, suggesting that mitochondrial dysfunction precedes overt systolic decline. We propose that doxorubicin-induced effects on mitophagy pathways may serve as a functional indicator of mitochondrial reserve, providing a basis for risk stratification and targeted cardioprotection. Reframing cardiotoxicity as a measurable biological signal-not only as injury-could improve early detection of heart failure susceptibility by revealing these hidden vulnerabilities. These insights are hypothesis-generating and require further clinical validation before implementation in diagnostic frameworks.
    Keywords:  Anthracyclines; BNIP3; Cardiotoxicity; Energetic unmasking; Mitochondrial dysfunction; Mitophagy; Risk stratification; TRDMT1
    DOI:  https://doi.org/10.1007/s43440-025-00760-3
  13. Phytomedicine. 2025 Jul 02. pii: S0944-7113(25)00686-5. [Epub ahead of print]145 157047
    Enhancing Sirt1-mediated deacetylation of p62 with a self-assembling nanopeptide and resveratrol hydrogel to mitigate sepsis-induced inflammation.
    Baoquan Wang, Ying Wang, Zhansheng Hu, Shuang Peng, Na Li, Zhang Dan, Haiyan Fu, Huiping Wu.
       BACKGROUND: Sepsis-induced inflammatory damage remains a significant clinical challenge with limited effective treatments. Elucidating the molecular mechanisms that regulate macrophage function may reveal key therapeutic targets to combat sepsis.
    PURPOSE: This study aimed to investigate the role of Sirtuin 1 (Sirt1) in regulating mitochondrial autophagy and immunometabolic remodeling in macrophages to alleviate inflammation associated with septic shock.
    STUDY DESIGN: A controlled laboratory study was conducted using a murine sepsis model to elucidate the contribution of Sirt1 to macrophage function during sepsis-induced inflammation, employing both in vivo and in vitro approaches.
    METHODS: Sepsis was induced in mice via cecal ligation and puncture (CLP). Peritoneal macrophages (PMs) from sham-operated and septic mice were analyzed using single-cell RNA sequencing (scRNA-seq). Differential gene expression, immunostaining, transmission electron microscopy (TEM), and metabolomics were performed to evaluate the roles of Sirt1 and Sqstm1 (p62) in modulating macrophage autophagy and inflammation.
    RESULTS: Sirt1 expression was markedly reduced in PMs from septic mice. Sirt1-mediated deacetylation of p62 activated mitochondrial autophagy, suppressed lipopolysaccharide (LPS)-induced pro-inflammatory responses, and decreased mitochondrial reactive oxygen species (mtROS) production. Treatment with a self-assembling nanopeptide and resveratrol (Res) composite hydrogel improved survival rates and reduced tissue damage in septic mice. Integrated single-cell transcriptomics and metabolomics analyses demonstrated that Sirt1 modulated macrophage mitophagy and immunometabolic reprogramming, providing new insights into the molecular mechanisms of sepsis.
    CONCLUSION: The self-assembling nanopeptide and Res hydrogel enhances Sirt1-mediated deacetylation of p62, promoting mitochondrial autophagy and immunometabolic remodeling, thereby mitigating sepsis-induced inflammation. This strategy represents a promising therapeutic approach for reducing inflammation-related damage in sepsis.
    Keywords:  Deacetylation; Resveratrol; Self-assembling nanopeptide; Sepsis; Sirtuin 1
    DOI:  https://doi.org/10.1016/j.phymed.2025.157047
  14. FASEB Bioadv. 2025 Jul;7(7): e70030
    PINK1 Loss of Function Selectively Alters the Mitochondrial-Derived Vesicle Pathway.
    Charlotte L Collier, Colleen Ruedi, Naomi J Thorne, David A Tumbarello.
      Cell homeostasis and metabolic control require the efficient function of mitochondria and implementation of quality control pathways following damage. Cells have various discrete pathways of mitochondrial quality control (mitoQC) to maintain the healthy network. PINK1 and Parkin are two key players in mitoQC, most highly associated with the ubiquitin-dependent capture and degradation of whole mitochondria by autophagy. However, these proteins have alternative roles in repair routes directing locally damaged cargo to the lysosome, such as the mitochondrial-derived vesicle (MDV) pathway. We aimed to clarify the role of PINK1 and determine how its loss of function impacts mitochondrial dynamics and quality control. Results indicate PINK1 knockout (KO) has little impact on whole mitochondrial turnover in response to damage in SH-SY5Y cells, whereas both PINK1 and Parkin KO cells have healthy mitochondrial networks with efficient ATP production. However, TOM20 positive outer-membrane and damage-induced PDH-positive inner-membrane MDVs are elevated in PINK1 KO cells. Although, in contrast to Parkin KO, this is not due to a defect in trafficking to a LAMP1-positive compartment and may instead indicate increased damage-induced flux. In comparison, loss of Atg5-dependent mitophagy has no effect on whole mitochondrial turnover and only results in a limited elevation in inner-membrane MDVs in response to damage, indicating autophagy-independent mechanisms of whole mitochondrial turnover and a minor compensatory increase in damage-induced MDVs. Therefore, these data suggest PINK1 and Parkin are dispensable for whole mitochondrial turnover, but following their perturbation have disparate effects on the MDV pathway.
    Keywords:  Parkinson's; lysosome; membrane trafficking; mitochondria; mitochondrial quality control; vesicle transport
    DOI:  https://doi.org/10.1096/fba.2024-00200
  15. Front Pharmacol. 2025 ;16 1593213
    Targeting mitophagy in diabetic retinopathy: novel insights into SQSTM1/BNIP3L pathway regulated by luteolin.
    Shuyan Zhang, Jiajun Wu, Yinjian Zhang.
       Objective: Diabetic retinopathy (DR) is a leading microvascular complication of diabetes. Luteolin, a flavonoid with known anti-inflammatory and antioxidant properties, has demonstrated therapeutic potential in early investigations for the treatment of DR. However, its precise molecular mechanisms remain inadequately defined. This study aimed to explore the local and systemic immunological mechanisms underlying luteolin's therapeutic effects on DR.
    Methods: Key regulatory genes and cell subpopulations were identified from single-cell RNA sequencing (scRNA-Seq) datasets derived from peripheral blood mononuclear cells (PBMCs) and retinal tissues of DR patients. The molecular interactions were analyzed using molecular docking simulations. Reactive oxygen species (ROS) were quantified through DCFDA assays, while retinal structural damage was assessed using Hematoxylin and eosin (H&E) and Periodic Acid-Schiff (PAS) staining. Comprehensive analyses, including enzyme-linked immunosorbent assays (ELISA), immunofluorescence, immunohistochemistry, and Western blotting were conducted to evaluate cytokine levels and protein expression.
    Results: The study revealed that luteolin exerted protective effects against DR primarily by activating mitophagy and reducing oxidative stress, with the SQSTM1/BNIP3L pathway emerging as a critical mediator. Furthermore, a novel mechanistic link was established between monocyte activity and DR progression, highlighting the VISFATIN signaling pathway's role in immune cell regulation and its contribution to disease pathology.
    Conclusion: This study offers novel insights into the luteolin's therapeutic potential in DR, particularly activating mitophagy through the SQSTM1/BNIP3L axis, which expands the scope of natural compounds in addressing this sight-threatening complication of diabetes.
    Keywords:  Bnip3L; Sqstm1; diabetic retinopathy; luteolin; monocytes
    DOI:  https://doi.org/10.3389/fphar.2025.1593213
  16. ACS Appl Mater Interfaces. 2025 Jul 06.
    Correction to "The P2X7-Mediated Mitochondrial ROS as an Emerging Core Target of Tuftsin Nanoparticles in Severe Acute Pancreatitis Therapy via Regulating Mitophagy".
    E Wen, Yu Tian, Mingxiao Fang, Yuezhou Zhang, Hongyun Zhao, Zhigang Wang, Liang Zhang, Xingsheng Li.
      
    DOI:  https://doi.org/10.1021/acsami.5c11986
  17. Biochim Biophys Acta Mol Cell Res. 2025 Jul 07. pii: S0167-4889(25)00124-7. [Epub ahead of print] 120019
    Modulation of mitochondrial quality control through autophagic pathway in familial Alzheimer's disease.
    Adriana Limone, Clelia Di Napoli, Giusy De Rosa, Silvia Bagnoli, Antonella Izzo, Claudio Procaccini, Giuseppe Matarese, Benedetta Nacmias, Antonio Lavecchia, Daniela Sarnataro.
      Autophagy is a highly conserved cellular catabolic process recognized as an essential pathway for the maintenance of cellular homeostasis. Growing evidence implicates autophagic dysfunction in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), thus its modulation might represent an interesting therapeutic tool. Searching for a compound that stimulates autophagic pathway, led us to identify the inhibitor of RPSA receptor, NSC47924. In this study, we show that, NSC47924 down-modulated Akt-mTOR-axis pathway, the master regulator of autophagy, which was abnormally hyperactivated in fibroblasts from genetic AD-affected patients. Consistently, by monitoring the conversion of LC3, we found that inhibition of RPSA enhanced and restored the compromised autophagic flux. Moreover, by qRT-PCR analysis we found that inhibitor treatment upregulated the expression of autophagy-linked genes. Importantly, AD-affected fibroblasts exhibited massive mitochondrial network fragmentation and mitophagy defects, which were restored through the stimulation of autophagy induced by RPSA inhibition. Consistent with an efficient elimination of dysfunctional mitochondria, we found that the turnover of both the mitophagy regulators PINK1 and Parkin and the autophagic receptors p62, NDP52, OPTN, was modulated, thus restoring a highly interconnected organelle's network. In addition, the improvement of mitochondrial morphology correlated with a functional recovery, as assessed by Seahorse analysis and mitochondrial ROS production evaluation. Collectively, our findings suggest that RPSA inhibition stimulates an autophagic pathway promoting the efficient removal of damaged mitochondria, favouring the recovery of cellular homeostasis, and counteracting crucial AD pathogenic mechanisms.
