bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–05–25
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Chronic mild stress disrupts mitophagy and mitochondrial status in rat frontal cortex.
  2. MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival.
  3. Enterovirus 71 Induces Mitophagy via PINK1/Parkin Signaling Pathway to Promote Viral Replication.
  4. Ginsenoside Rh1 attenuates chondrocyte senescence and osteoarthritis via AMPK/PINK1/Parkin-mediated mitophagy.
  5. How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?
  6. Global mitophagy inhibition via BNIP3 ablation is not sufficient to alleviate skeletal muscle impairments in male and female tumor-bearing mice.
  7. Combining doxorubicin and miR-218-5p: a new strategy to fight breast cancer?
  8. M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling.
  9. PINK1-mediated mitochondrial autophagy protects lens epithelial cells by reducing ROS and apoptosis.
  10. Machine learning explores the prognostic and immuno-oncological impact of mitochondrial unfolded protein response in CESC.
  11. Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp-1 Signaling Pathway in Ovarian Cancer Cells.
  12. FOXO3a regulation of non-small cell lung cancer radiotherapy resistance through the PINK1/Parkin pathway of protective mitophagy.
  13. Macrophage-derived S100A9 promotes diabetic cardiomyopathy by disturbing mitochondrial quality control via STAT3 activation.
  14. DAZAP1 maintains gastric cancer stemness by inducing mitophagy.
  15. Osteocytes burn out, give bone a break.
  16. Magnoflorine alleviates nonalcoholic fatty liver disease by modulating lipid metabolism, mitophagy and inflammation.
  17. Chuanxiong-Danggui herb pair alleviated cognitive deficits of APP/PS1 mice by promoting mitophagy.
  18. Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.
  19. A commentary on "SIRT1-Rab7 axis attenuates NLRP3 and STING activation through late endosomal-dependent mitophagy during sepsis-induced acute lung injury".
  20. Mitochondrial dysfunction in epilepsy: mechanistic insights and clinical strategies.
  21. Brevilin A, a novel BNIP3 inhibitor suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss via impairing mitophagy and mitochondrial metabolism.
  22. Autophagy receptor optineurin promotes spring viremia of carp virus replication via mitophagy and innate immune pathways in Cyprinus carpio.
  23. PINK1/PARKIN-mediated mitophagy inhibits the interferon response and promotes viral replication during Pseudorabies virus infection.
  24. 1,25(OH)2D3 up-regulated mitochondrial dynamics and biogenesis to modulate steroidogenesis in the scent glands of muskrats (Ondatra zibethicus).
  25. Apoptotic Bodies Restore NAD and Mitochondrial Homeostasis in Fibroblasts.
  26. Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.
  27. SIRT1 and its SUMOylation attenuate hyperoxia-induced lung injury by improving mitochondrial biogenesis and fusion.
  28. Excessive dietary saturated fat or fructose and their combination (found in ultra-processed foods) impair mitochondrial dynamics markers and cause brown adipocyte whitening in adult mice.
  29. Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos.
  30. High fat diet (HFD) induced hepatic lipogenic metabolism and lipotoxicity via Parkin-dependent mitophagy and Errα signal of Pelteobagrus fulvidraco.
  31. METTL14 promotes TBK1 mRNA stability through IGF2BP3-recognized m6A modification and enhances mitophagy in BMSCs.
  32. Short peptide perturbs spermatogenesis via immune microenvironment dysregulation and mitochondrial imbalance.
  33. A liver-fat crosstalk for iron flux during healthy beiging of adipose tissue.
  34. β-hydroxybutyrate enhances mitochondrial function via mitochondrial-derived vesicles.
  35. Peptide YY fragment PYY1-36 disrupts mitochondrial biogenesis via RBM43-dependent PGC-1α translation inhibition.
  36. SRSF1-mediated alternative splicing regulates bladder cancer progression and cisplatin sensitivity through HIF1A/BNIP3/mitophagy axis.
  37. Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.
  38. Maternal exposure to high-fat diet induces long-term mitochondrial alterations in the offspring heart.
  39. Cold storage effects on mitochondrial bioenergetics and protein expression in human mesenchymal stromal cells.
  40. Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis.