    Keywords:  37/67 kDa non-integrin laminin receptor; APP V717I mutant; Alzheimer's disease; Autophagy; Mitophagy; PS1 M146L mutant; RPSA
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120019
  18. Sci Rep. 2025 Jul 08. 15(1): 24486
    Promotion of pathological cardiac remodeling by excessive mitochondrial fission in physical inactivity and myocardial infarction.
    Masashi Miyao, Hikaru Oshima, Chihiro Kawai, Shota Furukawa, Hirokazu Kotani, Hirozo Minami, Hitoshi Abiru, Hideki Nagai, Hiromu Yanagisawa, Koh Ono, Keiji Tamaki, Yoko Nishitani.
      Physical inactivity and sedentary lifestyle, including prolonged sitting, are among the most important modifiable risk factors for morbidity and mortality in myocardial infarction (MI). Recently, mitochondrial dynamics (fusion and fission) have gained considerable attention as imbalanced dynamics may play central roles in various organ injuries, including MI. This study aimed to elucidate whether imbalanced mitochondrial dynamics of cardiomyocytes are involved in physical inactivity and MI using mouse models. An MI model created by permanent coronary artery ligation showed a decreased survival rate, and the hearts of mice developed cardiac necrosis in the apex, cardiomyocyte hypertrophy, reduced ejection fraction, inflammation, and fibrosis. Ultrastructural analysis revealed increased mitochondrial fission, abnormal cardiac remodeling such as sarcomere disruption, and increased mRNA expression of cardiac injury and mitochondrial fission markers. Compared to the simple MI model, the combined physical inactivity model created by narrow cage breeding and the MI model showed a further decrease in survival rate, cardiac hypertrophy, increased mitochondrial fission in cardiomyocytes, and myofibroblast activation with cardiac fibrosis. These findings suggest that mitochondrial fission could be involved in physical inactivity and MI via abnormal crosstalk between cardiomyocytes and fibroblasts. Our study highlights the importance of developing novel mitochondrial-dynamics-rebalancing treatments in patients with MI.
    Keywords:  Coronary artery disease; Metabolic syndrome; Mitochondrial dynamics; Mitochondrial dysfunction; Sedentary lifestyle
    DOI:  https://doi.org/10.1038/s41598-025-10373-8
  19. Neural Regen Res. 2025 Jul 05.
    Modulation of mitochondrial dysfunction: Mechanisms and strategies for the use of natural products to treat stroke.
    Na Qin, Rujuan Liu, Rong Deng, Liuliu Shi, Lei Wang, Ting Zhu.
      Modulations of mitochondrial dysfunction, which involve a series of dynamic processes such as mitochondrial biogenesis, mitochondrial fusion and fission, mitochondrial transport, mitochondrial autophagy, mitochondrial apoptosis, and oxidative stress, play an important role in the onset and progression of stroke. With a better understanding of the critical role of mitochondrial dysfunction modulations in post-stroke neurological injury, these modulations have emerged as a potential target for stroke prevention and treatment. Additionally, since effective treatments for stroke are extremely limited and natural products currently offer some outstanding advantages, we focused on the findings and mechanisms of action related to the use of natural products for targeting mitochondrial dysfunction in the treatment of stroke. Natural products achieve neuroprotective through multi-target regulation of mitochondrial dysfunction encompassing the following processes: (1) Mitochondrial biogenesis: Cordyceps and hydroxysafflor yellow A activate the peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor pathway, promote mitochondrial DNA replication and respiratory chain protein synthesis, and thereby restore energy supply in the ischemic penumbra. (2) Mitochondrial dynamics balance: Ginsenoside Rb3 promotes Opa1-mediated neural stem cell migration and diffusion for recovery of damaged brain tissue. (3) Mitochondrial autophagy: Gypenoside XVII selectively eliminates damaged mitochondria via the phosphatase and tensin homolog-induced kinase 1/Parkin pathway and blocks reactive oxygen species and the NOD-like receptor protein 3 inflammasome cascade, thereby alleviating blood-brain barrier damage. (4) Anti-apoptotic mechanisms: Ginkgolide K inhibits Bax mitochondrial translocation and downregulates caspase-3/9 activity, reducing neuronal programmed death induced by ischemia-reperfusion. (5) Oxidative stress regulation: Scutellarin exerts antioxidant properties and improves neurological function by modulating the extracellular signal-regulated kinase 5-Kruppel-like factor 2-endothelial nitric oxide synthase signaling pathway. (6) Intercellular mitochondrial transport: Neuroprotective effects of Chrysophanol are associated with accelerated mitochondrial transfer from astrocytes to neurons. Existing studies have confirmed that natural products exhibit neuroprotective effects through multidimensional interventions targeting mitochondrial dysfunction in both ischemic and hemorrhagic stroke models. However, their clinical translation still faces challenges, such as the difficulty in standardization due to component complexity, insufficient cross-regional clinical data, and the lack of long-term safety evaluations. Future research should aim to integrate new technologies, such as single-cell sequencing and organoid models, to deeply explore the mitochondria-targeting mechanisms of natural products and validate their efficacy through multicenter clinical trials, providing theoretical support and translational pathways for the development of novel anti-stroke drugs.
    Keywords:  apoptosis; autophagy; hemorrhagic stroke; ischemic stroke; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction modulations; mitochondrial transport; natural products; oxidative stress
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00016
  20. Animal Model Exp Med. 2025 Jul 09.
    Long noncoding RNA GCH1 mediates mitophagy via the PTEN-induced kinase 1/Parkin pathway to drive chondrocyte dysfunction and cartilage degeneration in osteoarthritis.
    Gang Zeng, Yujun Sun, Taihe Liu, Wenzhou Liu, Yanbo Chen, Jionglin Wu, Jiayuan Zheng, Weidong Song, Yue Ding.
       BACKGROUND: Osteoarthritis (OA) is a common degenerative joint disease characterized by the progressive degradation of articular cartilage. Mitochondrial dysfunction and autophagy, including mitophagy, have been implicated in OA pathogenesis. Long noncoding RNAs (lncRNA) are emerging as key regulators in various cellular processes, but their roles in OA, particularly in chondrocytes, remain poorly understood. This study explores the involvement of lncRNA-GCH1 in regulating mitophagy and its impact on chondrocyte function and cartilage degradation in OA.
    METHODS: Primary chondrocytes were isolated from the cartilage tissues of OA patients and healthy controls. lncRNA-GCH1 expression was assessed using RNA-seq, reverse transcription quantitative polymerase chain reaction, and RNA fluorescence in situ hybridization. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and Western blotting, were used to evaluate the effects of lncRNA-GCH1 knockdown on chondrocyte proliferation, apoptosis, cell cycle, and mitophagy. Mitochondrial function was assessed by measuring adenosine triphosphate production, reactive oxygen species levels, and mitochondrial membrane potential. In vivo, a murine OA model was used to examine the impact of lncRNA-GCH1 knockdown on cartilage degradation.
    RESULTS: lncRNA-GCH1 was upregulated in OA chondrocytes and localized in the cytoplasm. Knockdown of lncRNA-GCH1 enhanced cell proliferation and arrested cell cycle in G0/G1. It also suppressed mitophagy, improved mitochondrial function, and reduced matrix-degrading enzyme expression-effects that were reversed by rapamycin treatment. Meanwhile, lncRNA-GCH1 knockdown reduced PTEN-induced kinase 1 (PINK1) aggregation and in vivo local inhibition of PINK1 diminished cartilage degradation.
    CONCLUSION: lncRNA-GCH1 regulates mitophagy in OA chondrocytes, influencing mitochondrial function and matrix degradation. Targeting lncRNA-GCH1 may offer a potential therapeutic approach for OA treatment.
    Keywords:  PTEN‐induced kinase 1 (PINK1)‐Parkin axis; lncRNA‐GCH1; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.1002/ame2.70057
  21. Aquat Toxicol. 2025 Jul 01. pii: S0166-445X(25)00243-7. [Epub ahead of print]286 107479
    Vps34 knockdown attenuated AlNPs-induced neurodevelopmental toxicity in zebrafish larvae and adults by inhibiting mitophagy.
    Ying Zhang, Jinjin Zhao, Tao Huang, Xiaocheng Gao, Lan Zhang, Yanhong Wang, Xinyue Guo, Ling Zhang, Qiao Niu, Qinli Zhang.
      Nano-alumina (AlNPs) are susceptible to inducing neurotoxicity, mainly through excessive autophagy/mitophagy. Vacuolar protein sorting 34 (Vps34) is a target for modulating autophagy. This study aimed to investigate whether Vps34 knockdown could reduce AlNPs' neurodevelopmental toxicity. Zebrafish embryos were exposed to 100 mg/L of 13 nm AlNPs and 2.5 mmol/L of 3-methyladenine (3MA) until 144 h post-fertilization (hpf) to assess their development, neurobehavior, oxidative stress, and the expression of autophagy-related gene. Vps34 was knocked down using 500 µL of morpholino oligonucleotide (MO) at 1 mM. Additionally, embryos were treated with control, negative control, Vps34 knockdown, AlNPs (100 mg/L), and AlNPs + Vps34 knockdown. Evaluations included developmental parameters, locomotor activity, oxidative stress, autophagy/mitophagy gene expression, and neuronal cell counts at 144 hpf. Long-term effects were assessed up to 90 dpf, including locomotor activity, mitophagy-related genes expression, and ultrastructural analysis. The findings showed that 3MA effectively counteracted AlNPs-induced developmental stunting at 24 hpf, neurobehavioral impairments, oxidative damage, and upregulation of autophagy-related Beclin1, Vps34, and LC3II genes in larvae. AlNPs significantly elevated Vps34 gene expression in zebrafish. Additionally, Vps34 knockdown alleviated AlNPs-induced developmental retardation at 24 hpf, locomotor deficits, oxidative damage, neuronal loss, and abnormal expression of autophagy/mitophagy-related genes and P62 protein levels. Vps34 knockdown ameliorated AlNPs' early developmental retardation and neurobehavioral deficits in zebrafish larvae and adults by reducing mitophagy. These findings suggest that Vps34 could be a promising therapeutic target for attenuating the neurotoxic effects of AlNPs.
    Keywords:  Autophagy; Danio rerio; Mitophagy; Nano-alumina; Neurodevelopment toxicity; Vps34
    DOI:  https://doi.org/10.1016/j.aquatox.2025.107479
  22. Neuropharmacology. 2025 Jul 05. pii: S0028-3908(25)00292-8. [Epub ahead of print]278 110586
    Reciprocal c-Abl-GPx1 regulation controls CA1 neuronal viability to oxidative stress via ERK1/2-DRP1-mediated mitochondrial dynamics.
    Ji-Eun Kim, Su Hyeon Wang, Tae-Cheon Kang.
      Abelson murine leukemia viral oncogene homolog 1 (c-Abl, also known as ABL1) is a potent selenium-independent regulator of expression and activity of glutathione peroxidase-1 (GPx1) and extracellular signal-regulated kinase 1/2 (ERK1/2). Since GPx1-ERK1/2 pathway modulates dynamin-related protein 1 (DRP1) serine (S) 616 phosphorylation, we investigated whether c-Abl participates in GPx1-ERK1/2 interaction and DRP1-mediated mitochondrial dynamics in CA1 neurons in response to oxidative stress induced by L-buthionine sulfoximine (BSO, an oxidative stress inducer) and status epilepticus (SE). In the present study, BSO enhanced c-Abl tyrosine (Y) 245 phosphorylation, ERK1/2 activity and GPx1 upregulation in the CA1 region under physiological condition. Imatinib (a c-Abl inhibitor) ameliorated BSO-induced c-Abl Y245, but elicited further ERK1/2 phosphorylation without affecting GPx1 expression. GPx1 knockdown enhanced BSO-induced c-Abl Y245 phosphorylation, but decreased ERK1/2 activity. BSO also facilitated mitochondrial fission in CA1 neurons by augmenting DRP1 expression and its S616 phosphorylation in the CA1 region, which were diminished by GPx1 knockdown and U0126 (an ERK1/2 inhibitor), but reinforced by imatinib. SE increased c-Abl Y245 phosphorylation and mitochondrial length in CA1 neurons, accompanied by reduced GPx1 expression and ERK1/2 phosphorylation. Imatinib and N-acetylcysteine (NAC, an antioxidant) attenuated these post-SE events and CA1 neuronal death. However, GPx1 knockdown deteriorated SE-induced CA1 neuronal degeneration accompanied by augmenting c-Abl Y245 phosphorylation and mitochondrial elongation in CA1 neurons. These findings indicate that the impaired reciprocal regulation between c-Abl and GPx1 may cause CA1 neuronal degeneration in response to oxidative stress by abrogating ERK1/2-DRP1-mediated mitochondrial fission.
    Keywords:  BSO; CREB; Epilepsy; Imatinib; NAC; Seizure; U0126; WY14643
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110586
  23. Vet J. 2025 Jul 03. pii: S1090-0233(25)00102-9. [Epub ahead of print]313 106398
    Mitochondrial dysfunction and mitophagy as a driver of chronic kidney disease; An area for future exploration in feline chronic kidney disease?
    Michael Frill, Claire Thornton, Jonathan Elliott, Elisavet Vasilopoulou, Rosanne Jepson.
      Feline chronic kidney disease (CKD) is a leading cause of mortality in older cats and though understanding of the underlying pathophysiology of this heterogenous disease is improving, many details remain elusive. Dysregulation of mitophagy, a normal cellular process whereby dysfunctional mitochondria are cleared from the cell, may contribute to ongoing inflammation, fibrosis, and ultimately worsening kidney function. Whilst advancement in the study of model species and humans have revealed differential patterns of mitophagy in the kidney in different disease states, knowledge about mitophagy in feline CKD remains unexplored. This review summarises the current knowledge based around the contribution that dysregulated mitochondrial function and mitophagy make to oxidative stress, inflammation and fibrosis in CKD, considers their potential involvement in feline CKD and how this knowledge could be used to identify potential therapeutic targets for the future.
    Keywords:  Chronic kidney disease; Feline; Mitochondria; Mitophagy; Therapeutics
    DOI:  https://doi.org/10.1016/j.tvjl.2025.106398
  24. Cell Mol Neurobiol. 2025 Jul 11. 45(1): 68
    The Role of Estrogen in Mitochondrial Disease.
    Xi Huang, Cun-Hui Pan, Fei Yin, Jing Peng, Li Yang.
      This review aims to investigate the potential role of estrogen in various mitochondrial diseases, such as Leber's Hereditary Optic Neuropathy and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes, focusing on its effects on aging, oxidative stress, mitochondrial biogenesis, and mitophagy. Mitochondrial diseases have become important in modern medical research due to their complex genetic background and diverse clinical manifestations. Studies in recent years have shown that estrogen plays an essential role in physiological regulation and may also affect the health status of cells by regulating mitochondrial function, which in turn affects the occurrence and development of diseases. However, there is still a lack of systematic review of estrogen's specific mechanisms and roles in these diseases. This review will synthesize the relevant literature to explore the association between estrogen and mitochondrial diseases and its possible therapeutic prospects, aiming to provide a theoretical basis and reference for future research.
    Keywords:  Aging; Estrogen; Mitochondrial biogenesis; Mitochondrial disease; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s10571-025-01592-8
  25. Redox Biol. 2025 Jul 03. pii: S2213-2317(25)00264-2. [Epub ahead of print]85 103751
    Targeting Dio3 to enhance mitophagy and ameliorate skeletal muscle wasting in sepsis.
    Gang Wang, Ming Chen, Yuheng Zhang, Dacheng Wang, Tao Gao, Jianfeng Duan, Huimin Lu, Minhua Cheng, Yun Xu, Xiaoyao Li, Yan Wang, Ke Cao, Wenkui Yu.
      Recent studies highlight the role of skeletal muscle wasting in the sepsis-associated long-term mortality. Despite clinical recommendations for increased protein intake to counteract muscle wasting, the outcomes have been suboptimal, suggesting that anabolic resistance should be considered in addition to nutritional support. Emerging evidence suggests that impaired mitophagy hampers anabolic processes in skeletal muscle, exacerbating muscle wasting in sepsis. Furthermore, thyroid hormone (TH), which is essential for both anabolism and mitophagy, is locally inactivated by type 3 Deiodinase (Dio3) at the onset of sepsis, potentially disrupting mitophagy and contributing to anabolic resistance. Here we demonstrate that local hypothyroidism is a key factor impairing mitophagy in skeletal muscle during early sepsis, leading to metabolic disturbances and muscle wasting. Dio3 knockdown preserves muscle mass, and ameliorates metabolic dysfunction via mitophagy promotion in sepsis models. Mechanistically, the knockdown of Dio3 triggers an upregulation of NRK2, facilitating the restoration of NAD salvage synthesis. This enhancement of NAD levels subsequently activates Sirtuins deacetylase, which in turn decreases PINK1 acetylation, preventing its proteolytic processing by OMA1. Therefore, targeting Dio3 offers a promising therapeutic approach to counteract sepsis-induced muscle wasting.
    DOI:  https://doi.org/10.1016/j.redox.2025.103751
  26. Phytomedicine. 2025 Jul 01. pii: S0944-7113(25)00673-7. [Epub ahead of print]145 157034
    Nrf2-activated mitophagy and ferroptosis suppression synergistically mediate tangeretin's protection against hepatic ischemia-reperfusion injury.
    Deng Liu, Ruixin Zhang, Lixia Zha, Lei Yao, Youwen Han, Xiaolu Zhang, Yujia Chen, Mengting Zhan, Jian Du, Lijian Chen.
       BACKGROUND: Liver ischemia-reperfusion (I/R) injury frequently arises during liver surgery and significantly contributes to postoperative liver failure and graft dysfunction. Tangeretin (TAN), a polymethoxy flavone present in citrus peel, has demonstrated notable antioxidant and anti-inflammatory effects. Despite this, its effects and mechanisms underlying liver I/R injury remain unclear.
    PURPOSE: This study aimed to investigate the potential effects and underlying mechanisms of TAN in mitigating liver I/R injury.
    METHODS: We utilized in vivo liver I/R models in mice, as well as in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models in primary hepatocytes, and to assess the role of TAN against liver I/R injury.
    RESULTS: This study elucidated the protective mechanisms of TAN against hepatic I/R and OGD/R injury in primary hepatocytes. RNA-seq analysis indicated that TAN enhanced mitochondria-related biological functions, specifically mitophagy and ferroptosis. Our findings showed that TAN reduced mitochondrial membrane potential (ΔΨm) loss and superoxide levels. Furthermore, TAN activated mitophagy and lowered ferrous ion (Fe2+) and lipid peroxide (LPO) levels in hepatocytes. Remarkably, TAN-induced mitophagy reduced the accumulation of Fe2+ and LPO within the mitochondria, thereby synergistically inhibiting ferroptosis. Mechanistically, molecular docking and dynamic simulation studies indicated a strong binding affinity between TAN and the Nrf2/Keap1 complex, facilitating Nrf2 nuclear translocation, which subsequently activated mitophagy and suppressed hepatocytes ferroptosis. Consistent with our results, liver-specific Nrf2 knockdown abolished the mitophagy-activating and anti-ferroptosis effects of TAN.
    CONCLUSIONS: By synergistically inhibiting hepatocytes ferroptosis through the Nrf2 pathway and mitophagy activation, TAN alleviates liver ischemia-reperfusion injury, highlighting the novel therapeutic potential in liver I/R injury.
    Keywords:  Ferroptosis; Liver ischemia-reperfusion injury; Mitophagy; Nrf2; Tangeretin
    DOI:  https://doi.org/10.1016/j.phymed.2025.157034
  27. Cell Death Dis. 2025 Jul 07. 16(1): 498
    HDAC3-YY1-RAB5A axis remodels AML-supportive niche by modulating mitochondrial homeostasis in bone marrow stromal cells.