  41. Ganoderma lucidum extract reduces skin aging by reducing mitochondrial stress and controlling mitochondrial numbers.
  42. TBRG4 regulates ubiquitination of Beclin1 and participates in autophagy pathway to inhibit intervertebral disc degeneration.
  43. ShenQi ShenKang Granule Alleviates Chronic Kidney Disease by Inhibiting the PI3K/AKT/mTOR Pathway and Restoring Autophagy Flux and Mitochondrial Integrity.
  44. OGT-mediated O-GlcNAc of PINK1 promotes the progression of obesity-related hypertension via regulating mitophagy.
  45. Vitamin K2 Attenuates Mitochondrial Damage in Renal Proximal Tubular Cells.
  46. Disrupted host-microbiota crosstalk promotes nonalcoholic fatty liver disease progression by impaired mitophagy.
  47. Validation of the Mechanism of Action of Jiedu Shengji Oil in the Treatment of Radiation Dermatitis based on Network Pharmacology and In Vivo Experiments.
  48. Varespladib attenuates Naja atra-induced acute liver injury via reversing Nrf2 signaling-mediated ferroptosis and mitochondrial dysfunction.
  49. Mitochondrial Distribution and Osteocyte Mechanosensitivity.
  50. Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy.
  51. Identification of the hub genes involved in ATF5 mediated stress response in vitrified mouse oocytes based on WGCNA.
  52. Protein misfolding and mitochondrial dysfunction in glaucoma.
  53. Maternal exposure to urban particulate matter induces cardiac developmental toxicity in zebrafish offspring by disrupting mitochondrial homeostasis.
  54. FOXK2 in skeletal muscle development: a new pathogenic gene for congenital myopathy with ptosis.
  55. Baicalein based nano-delivery system restores mitochondrial homeostasis through PPAR signaling pathway to promote wound healing in diabetes.
  56. Re-exploration of all ATG genes.
  57. Powering immunity: mitochondrial dynamics in natural killer cells.
  58. Hyperbaric Oxygen Increases Mitochondrial Biogenesis and Function with Oxidative Stress in HL-1 Cardiomyocytes.
  1. J Transl Med. 2025 May 23. 23(1): 580
    Chronic mild stress disrupts mitophagy and mitochondrial status in rat frontal cortex.
    Cristina Ulecia-Morón, Álvaro G Bris, Karina S MacDowell, José L M Madrigal, Borja García-Bueno, Juan C Leza, Javier R Caso.
       BACKGROUND: Mitochondria are very dynamic organelles that maintain cellular homeostasis, crucial in the central nervous system. Mitochondrial abnormalities have been described in neuropsychiatric diseases, namely major depression disorder (MDD) and schizophrenia. Since stress is the predominant non-genetic cause of MDD, and has a direct impact on mitochondrial networks, understanding how psychological stress affects mitochondrial health is vital to improve the current pharmacological therapies.
    METHODS: The effect of 21 days of unpredictable stress was evaluated in frontal cortex of Wistar male rats comparing protein and gene markers of mitophagy (PINK1, PARKIN, BNIP3, NIX, FUNDC1), mitochondrial biosynthesis (PGC1α, NRF1, TFAM) and dynamics (MFN1, MFN2, OPA1, DRP1), and mitochondrial presence within microglia with the MitoTracker Green FM™ probe.
    RESULTS: Chronic mild stress (CMS) caused the upregulation of mitochondrial mass, mitochondria depolarization, dysregulation in mitochondrial dynamics towards fusion, the increase of mitophagy markers and the induction of genes that activate mitochondrial biogenesis in frontal cortex. CMS also promoted microglia recruitment and mitochondrial number boosting within them.
    CONCLUSIONS: There is a dysregulation of mitochondrial dynamics towards fusion, an upregulation of mitophagy markers, and the induction of genes associated with mitochondrial biogenesis in response to CMS in the frontal cortex of adult rats. This study highlights the impact of psychological stress on brain mitochondrial networks.
    Keywords:  Chronic mild stress (CMS); Microglia; Mitochondria; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12967-025-06604-1
  2. Autophagy Rep. 2023 ;2(1): 2267882
    MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival.
    Debasna P Panigrahi, Sujit K Bhutia.