    Chao He, Yue Xiong, Yuqing Zeng, Jianhua Feng, Fuxia Yan, Manqi Zhang, Zhili Tan, Yaling Zheng, Hongbo Chen, Rui Huang, Fang Cheng.
      Recent studies have shown that the interaction between acute myeloid leukemia (AML) and bone marrow stromal cells (BMSCs) plays a vital role in the progression of leukemia and the development of drug resistance, while the underlying mechanisms remain inconclusive. In this study, we found that AML patient-derived BMSCs exhibit a hyperinflammatory phenotype. Histone deacetylase 3 (HDAC3) in BMSCs enhances mitochondrial reactive oxygen species (ROS) production by RAB5A-mediated blockade of mitophagy. Furthermore, we confirmed that HDAC3 regulates RAB5A expression through transcription factor YY1. Excessive ROS accelerates the senescence of BMSCs and promotes the secretion of senescence-associated secretory phenotype, creating a hyperinflammatory bone marrow niche, activating the NF-κB pathway in AML cells to promote their survival and drug resistance. The inhibition of HDAC3 in BMSCs reduces the mitochondrial ROS production and thus delays BMSCs senescence. Consequently, HDAC3 inhibition in BMSCs decreases AML proliferation and synergizes with the anti-AML efficacy of venetoclax. Therefore, our study suggests that targeting HDAC3 in BMSCs may be used for the combination therapy of AML by remodeling the AML-supportive niche.
    DOI:  https://doi.org/10.1038/s41419-025-07777-9
  28. Physiol Rep. 2025 Jul;13(13): e70451
    Altered endothelial mitochondrial Opa1-related fusion in mouse accelerates age-associated vascular and kidney damage.
    Carlotta Turnaturi, Loïck L'Hoste, Coralyne Proux, Linda Grimaud, Emilie Vessieres, Antonio Zorzano, Anne Teissier, Pascal Reynier, Raffaella Sorrentino, Guy Lenaers, Laurent Loufrani, Daniel Henrion.
      Cardiovascular diseases are the major cause of death worldwide, and their frequency increases with age in association with kidney damage. As a reduction in fusion protein optic atrophy type 1 (Opa1) level in endothelial cells (ECs) decreases the vascular response to flow and increases oxidative stress in perfused kidneys, we hypothesized that reduced Opa1 expression contributes to vascular aging. We used male and female mice with ECs specific Opa1 knock-out (EC-Opa1), and littermate wild-type (EC-WT) mice aged 6 (young) and 20 months (old). Mesenteric resistance arteries (MRA) and kidneys were collected for vascular reactivity and western-blot analysis. In old EC-Opa1 mice, blood urea was greater than in EC-WT mice, and MRA showed reduced endothelium-dependent relaxation. In kidneys, the mitochondria fission protein fission-1 (Fis-1) and the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1α) were increased in old EC-Opa1 mice. The level of caveolin-1 expression was greater in old EC-Opa1 mice. Moreover, in kidneys from EC-Opa1 old mice, NADPH-oxidase subunit gp91 expression was greater than in age-matched EC-WT mice. Thus, reduced mitochondrial fusion in mouse ECs altered mesenteric vascular reactivity and increased markers of oxidative stress in aging kidneys. Thus, Opa1 might protect the vascular tree in target organs such as the kidney.
    Keywords:  aging; arteries; endothelial cell; kidney; mitochondrial fusion
    DOI:  https://doi.org/10.14814/phy2.70451
  29. In Vitro Cell Dev Biol Anim. 2025 Jul 07.
    Dexmedetomidine preserves neuronal function by promoting mitochondrial biogenesis through the AMPK/PGC-1α pathway.
    Li Wang, Meng Zhang, Shaowei Wang, Zhen Xing, Tong Jia, Xiaojia Sun, Hui Liu, Jie Yao, Yanlin Chen.
      Mitochondrial dysfunction, often linked to the deregulation of mitochondrial biogenesis, plays a significant role in the progression of neurological diseases. Dexmedetomidine (Dex), a selective alpha-2 adrenergic agonist utilized for anesthesia and sedation, has a largely unexplored impact on mitochondrial function. In this study, cells were treated with Dex at concentrations of 10 μg/mL and 20 μg/mL. Mitochondrial function was assessed by measuring mitochondrial membrane potential, adenosine triphosphate (ATP) production, and oxygen consumption rates. The expression levels of key mitochondrial genes and proteins were analyzed using quantitative polymerase chain reaction (qPCR) and Western blot. To investigate the role of AMP-activated protein kinase α (AMPK), cells were co-treated with the AMPK inhibitor Compound C. Our results demonstrate that treating cells with Dex significantly enhances mitochondrial membrane potential, ATP production, and oxygen consumption rates. Additionally, Dex increases the expression of vital mitochondrial genes, including Mitochondrially Encoded NADH: Ubiquinone Oxidoreductase Core Subunit 6 (mtND6), Mitochondrially Encoded Cytochrome c Oxidase II (mtCO2), and Mitochondrially Encoded ATP Synthase 6 (mtATP6), while also improving the mtDNA-to-nDNA ratio. The treatment raises Messenger Ribonucleic Acid (mRNA) and protein levels of essential mitochondrial biogenesis regulators such as Nuclear Respiratory Factor 1(Nrf1), Mitochondrial Transcription Factor A (TFAM), Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α (PGC-1α), and phosphorylated AMP-Activated Protein Kinase α (p-AMPKα). However, when cells are co-treated with the AMPK inhibitor compound C, these positive effects are lost, highlighting the necessity of AMPK activation for the mitochondrial enhancements induced by Dex. These findings suggest a promising therapeutic potential for Dex in supporting neuronal function through mitochondrial pathways.
    Keywords:  AMPK; Dexmedetomidine; Mitochondrial DNA; Mitochondrial biogenesis; PGC-1α
    DOI:  https://doi.org/10.1007/s11626-025-01059-6
  30. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2025 Jul;41(7): 629-636
    [Impact of tyrosine phosphorylation site mutation in FUNDC1 protein on mitophagy in H9c2 cardiomyocytes].
    Zhaoyang Zhang, Yanli Yu, Jieyun Wu, Wei Tian, Jingman Xu.
      Objective To investigate the effect of FUNDC1 tyrosine phosphorylation site mutations on mitophagy in H9c2 myocardial cells by constructing tyrosine site mutant plasmids (Y11 and Y18) of the FUN14 domain-containing protein 1 (FUNDC1). Methods The mutant plasmids constructed by whole-gene synthesis were transfected into rat myocardial H9c2 cells and divided into five groups: empty plasmid group, FUNDC1 overexpression group, Y11 mutant group, Y18 mutant group, and Y11 combined with Y18 mutant group. The viability of H9c2 cells was assessed using the CCK-8 assay. Additionally, tetramethylrhodamine ethyl ester (TMRE) staining was utilized to detect mitochondrial membrane potential. The protein expression levels of FUNDC1, translocase of the outer mitochondrial membrane 20 (TOM20), and cytochrome c oxidase IV (COX IV) were detected by Western blot analysis. Confocal microscopy was used to evaluate transfection efficiency as well as the co-localization of mitochondria and lysosomes. Results The FUNDC1 overexpression, Y11, Y18, and Y11 combined with Y18 mutant plasmids were successfully constructed. After plasmid transfection, widespread GFP fluorescence expression was observed under confocal microscopy. Compared with the empty plasmid group, FUNDC1 protein expression levels were significantly increased in the FUNDC1 overexpression group, Y11 mutation group, Y18 mutation group, and Y11 combined with Y18 mutation group, while cell viability and mitochondrial membrane potential showed no significant changes. Compared to the empty plasmid group, cells transfected with Y18 and Y11 combined with Y18 mutant plasmids showed increased TOM20 and COX IV expression levels and decreased mitochondrial-lysosomal co-localization. Conclusion Transfection with FUNDC1 Y18 or Y11 combined with Y18 mutant plasmids inhibited mitophagy in H9c2 myocardial cells.
  31. J Am Chem Soc. 2025 Jul 08.
    Drp1 Proteins Released from Hydrolysis-Driven Scaffold Disassembly Trigger Nucleotide-Dependent Membrane Remodeling to Promote Scission.
    Elizabeth Wei-Chia Luo, Kelsey A Nolden, Haleh Alimohamadi, Michelle W Lee, Liting Duan, R Blake Hill, Gerard C L Wong.
      Dynamin-related protein (Drp1) drives mitochondrial fission, dysregulation of which leads to neurodegenerative, metabolic, and apoptotic disorders. The precise mechanism of fission completion is unclear. One prevailing model is based on GTP-driven assembly of Drp1 helices that increase confinement via force generation. However, constriction to nanoscopic tubule radii appears necessary but not sufficient for scission. The other is based on GTP-driven disassembly of a constricting Drp1 scaffold that drives a membrane disturbance, but the relation of disassembly to scission and GTP hydrolysis remain uncertain. Elucidation of mitochondrial fission is complicated by the multiple time-involved in the dynamics of mechanoenzyme activity, oligomer disassembly, and membrane remodeling. Using machine learning, synchrotron X-ray scattering, and a theoretical model, our data support a model where progressive GTP hydrolysis enables free Drp1s to increase their capacity for inducing membrane negative Gaussian curvature (NGC). Furthermore, we identify Drp1 variants that diminish this progressive capacity. Machine learning reveals that predicted NGC-generating sequences of the Drp1 oligomer are not in contact with the confined lipid tube and that scission-enhancing membrane remodeling is triggered by free Drp1 released upon disassembly.
    DOI:  https://doi.org/10.1021/jacs.4c15836
  32. Front Mol Neurosci. 2025 ;18 1554802
    Silencing ATF3 mediates mitochondrial homeostasis and improves ischemic stroke through regulating the MAPK signaling pathway.
    Haifengqing Li, Fan Zhang, Cong Zhang, Min Zhou, Qing Liu, Guoyong Zeng.
      Mitochondrial homeostasis is crucial for preventing and treatment of ischemic stroke. This study aimed to investigate the role of activating transcription factor 3 (ATF3) in ischemic stroke and mitochondrial homeostasis. ATF3 was silenced in oxygen glucose deprivation/reperfusion (OGD/R)-treated HT22 cells to evaluate its effects on cell apoptosis and mitochondrial function. The effects of silencing ATF3 on neurological injury, infarction, adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+), mitofusin 1 (MFN1) and MFN2 were evaluated in stroke rats. Transcriptome sequencing and differential expression analysis were conducted to identify differential expressed genes (DEGs) associated with silencing ATF3, followed by functional enrichment analysis. The mitogen activated protein kinase (MAPK) agonist, anisomycin, was used to investigate the regulation of ATF3 in ischemic stroke and mitochondrial homeostasis via the MAPK pathway. Silencing ATF3 increased cell viability and inhibited apoptosis of OGD/R-induced cells. In stroke rats, silencing ATF3 reduced brain water content, decreased neurological injury and alleviated cerebral infarction. Notably, silencing ATF3 significantly inhibited the production of reactive oxygen species (ROS), increased the concentrations of ATP and NAD+, and upregulated the expression of MFN1 and MFN2. Next, 4,517 DGEs associated with silencing ATF3 were mainly enriched in MAPK signaling pathway. Silencing ATF3 downregulated the expression of phosphorylation-extracellular signal-regulated kinase (p-ERK)/ERK in OGD/R cells. Anisomycin notably reversed the effect of silencing ATF3 on ischemic stroke and mitochondrial homeostasis. Silencing ATF3 attenuates ischemic stroke and improves mitochondrial homeostasis via the MAPK signaling pathway, which shares a novel direction for maintaining mitochondrial homeostasis in ischemic stroke.
    Keywords:  activating transcription factor 3; ischemic stroke; mitochondrial homeostasis; mitogen activated protein kinase; signaling pathway
    DOI:  https://doi.org/10.3389/fnmol.2025.1554802
  33. Biomed Pharmacother. 2025 Jul 09. pii: S0753-3322(25)00529-3. [Epub ahead of print]189 118335
    Crosstalk between mitochondrial quality control and novel programmed cell death in pulmonary diseases.
    Qian Gao, Xiaoyu Han, Jun Wang, Xiaodan Liu, Weibing Wu.
      Dysfunctional mitochondrial quality control (MQC) and dysregulated programmed cell death (PCD) are increasingly recognized as key drivers of pulmonary diseases. This review explores the intricate crosstalk between MQC mechanisms, encompassing mitochondrial biogenesis, dynamics, mitophagy, and mitocytosis, and novel PCD pathways such as pyroptosis, ferroptosis, necroptosis, PANoptosis, cuproptosis, and disulfidptosis. We highlight how mitochondrial dysfunction triggers PCD and how PCD exacerbates mitochondrial damage, creating a vicious cycle that amplifies lung injury and inflammation. Emerging therapeutic strategies targeting these interconnected pathways show promise in mitigating pulmonary diseases. However, challenges remain in understanding the context-dependent roles and translating preclinical findings into clinical applications. Further research is still needed to elucidate the precise regulatory mechanisms governing MQC and PCD, identify novel therapeutic targets, and develop biomarkers for early disease detection and prognosis. This review underscores the potential of targeting MQC and PCD as a therapeutic direction for pulmonary diseases, offering new insights into disease pathogenesis and treatment.
    Keywords:  Mitochondrial quality control; programmed cell death; pulmonary diseases
    DOI:  https://doi.org/10.1016/j.biopha.2025.118335
  34. Cells. 2025 Jul 02. pii: 1015. [Epub ahead of print]14(13):
    Regulation of Mitochondrial Metabolism by Mfn1 Gene Encoding Mitofusin Affects Cellular Proliferation and Histone Modification.
    Han Xu, Xiaoyu Zhao, Yuan Yun, Yuxin Gao, Chunjie Bo, Lishuang Song, Chunling Bai, Lei Yang, Guangpeng Li, Guanghua Su.
      Mitochondria maintain cellular homeostasis through the dynamic balance of fusion and fission, which relies on nuclear-encoded mitochondrial fusion proteins, mitofusins 1 and 2 (Mfn1, Mfn2). Changes in Mfn1 and Mfn2 expression significantly affect mitochondrial fusion and fission, thereby affecting cellular metabolism. This study investigated the effect of Mfn1 expression on cell proliferation, apoptosis, and mitochondrial function by overexpressing Mfn1 (in OE-Mfn1 cells) and silencing Mfn1 using short hairpin RNA (shRNA) (in shMfn1 cells). Cell proliferation capacity, mitochondrial membrane potential, and mitochondrial ATP content were measured. To investigate the effects of Mfn1 on cellular metabolism and epigenetic modifications, the levels of metabolites α-KG, A-CoA, and SAM, as well as the levels of cellular methylation and acetylation, were detected by ELISA. Differentially expressed genes and metabolites were assessed by RNA-seq and LC-MS. This study demonstrates that alterations in Mfn1 gene expression can significantly affect mitochondrial metabolism and cell proliferation and apoptosis. In addition, Mfn1 affects the expression of genes encoding enzymes that are responsible for histone methylation and acetylation, thereby regulating these modifications. These findings provide a theoretical basis for further elucidation of the mechanisms by which Mfn1 affects cell proliferation, regulates metabolites, and modulates chromatin epigenetic modification.
    Keywords:  Mfn1; cell proliferation; epigenetic modifications; mitochondrial dynamics; mitochondrial metabolism
    DOI:  https://doi.org/10.3390/cells14131015
  35. FASEB J. 2025 Jul 31. 39(14): e70811
    Adipose Mesenchymal Stem Cells Derived Exosomes Ameliorates KOA Cartilage Damage and Inflammation by Activation of PINK1-Mediated Mitochondrial Autophagy.
    Junfeng Kang, Lishi Jie, Houyu Fu, Lu Zhang, Guozhen Lu, Likai Yu, Di Tian, Taiyang Liao, Songjiang Yin, Runlin Xin, Peimin Wang.
      Knee osteoarthritis (KOA) is characterized by degenerative destruction of knee cartilage. Adipose tissue-derived mesenchymal stem cells (MSCs) have been widely used in the clinic to treat joint diseases, and the exosomes secreted by adipose tissue-derived MSCs (ADSC-Exos) are more stable and easier to store than stem cell therapy alone. The aim of this study was to investigate whether ADSC-Exos could reduce KOA chondrocyte damage and inflammation by activating mitochondrial autophagy. In vitro, we induced a KOA chondrocyte model with lipopolysaccharide (LPS), and after treatment with ADSC-Exos, we assessed chondrocyte damage and inflammation by using HE, Senna O solid green, and Alcian blue staining and IL-1β immunofluorescence analysis. We also labeled chondrocytes and assessed their intracellular levels of reactive oxygen species (ROS) using the DCFH-DA probe, assessed the mitochondrial membrane potential of chondrocytes using a mitochondrial membrane potential detection kit (JC-1). In vivo, we constructed a KOA rat model by anterior cruciate ligament tenotomy (ACLT) surgery, treated the knee joint with a local injection of ADSC-Exos, reconstructed the knee joint in three dimensions using micro-CT, and evaluated the pathological changes in cartilage tissues by using HE, Senna O solid green, and Alcian blue staining. The in vivo and in vitro results showed that ADSC-Exos upregulated the expression of PINK1/Parkin pathway components, promoted mitochondrial autophagy in chondrocytes, increased the mitochondrial membrane potential, protected mitochondrial function in chondrocytes, and ameliorated the degradation of the cartilage matrix and inflammation during KOA.
    Keywords:  PINK1/Parkin; adipose‐derived stem cells; exosome; knee osteoarthritis; mitophagy
    DOI:  https://doi.org/10.1096/fj.202501185R
  36. J Am Chem Soc. 2025 Jul 08.
    Dynamin-like Proteins Combine Mechano-constriction and Membrane Remodeling to Enable Two-Step Mitochondrial Fission via a "Snap-through" Instability.
    Haleh Alimohamadi, Elizabeth Wei-Chia Luo, Xiaoying Liu, Wasi Iqbal, Rena Yang, Shivam Gupta, Kelsey A Nolden, Taraknath Mandal, R Blake Hill, Liting Duan, Gerard C L Wong.
      Mitochondrial fission is controlled by dynamin-like proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamin-like proteins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membranes to achieve fission while also remodeling membranes by inducing negative Gaussian curvature, which is essential for the completion of fission. Despite advances in optical and electron imaging technologies, the underlying mechanics of mitochondrial fission remain unclear due to the multiple times involved in the dynamics of mechanoenzyme activity, oligomer disassembly, and membrane remodeling. Here, we examine how multiscale phenomena in dynamin Drp1 synergistically influence membrane fission using a mechanical model calibrated with small-angle X-ray scattering structural data and informed by a machine learning analysis of the Drp1 sequence, and tested the concept using optogenetic mechanostimulation of mitochondria in live cells. We find that free dynamin-like proteins can trigger a "snap-through instability" that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of assembly and paradoxically disassembly of dynamin-like proteins can lead to diverse pathways to scission.
    DOI:  https://doi.org/10.1021/jacs.5c06352
  37. J Virol. 2025 Jul 09. e0049825
    PEDV Nsp14 induces mitophagy-mediated degradation of MAVS to antagonize host innate immunity and facilitate viral proliferation.
    Lei Yang, Qisheng Qian, Yan-Gang Sun, Xin-Xin Chen, Guangxu Xing, Jia-Qing Zhang, Bao-Song Xing, Songlin Qiao, Rui Li, Gaiping Zhang.