      MTFP1 (mitochondrial fission process 1), an inner mitochondrial membrane protein, plays a crucial role in mitochondrial fission to maintain mitochondrial morphology. Our study found that MTFP1 contains a LIR (LC3-interacting region) to interact with MAP1LC3B (microtubule-associated protein 1 light chain 3 beta) and serves as a mitophagy receptor to eliminate damaged mitochondria. Interestingly, mutation of MTFP1 LIR motif (MTFP1mLIR) inhibits this interaction, decreasing mitophagy in oral cancer cells. Moreover, knockdown of PRKN (parkin RBR E3 ubiquitin protein ligase) or PINK1 (PTEN-induced kinase 1) abolished mitophagy in MTFP1-overexpressing oral cancer cells. In this setting, we observed that MTFP1mLIR-expressing cells display a decrease in TOMM20 (translocase of outer mitochondrial membrane 20) levels without affecting those of COX4 (cytochrome c oxidase subunit 4). In contrast, loss of PRKN or PINK1 caused inhibition of both TOMM20 and COX4 degradation in MTFP1mLIR-expressing cells exposed to cellular stress, suggesting that PRKN may activate the rupture of outer mitochondrial membrane in MTFP1-overexpressing cells for effective mitophagy. We also observed that MTFP1 is beneficial to oral cancer cell survival exposed to anticancer drugs, such as cisplatin, through mitophagy, since inhibition of MTFP1-dependent mitophagy induced cell death. Thus, targeting MTFP1-associated mitophagy could represent a strategy for oral cancer therapy. Abbreviations: BBC3/PUMA, BCL2 binding component 3; BCL2L13, BCL2 like 13; BINIP3L, BCL2 interacting protein 3 like; BNIP3, BCL2 interacting protein 3; CCCP, Carbonyl cyanide m-chlorophenylhydrazone; COX4, cytochrome c oxidase subunit 4; DNM1L, dynamin 1 like;FKBP8, FKBP prolyl isomerase 8; FIS1, fission, mitochondrial 1; FUNDC1, FUN14 domain containing 1; LIR, LC3 interacting region; MTFP1, mitochondrial fission process 1; PHB2, prohibitin 2; PI3K, Phosphatidylinositol 3-kinase; PRKN, Parkin RBR E3 ubiquitin protein ligase; PINK1, PTEN induced kinase 1; TOMM20, translocase of outer mitochondrial membrane 20.
    Keywords:  Apoptosis; MTFP1; Mitochondrial fission; Mitophagy; PRKN
    DOI:  https://doi.org/10.1080/27694127.2023.2267882
  3. FASEB J. 2025 May 31. 39(10): e70659
    Enterovirus 71 Induces Mitophagy via PINK1/Parkin Signaling Pathway to Promote Viral Replication.
    Xiaoyan Tian, Meng Yuan, Linrun Li, Deyan Chen, Bingxin Liu, Xue Zou, Miao He, Zhiwei Wu.
      Enterovirus 71 (EV71) infection poses a global public health challenge, especially in infants and young children, with severe cases leading to fatal consequences. EV71 infection modulates various biological processes of the host and evades host immunity through multiple mechanisms. The balance of mitochondrial dynamics is important for cellular homeostasis. However, the mechanisms underlying EV71-induced cellular damage via mitophagy remain unclear. In the current study, we showed that EV71 infection significantly reduced the total and mitochondrial ATP contents in cells, as well as the expression of mitochondrial proteins TOM20 and TIM23. Then, EV71 infection increased the protein levels of PINK1, Parkin, and LC3B, suggesting that EV71 infection triggers the mitophagy. Silencing PINK1 caused a significant reduction in viral replication, while overexpressing Parkin promoted the replication of EV71. Moreover, CsA treatment, as a mitophagy inhibitor, alleviated pathological damage and suppressed the replication of EV71 in vivo. Mechanistic study showed that silencing PINK1 inhibited the cleavage of MAVS by EV71, while overexpressing Parkin enhanced the cleavage of MAVS by EV71, suggesting that PINK1-mediated mitophagy was involved in regulating innate immunity. Furthermore, we found that EV71 infection promoted the release of mitochondria carrying EV71 virions into the extracellular environment, which mediated infection of other cells, thus facilitating virus spreading. In addition, we also demonstrated that the extracellular mitochondria induced the degradation of MAVS and mitophagy promoted the release of mitochondria in EV71-infected HeLa cells. In conclusion, these findings suggest that EV71 infection induces PINK1-mediated mitophagy, which inhibits innate immunity and facilitates virus replication.