      Porcine epidemic diarrhea virus (PEDV) leads to a high mortality in neonatal piglets and causes serious harm to the global swine industry. PEDV has been shown to exploit diverse strategies for antagonism of host innate immunity and promotion of self-replication. However, the underlying mechanisms involved in PEDV immunosuppression remain to be fully elucidated. The current study reveals that PEDV triggers mitophagy to suppress host innate immune responses and facilitate viral proliferation. Mechanistically, PEDV non-structural protein (Nsp) 14 was identified to mediate the interaction between the mitophagy receptor NDP52 and mitochondrial outer membrane protein TOM20 to induce mitophagy. Subsequently, Nsp14-induced mitophagy resulted in the degradation of mitochondrial antiviral signaling protein (MAVS) to suppress interferon-β (IFN-β) production and promote viral propagation. These findings deepen the understanding of PEDV pathogenesis and provide novel targets for the development of antiviral avenues.
    IMPORTANCE: The global pig farming industry has suffered huge economic losses from PEDV, underscoring an urgent need for in-depth research on its pathogenesis. Host innate immunity functions as the first line of defense against PEDV propagation, and PEDV has developed multiple countermeasures to dampen host antiviral responses. Here, we found that PEDV Nsp14 induced mitophagy via mediating the interaction between NDP52 and TOM20, which led to MAVS degradation and hampered IFN-β production. Therefore, our work unveils a novel mechanism by which PEDV antagonizes host innate immunity to facilitate its proliferation and is beneficial for the prevention and control of the virus.
    Keywords:  IFN-β; NDP52; Nsp14; PEDV; mitophagy
    DOI:  https://doi.org/10.1128/jvi.00498-25
  38. Cell Prolif. 2025 Jul 04. e70085
    Targeting ROCK1/YAP1 Axis Ameliorates Inflammation-Induced Prostatic Hyperplasia via Stabilising SIRT1-Dependent Mitochondrial Dynamics.
    Dongxu Lin, Pengyu Wei, Mengyang Zhang, Kang Li, Lina Li, Zhipeng Li, Changcheng Luo, Wenbo Kuang, Kai Cui, Zhong Chen.
      Benign prostatic hyperplasia (BPH) is a common condition in older men, with its prevalence increasing as age advances. Chronic inflammation orchestrates oxidative stress to exacerbate BPH. YAP1, which regulates organ size, cellular homeostasis, and tissue fibrosis, can be activated by ROCK1. Given the urgent clinical need for more effective therapies, this study explored whether targeting the ROCK1/YAP1 axis could mitigate BPH progression. Here, rats received in situ adeno-associated virus (AAV) injection to induce prostate-specific YAP1 overexpression. An inflammation-associated experimental autoimmune prostatitis (EAP) model was established by prostate antigen immunisation, followed by treatment with ROCK1 inhibitor fasudil and YAP1 inhibitor verteporfin. Cell models were treated with specific inhibitors to confirm the critical role of YAP1 in modulating mitochondrial function. As a result, YAP1 overexpression was sufficient to induce a pathological BPH phenotype. Specifically, YAP1 activated the inflammatory cascade to provoke an immune response, disrupted proliferation/apoptosis balance to induce tissue hyperplasia, triggered epithelial-mesenchymal transition (EMT) and reactive stroma to drive fibrosis, and promoted NOX4/ROS generation and antioxidant depletion to cause oxidative stress. The inflammation-induced experimental autoimmune prostatitis (EAP) model also presented analogous BPH lesions, which were significantly alleviated when treated with ROCK1 inhibitor fasudil and YAP1 inhibitor verteporfin. Mechanistically, YAP1 activation under inflammatory conditions suppressed SIRT1 expression, thereby exacerbating oxidative stress through the disruption of DRP1/MFN2-mediated mitochondrial dynamics. Overall, inflammation-driven activation of the ROCK1/YAP1 axis aggravates oxidative stress, promoting BPH hyperplasia and fibrosis by impairing SIRT1-regulated mitochondrial dynamics. These findings provide a preclinical rationale for developing ROCK1 or YAP1 inhibitors as targeted therapies for BPH patients with chronic inflammation.
    Keywords:  SIRT1; YAP1; benign prostatic hyperplasia; inflammation; mitochondrial dynamics
    DOI:  https://doi.org/10.1111/cpr.70085
  39. Int J Biol Macromol. 2025 Jul 05. pii: S0141-8130(25)06305-6. [Epub ahead of print]320(Pt 1): 145750
    Hesperidin mitigates copper nanoparticle exposure-induced mitochondrial unfolded protein response through the SIRT3-FOXO3A signaling pathway.
    Yijin Wu, Shaofeng Wang, Hui Huang, Jingling Yu, Jieren Liang, Hai Huang, Jianying Guo, Zhaoxin Tang, Jianzhao Liao.
       BACKGROUND: With the increasing application of copper nanoparticles (CuNPs) across various fields, its toxicity and hazards are gradually being confirmed. Hesperidin (Hes), a flavonoid compound with extensive antioxidant and anti-inflammatory effects, has recently attracted public attention.
    METHODS: Molecular docking was employed to investigate the potential binding sites between Hes and SIRT3. The activation of the SIRT3-FOXO3A signaling pathway by Hes was further validated through a series of experiments in vitro and vivo.
    RESULTS: The results indicate that exposure to CuNPs can cause pathological damage to liver. Compared with the control group, exposure to CuNPs induced the accumulation of reactive oxygen species and mitochondrial UPRmt in broiler liver, specifically manifested as an increase in reactive oxygen species and the gene and protein levels of UPRmt related proteins. The molecular docking results indicate that Hes and SIRT3 have potential binding sites. However, after treatment with Hes, pathological damage in liver was alleviated. At the same time, we found that the SIRT3-FOXO3A signaling pathway was activated, leading to a significant decrease in the expression levels of proteins and genes related to UPRmt.
    CONCLUSION: Hes can ameliorate hepatic oxidative damage and UPRmt induced by exposure to CuNPs by activating the SIRT3-FOXO3A pathway.
    Keywords:  Copper nanoparticles; FOXO3A; Hesperidin; Liver; Mitochondrial unfolded protein response; SIRT3
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145750
  40. Autophagy. 2025 Jul 07.
    Activation of endogenous PRKN by structural derepression is linked to increased turnover of the E3 ubiquitin ligase.
    Fabienne Fiesel, Bernardo Bustillos, Jens Watzlawik, Carol Chen, Martin Berryer, Jiazhen Zhang, Paige Boneski, Caleb Hayes, Jenny Bredenberg, Eric Deneault, Zhipeng You, Narges Abdien, Nathalia Aprahamian, Taylor Goldsmith, Zahra Baninameh, Liam Cocker, Haonan Zhang, Matthew Goldberg, Edward Fon, Jean-François Trempe, Satpal Virdee, Thomas Durcan, Wolfdieter Springer.
      Loss-of-function mutations in the PINK1 and PRKN genes are the most common cause of early-onset Parkinson disease (PD). The encoded enzymatic pair selectively identifies, labels, and targets damaged mitochondria for degradation via the macroautophagy/autophagy-lysosome system (mitophagy). This pathway is cytoprotective and efforts to activate mitophagy are pursued as therapeutic avenues to combat PD and other neurodegenerative disorders. When mitochondria are damaged, the ubiquitin kinase PINK1 accumulates and recruits PRKN from the cytosol to activate the E3 ubiquitin ligase from its auto-inhibited conformation. We have previously designed several mutations that effectively derepress the structure of PRKN and activate its enzymatic functions in vitro. However, it remained unclear how these PRKN-activating mutations would perform endogenously in cultured neurons or in vivo in the brain. Here, we gene-edited neural progenitor cells and induced pluripotent stem cells to express PRKN-activating mutations in dopaminergic cultures. All tested PRKN-activating mutations indeed enhanced the enzymatic activity of PRKN in the absence of exogenous stress, but their hyperactivity was linked to their own PINK1-dependent degradation. Strikingly, in vivo in a mouse model expressing an equivalent activating mutation, we find the same relationship between PRKN enzymatic activity and protein stability. We conclude that PRKN degradation is the consequence of its structural derepression and enzymatic activation, thus resulting only in a temporary gain of activity. Our findings imply that pharmacological activation of endogenous PRKN will lead to increased turnover and suggest that additional considerations might be necessary to achieve sustained E3 ubiquitin ligase activity for disease treatment.
    Keywords:  Autophagy; PINK1; Parkin; mitophagy; parkinson’s disease
    DOI:  https://doi.org/10.1080/15548627.2025.2531025
  41. Sci Rep. 2025 Jul 08. 15(1): 24369
    Extremely low-frequency electromagnetic field (ELF-EMF) enhances mitochondrial energy production in NARP cybrids.
    Mikako Ito, Zhizhou Huang, Kosaku Nomura, Masaki Teranishi, Fei Zhao, Hiroyuki Mino, Makoto Yoneda, Masashi Tanaka, Kinji Ohno.
      A mutation (m.8993T > G) in MT-ATP6 in mitochondrial DNA (mtDNA) causes the neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome by impairing mitochondrial energy production. Extremely low-frequency electromagnetic field (ELF-EMF) suppresses mitochondrial oxidative phosphorylation (OXPHOS) Complex II and induces mitohormetic activation of mitochondrial OXPHOS activities. We examined the effects of ELF-EMF on normal cybrids carrying 100% wild-type mtDNA (2SA cybrids) and NARP cybrids carrying 40% wild-type and 60% mutant mtDNA (NARP3-2 cybrids). We found that ELF-EMF had no effect on the copy number of mtDNA either in 2SA or NARP3-2 cybrids, or the ratio of wild-type-to-mutant mtDNA in NARP3-2 cybrids. Instead, ELF-EMF increased the transcription of mtDNA and the transcription ratio of wild-type-to-mutant mtDNA in NARP3-2 cybrids. In addition, ELF-EMF increased the expression of mitochondrial OXPHOS proteins and the mitochondrial OXPHOS Complex V activity in NARP3-2 cybrids. ELF-EMF upregulated fission-promoting phosphorylation of DRP1, as well as the expression of fusion-promoting MFN1 and MFN2, in NARP3-2 cybrids. ELF-EMF also increased ATP production estimated by oxygen consumption rates (OCR) and by a biochemical assay in NARP3-2 cybrids. Hormetic activation of mitochondria by ELF-EMF is likely to be effective to ameliorate defective mitochondrial energy production in NARP and other mitochondrial diseases.