    Keywords:  EV71; PINK1; Parkin; extracellular mitochondria; mitophagy
    DOI:  https://doi.org/10.1096/fj.202403315R
  4. Int Immunopharmacol. 2025 May 22. pii: S1567-5769(25)00901-4. [Epub ahead of print]159 114911
    Ginsenoside Rh1 attenuates chondrocyte senescence and osteoarthritis via AMPK/PINK1/Parkin-mediated mitophagy.
    Haitao Chen, Danyang Zhao, Siyi Liu, Yongkang Zhong, Yinxian Wen, Liaobin Chen.
      Osteoarthritis (OA) is the most common joint disease characterized by disruption of extracellular matrix (ECM) homeostasis, chronic inflammation, and upregulation of senescent phenotypes. Ginsenoside Rh1 (Rh1) exerted various pharmacological activities, including anti-inflammatory, anti-cancer, and neuroprotective effects. Herein, we aimed to explore the role and mechanism of Rh1 in OA. In IL-1β-induced OA chondrocytes, Rh1 alleviated the imbalance of ECM and senescence phenotypes. Furthermore, we found that Rh1 mitigated mitochondrial damage and the impaired mitophagy of chondrocytes induced by IL-1β, and these effects could be prevented by Mdivi-1 (a mitophagy inhibitor). Knockdown of PINK1 or Parkin partially abolished Rh1-mediated chondroprotection, indicating that Rh1 exerts its therapeutic effects via PINK1/Parkin-dependent mitophagy. Based on molecular docking, Compound C (an AMPK inhibitor), and AMPK siRNA, we found that Rh1 regulated PINK1/Parkin-mediated mitophagy through AMPK. Besides, Rh1 alleviated OA by promoting AMPK-mediated mitophagy in the anterior cruciate ligament transection (ACLT) rats. In conclusion, Rh1 alleviated OA progress by regulating AMPK/PINK1/Parkin-mediated mitophagy and is a potentially effective therapeutic target for age-related OA.
    Keywords:  Chondrocyte senescence; Ginsenoside Rh1; Mitophagy; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114911
  5. Curr Protein Pept Sci. 2025 May 16.
    How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?
    Drew Hindrer, Tyler Stark, Selman Aydogdu, Cade Ward, Mohamed Eldeeb.
      
    Keywords:  Mitochondrial fission; mitochondrial fusion; mitochondrial quality control.; mitochondrial stress; molecular metabolism; redox reactions
    DOI:  https://doi.org/10.2174/0113892037381885250506091434
  6. J Appl Physiol (1985). 2025 May 16.
    Global mitophagy inhibition via BNIP3 ablation is not sufficient to alleviate skeletal muscle impairments in male and female tumor-bearing mice.
    Francielly Morena, Ana Regina Cabrera, Toby L Chambers, Pieter J Koopmans, Seongkyun Lim, Stavroula Tsitkanou, Sabin Khadgi, Calvin Peterson, Eleanor R Schrems, Ruqaiza Muhyudin, Sepideh Shakeri, Kevin Zhao, Devan Mishra, Tyrone Washington, Kevin A Murach, Nicholas P Greene.
      Cancer cachexia (CC) is marked by severe skeletal muscle loss and dysfunction, associated with mitochondrial degeneration. Our previous studies showed induction of the mitophagy marker BNIP3 3-weeks post-Lewis Lung Carcinoma (LLC) induction. We hypothesize excessive mitophagy contributes to muscle wasting in CC. To test this, we used a Bnip3 knockout (KO) mouse model with LLC-induced CC to assess its impact on muscle outcomes. 8-weeks-old male and female mice were injected with 1x106 LLC cells or PBS (sham controls). After 4 weeks, we assessed muscle function through dorsiflexor electrophysiology, muscle protein synthesis via deuterium oxide labeling, and mitochondrial respiration. Plantaris and white-gastrocnemius muscles were analyzed for mitochondrial respiratory function, tibialis anterior (TA) for muscle cross-sectional area, and mixed-gastrocnemius for protein and mRNA analysis. Bnip3 KO showed some benefits in males, including attenuated fat loss and splenomegaly and near-significant attenuation of EDL mass loss. In females, Bnip3 KO did not prevent relative muscle atrophy or functional impairments. In males, KO lowered protein synthesis independent of cancer. Despite KO reducing mitophagy markers, it did not improve muscle mitochondrial respiration or functional outcomes. In both sexes, KO mice exhibited unbalanced mitochondrial dynamics with increased fission and reduced fusion, processes also impaired by LLC. Overall, global Bnip3 ablation may not offer significant benefits for CC by itself. These findings suggest targeting aberrant mitophagy via complete Bnip3 deletion is insufficient to alleviate cancer-induced muscle detriments in both biological sexes, while BNIP3-mediated mitophagy may be needed to maintain protein anabolism.