    Keywords:  And mitohormesis; Extremely low-frequency electromagnetic field (ELF-EMF); Mitochondrial DNA; Mitochondrial biogenesis; Mitophagy; Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome
    DOI:  https://doi.org/10.1038/s41598-025-10536-7
  42. Mol Biol Rep. 2025 Jul 09. 52(1): 690
    A narrative review on bridging the gap between periodontitis and cardiovascular disease: exploring the cellular and molecular mechanisms of periodontitis-driven atherosclerosis.
    Rithwik Kumar, Anuradha Dhanasekaran, Priyanka Venugopal.
      Periodontitis and atherosclerosis are chronic inflammatory diseases which share some common risk factors including aberrant release of pro-inflammatory cytokines and an imbalance in the levels of reactive oxygen species (ROS). Several studies have suggested a potential link between the two diseases with supporting evidence of periodontal pathogens detected in atherosclerotic lesions. The proposed mechanism as reported in the literature involves the accumulation of periodontal pathogens entering into the bloodstream and thereby contributing to atherosclerotic plaque formation. However, the underlying factors contributing to this association remain largely underexplored. Hence, this review is crucial in addressing this gap in knowledge by emphasizing the roles of endothelial dysfunction, autophagy and mitophagy as key mechanisms linking periodontitis to an increased risk of future cardiovascular complications, particularly atherosclerosis. Exploring and understanding these cellular pathways would provide valuable insights into the predisposition of periodontitis to future cardiovascular events. Furthermore, this review also aims to bring awareness to the serious systemic complication of periodontitis and highlight the need for the development of targeted therapeutic strategies to control atherosclerosis in periodontitis patients and prevent future cardiovascular complications.
    Keywords:  Atherogenesis; Autophagy; Endothelial dysfunction; Mitophagy; Periodontitis
    DOI:  https://doi.org/10.1007/s11033-025-10806-7
  43. J Nanobiotechnology. 2025 Jul 08. 23(1): 496
    Mitochondrial homeostasis restoring peptide-drug conjugates with ROS-responsive NO releasing ability for targeted therapy of myocardial infarction.
    Zhaoyang Lu, Quanyou Chai, Wenbin Dai, Bo Yu, Qingbo Lv, Fuyu Qiu, Jing Gao, Juhong Zhang, Xiaohua Shen, Shengyu Chen, Zhida Shen, Min Shang, Wenbin Zhang, Guosheng Fu, Qiao Jin, Yanbo Zhao, Fan Jia.
      Myocardial infarction (MI) is the leading cause of death worldwide. Exogenous delivery of nitric oxide (NO) shows great potential in MI treatment. However, the burst generation of reactive oxygen species (ROS) in ischemic microenvironment of MI oxidize NO to harmful peroxynitrite (ONOO-). It renders secondary damage to cardiomyocyte, causing the failure of NO based therapies. Herein, we proposed an ROS responsive peptide-drug conjugates (PDCs) to overcome the dilemma of NO based therapy. The conjugated cardiac injury targeting peptide (CTP) in the PDC (named CTP-PBA-ISN) promoted selective accumulation of drugs in MI sites. Besides, controlled release of NO prodrug isosorbide mononitrate (ISN) was achieved by pathological ROS triggered hydrolysis of boronate ester. Meanwhile the antioxidant byproduct 4-hydroxybenzyl alcohol further scavenges the overwhelming ROS, reducing the production of RNS and improving the bioavailability of NO. The CTP-PBA-ISN efficiently inhibited myocardial apoptosis, improved myocardial function, and ameliorated adverse cardiac remodeling post-MI in mice by relief of oxidative stress, promotion of angiogenesis and restoration of mitochondrial homeostasis and function. These findings prove that the synergic ROS regulation is essential in maximizing therapeutic effects of NO. Our CTP-PBA-ISN may serve as a valuable inspiration for development of other treatments of myocardial infarction and other ischemic diseases.
    Keywords:  Mitochondrial homeostasis; Myocardial infarction; Nitric oxide; Peptide-drug conjugate; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s12951-025-03578-6
  44. Environ Pollut. 2025 Jul 05. pii: S0269-7491(25)01153-4. [Epub ahead of print]382 126780
    Chronic exposure to bisphenol S impairs hepatic mitochondrial dynamics, induces endoplasmic reticulum stress, and worsens metabolism in high-fat diet fed mice.
    Emanuelle Barreto-Reis, Vinicius Sepúlveda-Fragoso, Luiza Gil Diniz, Débora Júlia Silva Soares, Thaís de Souza Carvalho-Laureano, Ana Paula de Paula Alves, Beatriz Gouvêa de Luca, Beatriz Alexandre-Santos, Milena Barcza Stockler-Pinto, Denise Pires de Carvalho, Eliete Dalla Corte Frantz, Leandro Miranda-Alves, D'Angelo Carlo Magliano.
      Obesity triggers numerous other disorders, such as type 2 diabetes mellitus, dyslipidemia, and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Endocrine Disrupting Chemicals (EDC) such as Bisphenol A (BPA) have obesogenic effects, which have been replaced by Bisphenol S (BPS). The chronicity of obesity and MASLD, as well as BPS exposure, compromises Mitochondrial Biogenesis (MBG) and triggers the endoplasmic reticulum (ER) stress. Therefore, this study aims to investigate whether BPS exposure affects hepatic morphology, MBG, and ER stress pathways in the liver in male mice fed a standard and high-fat diet. C57BL/6 adult male mice were fed a control (SC) or high fat (HF) diet for 12 weeks and exposed or not to BPS (25 μg/kg of body mass/day) by drinking water. The animals were divided into a control diet not exposed to BPS (SCD), a control diet exposed to BPS (SCDB), a high-fat diet not exposed to BPS (HFD), and a high-fat diet exposed to BPS (HFDB) for 12 weeks. Body mass, glucose, and lipid profile were evaluated. In the liver, morphology and lipid metabolism, ER stress, and MBG markers were assessed. Data were presented as mean ± standard deviation and analyzed by one-way ANOVA, followed by the Holm-Sidak post-test. p < 0.05 was considered significant. BPS exposure led to increased body mass, and disrupted lipid and glucose metabolism, leading to alterations in hepatic mitochondrial dynamics, ER stress, and compromised hepatic structural support. The combination with a high-fat diet augmented insulin levels disrupted cholesterol metabolism, and compromised mitochondrial and endoplasmic reticulum homeostasis, resulting in more severe structural damage. In conclusion, BPS was able to facilitate the development of obesity and increase the risk of manifesting associated comorbidities when combined with a high-fat diet.
    Keywords:  Bisphenol S; Endoplasmic reticulum stress; High-fat diet; Metabolic dysfunction-associated steatotic liver disease; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.envpol.2025.126780
  45. Cardiovasc Diabetol. 2025 Jul 10. 24(1): 272
    Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis.
    Yu Wei, Yang Ji, Jiahui Meng, Li Yu, Yongzhong Tang, Wei-Jin Fang.
       BACKGROUND: Impaired Ca2+ handling is involved in diabetic cardiomyopathy (DCM) progression. The activation of acid sphingomyelinase (ASMase) stimulated cardiomyocytes apoptosis and caused DCM. Here, we aimed to investigate whether ASMase regulates mitochondrial Ca2+ homeostasis by acting on mitochondrial calcium uptake 1 (MICU1) and mitochondria-associated endoplasmic reticulum membranes (MAMs) formation to induce apoptosis during DCM.
    METHODS AND RESULTS: We established a type 2 diabetes model by combining high-fat diet (HFD) with streptozotocin (STZ) injection in wild-type and cardiomyocyte-specific ASMase deletion (ASMaseMyh6KO) mice. ASMase deletion restored HFD/STZ-induced cardiac dysfunction, remodeling, myocardial lipid accumulation and apoptosis. Single cell sequencing and Gene ontology (GO) enrichment analysis pointed to "cardiac muscle contraction" and "positive regulation of mitochondrial calcium ion concentration", which were confirmed by high glucose (HG, 30 mM) and palmitic acid (PA, 200 μM) induced mitochondrial Ca2+ overload in H9c2 cell lines at time dependence, accompanied by the upregulation of ASMase and MICU1 protein expressions. The similar effects were noted in ASMase overexpressed cardiomyocytes. Interestingly, endoplasmic reticulum (ER) Ca2+ level was decreased at the corresponding time, suggesting that increased mitochondrial Ca2+ level may be derived from ER. Notably, enhanced MAMs formation was found in HG + PA treated H9c2 cells, accompanied by blocked autophagy, similar results were obtained in ASMase overexpressing cells or HFD/STZ hearts. Loss of ASMase prevented HFD/STZ or HG + PA incubation induced cardiac hypertrophy, mitochondrialCa2+ overload, ROS production, autophagy blockage and MICU1 upregulation.
    CONCLUSIONS: HFD/STZ-induced ASMase upregulation enhances MAMs formation, promoting mitochondrial Ca2+ overload through MICU1 activation, leading to ROS generation, autophagy blockage and apoptosis in DCM. Therefore, targeting ASMase-MICU1 pathway emerges as a potential therapeutic approach for managing DCM.
    Keywords:  ASMase; Diabetic cardiomyopathy; MICU1; Mitochondrial calcium homeostasis
    DOI:  https://doi.org/10.1186/s12933-025-02801-w
  46. J Int Med Res. 2025 Jul;53(7): 3000605251355996
    A review of mitochondrial dysfunction in diabetic sarcopenia: Mechanisms, diagnosis, and treatment approaches.
    Zhilin Xie, Yuanhao Li, Xiaoliu Li, Jing Zhang.
      Diabetic sarcopenia is a common complication of diabetes, substantially impacting patients' quality of life and prognosis. Its pathogenesis is closely related to energy metabolism, with mitochondria-often referred to as the cellular "powerhouse"-playing a central role in this process. This review focuses on the role of mitochondrial dysfunction in diabetic sarcopenia, emphasizing mechanisms such as energy metabolism imbalance, oxidative stress-induced damage, and abnormalities in mitochondrial biogenesis and dynamics. Additionally, we discussed current research on diagnostic and therapeutic strategies targeting mitochondrial dysfunction. This narrative review aims to provide a theoretical foundation for a deeper understanding of the pathophysiology of diabetic sarcopenia and the development of novel therapeutic approaches.
    Keywords:  Mitochondrial dysfunction; diabetes; insulin resistance; mitochondrial dynamics; oxidative stress; sarcopenia
    DOI:  https://doi.org/10.1177/03000605251355996
  47. Int J Biochem Cell Biol. 2025 Jul 03. pii: S1357-2725(25)00095-0. [Epub ahead of print]186 106827
    Mitochondrial homeostasis and their impact on gastric carcinoma.
    Amrutha Arjunan, Ganesh Venkatraman, Leena Dennis Joseph, Lakshmi R Perumalsamy.
      Gastric cancer is the fifth most diagnosed cancer and the third most common cause of cancer-related deaths worldwide. Mitochondrial dysfunction, with its impaired energy production and increased oxidative stress, fuels the development of gastric tumours. Gastric cancer exhibits dysregulated mitochondrial functions, which contribute to metabolic reprogramming, decreased apoptosis sensitivity, therapeutic resistance, and enhanced tumour progression and metastasis. In addition, aberrations in mitochondrial DNA, respiratory chain complexes, and epigenetic alterations foster a pro-tumorigenic microenvironment. Although significant progress has been made in understanding the various molecular mechanisms involved in gastric carcinogenesis, further studies are needed to elucidate mitochondrial homeostasis in gastric cancer. Unravelling mitochondrial intricacies in gastric cancer could open the development of definitive diagnostic and therapeutic interventions driving tumour growth. This review focuses on investigating the altered mitochondrial functionalities in gastric cancer.
    Keywords:  Gastric cancer; Helicobacter pylori; Metabolic homeostasis; Mitochondria; Mitochondria-targeted drug therapy; MtDNA mutations
    DOI:  https://doi.org/10.1016/j.biocel.2025.106827
  48. CNS Neurosci Ther. 2025 Jul;31(7): e70508
    Downregulation of Mfn2 Contributes to Chronic Postsurgical Pain via Inducing the Pyroptosis of GABAergic Neurons in the Spinal Cord.
    Yingjie Hu, Xiao He, Hu Zang, Yuye Chen, Li Li, Tongtong Liu, Li Wan, Chang Zhu, Wenlong Yao.
       BACKGROUND: Chronic postoperative pain (CPSP) is a significant public health issue due to the complex pathophysiological mechanism. Existing evidence has pointed out that the loss of gamma-aminobutyric acid-ergic (GABAergic) neurons played a critical role in various neuropathic pain models. Previous studies also found that pyroptosis-mediated neuroinflammation was involved in neuropathological pain. However, it remains unclear what the relationship is between pyroptosis and the loss of spinal GABAergic neurons in CPSP. This study aimed to investigate the role and mechanism of GABAergic neuron pyroptosis in CPSP.
    METHODS: We used skin/muscle incision and retraction (SMIR) to establish the CPSP model in rats. Mechanical allodynia was assessed using the Von Frey test. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the role and mechanism of GABAergic neuron pyroptosis during CPSP.
    RESULTS: We observed the pyroptosis of GABAergic neurons in the spinal cord following SMIR. Intrathecal administration of the GSDMD inhibitor decreased the pyroptosis of GABAergic neurons in the spinal cord and reversed SMIR-induced mechanical allodynia. In addition, we found that SMIR induced a significant decrease in the level of Mfn2 in the neurons, accompanied by mitochondrial dysfunction and reactive oxygen species (ROS) accumulation in SMIR rats. Intrathecal injection of the Mfn2 activator reduced mitochondrial dysfunction and ROS, alleviated the pyroptosis of GABAergic neurons in the spinal cord, which alleviated the SMIR-induced mechanical allodynia.
    CONCLUSIONS: Our study demonstrated that downregulation of Mfn2 leads to mitochondrial dysfunction and ROS accumulation, which promotes the pyroptosis of spinal GABAergic neurons and the development of chronic pain.
    Keywords:  GABAergic neuron; Mfn2; chronic postsurgical pain; mitochondrial dysfunction; pyroptosis
    DOI:  https://doi.org/10.1111/cns.70508
  49. J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):
    MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
    Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.
      Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.
    Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH
    DOI:  https://doi.org/10.1242/jcs.263701
  50. Stem Cell Res Ther. 2025 Jul 09. 16(1): 356
    DPSCs modulate synovial macrophage polarization and efferocytosis via PINK1/Parkin-dependent mitophagy.
    Jinjin Ma, Xinyu Wang, Dalei Sun, Jiali Chen, Linyi Zhou, Kaiao Zou, Xinxin Ni, Hongting Jin, Jun Lin.
      
    DOI:  https://doi.org/10.1186/s13287-025-04468-2
  51. Biomed Pharmacother. 2025 Jul 05. pii: S0753-3322(25)00510-4. [Epub ahead of print]189 118316
    Soyasapogenol B prevents sarcopenia by increasing skeletal muscle mass and function through the Sirt1/PGC-1α and PI3K pathway.
    Byeong Min Ahn, Yuran Noh, Justin Jaesuk Lee, Jung Han Yoon Park, Ki Won Lee, Young Jin Jang.
      Sarcopenia, caused by aging, is characterized by the reduction of muscle mass and function. In this study, we investigated the effects of soyasapogenol B on skeletal muscle and the underlying mechanisms to determine its potential as a prevention for sarcopenia. Soyasapogenol B, a natural triterpenoid found in soybeans, has biological effects that inhibit cancer, inflammation, and obesity; however, its effects on skeletal muscle remain unclear and require further investigation. C57/BL6 mice were fed soyasapogenol B for 8 weeks, after which skeletal muscle mass, function, and protein analysis for muscle synthesis and exercise mimetics were evaluated. The mechanism of skeletal muscle improvement by soyasapogenol B was identified through in vitro experiments. Soyasapogenol B increased the weight of the quadriceps and gastrocnemius muscles, grip strength, and running endurance. It also enhanced oxidative muscle fiber switching, mitochondrial enzyme complex, and mitochondria biogenesis through the Sirt1/PGC-1α pathway. Soyasapogenol B increased myogenic differentiation and protein synthesis, through the PI3K pathway. The upregulation of mitochondrial biogenesis and myogenic differentiation by soyasapogenol B was attenuated by treatment with EX-527, a SIRT1 inhibitor, and LY294002, a PI3K inhibitor. Molecular docking analyses showed that soyasapogenol B has the potential to directly bind to Sirt1. In conclusion, soyasapogenol B increased skeletal muscle mass, skeletal muscle strength and endurance by activating the Sirt1 and PI3K pathways. Thus, by promoting protein synthesis and mitochondrial biogenesis, soyasapogenol B could be a potential prevention option for sarcopenia.
    Keywords:  PI3K pathway; Sarcopenia; Sirt1/PGC-1α pathway; Soyasapogenol B; mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.biopha.2025.118316
  52. Redox Biol. 2025 Jun 28. pii: S2213-2317(25)00258-7. [Epub ahead of print]85 103745
    USP10 protects against pressure overload-induced mitochondrial morphofunctional defects and pathological cardiac hypertrophy through stabilizing cytoplasmic Mfn2.
    Runjing Li, Feng Gao, Yunan Chen, Jiamin Zhao, Rui Shi, Man Li, Zhenzi Zuo, Pan Chang, Dema De, Lin Chen, Feng Fu, Mingge Ding.
      Increasing evidence has implicated the important role of mitochondrial morphofunctional defects in pathological myocardial hypertrophy and heart failure. Deubiquitinating enzymes (DUBs) are involved in protein stability maintenance and regulate multiple cellular processes, while it remains largely unclear whether DUBs participate in the maintenance of mitochondrial morphofunction. The aim of this study was to investigate the possible link between DUBs and abnormal mitochondrial morphofunction in pressure overload-induced pathological cardiac hypertrophy and explore the underlying molecular mechanism. RNA sequencing results showed that ubiquitin-mediated proteolysis was markedly enriched in pressure overload-induced hypertrophied and failing myocardium, and USP10 was identified as the most significantly downregulated gene among them and correlated with heart failure severity in human heart samples. Restoration of USP10 mitigates cardiac hypertrophy and dysfunction as well as abnormal mitochondrial morphofunction in vitro and in vivo. Immunoprecipitation and mass spectrometry analysis mechanistically revealed that USP10 directly interacted with Mfn2 (a mitochondrial outer membrane protein). Interestingly, the interaction between Mfn2 and USP10 occurred in cytoplasm but not on mitochondria. His-679 in the UCH domain of USP10 exerted deubiquitination to maintain the stability of the Mfn2 by removing the K11/K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining mitochondrial function and homeostasis. Knockdown or knockout of Mfn2 largely eliminated the cardioprotection of USP10. Additionally, reduced USP10 expression in hypertrophied myocardium was induced by impaired translation of Yy1. Together, our findings provide a USP10-modulated mitochondrial homeostasis mechanism that enhances the stability of cytoplasmic Mfn2 before its translocation to mitochondria. USP10 may represent a novel therapeutic target for combating pressure overstress-induced cardiac hypertrophy and heart failure.
    Keywords:  Heart failure; Mfn2; Mitochondrial morphofunction; Pathological cardiac hypertrophy; USP10
    DOI:  https://doi.org/10.1016/j.redox.2025.103745
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