    Keywords:  Cachexia; Lung cancer; fractional synthesis rates; mitochondrial respiration; muscle contractility
    DOI:  https://doi.org/10.1152/japplphysiol.00009.2025
  7. Autophagy Rep. 2024 ;3(1): 2342129
    Combining doxorubicin and miR-218-5p: a new strategy to fight breast cancer?
    Francesco Davide Naso, Flavie Strappazzon.
      Autophagy has been associated with responses to chemotherapies in several types of cancer, highlighting its contribution to the development of resistance to treatments. Breast cancer (BC) is one of the most common tumors and is known for its ability to develop resistance to treatments. Doxorubicin (DXR) is a drug commonly used in BC and known to damage mitochondria. Thus, we thought to investigate if DXR treatment induces mitophagy, a selective form of autophagy specifically degrading mitochondria, in BC cells. By performing a global analysis of mitophagy-associated genes, we found a relationship between their expressions and DXR treatment. We revealed that PINK1/PARKIN-mediated mitophagy is induced following DXR treatment in different cellular BC models, such as the luminal subtype A cell line MCF7 and in the triple-negative BC cell line MDA-MB-231. By Interfering the E3 ubiquitin ligase PARKIN using miR-218-5p, we showed the efficacy in specifically targeting mitophagy in the treatment of BC. Indeed, PARKIN depletion improves cancer cells sensitivity to DXR treatment in vitro, in both stem-like and non-stem-like BC cells. Our approach, which combines two tumoricidal methods, mitophagy inhibition and chemotherapy, could therefore represent a new strategy for BC treatment. Abbreviations: BC: breast cancer; DXR: doxorubicin; MFN1: mitofusin 1; MFN2: mitofusin 2; miRNA: micro RNA; NPs: nanoparticles; OMM: outer mitochondrial membrane; PINK1: PTEN induced kinase 1; SPATA18: spermatogenesis Associated 18; TBNC: triple negative breast cancer.
    Keywords:  Doxorubicin; MiR-218-5p; breast cancer; mitophagy
    DOI:  https://doi.org/10.1080/27694127.2024.2342129
  8. Sci Rep. 2025 May 23. 15(1): 17955
    M2 microglia-derived exosomes reduce neuronal ferroptosis via FUNDC1-mediated mitophagy by activating AMPK/ULK1 signaling.
    Jian Li, Qing Chen, Hao Gu.
      Neuronal ferroptosis plays a vital role in the progression of neonatal hypoxic-ischemic brain damage (HIBD). M2-type microglia-derived exosomes (M2-exos) have been shown to protect neurons from ischemia-reperfusion (I/R) brain injury, but their impact on I/R-induced neuronal ferroptosis and the underlying mechanisms remain poorly understood. In this study, we used an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT-22 neuronal cells to investigate how M2-exos modulate ferroptosis. We found that M2-exos were internalized by HT-22 cells and significantly attenuated OGD/R-induced ferroptosis. Mechanistically, M2-exos enhanced mitophagy, which was mediated by the upregulation of FUN14 domain-containing protein 1 (FUNDC1), thereby inhibiting ferroptosis. Further analysis revealed that M2-exos activated FUNDC1-dependent mitophagy through the AMP-activated protein kinase (AMPK)/UNC-51-like kinase 1 (ULK1) signaling pathway. Taken together, these findings suggest that M2-exos ameliorate I/R-induced neuronal ferroptosis by enhancing FUNDC1-mediated mitophagy through the activation of AMPK/ULK1 signaling pathway.
    Keywords:  Exosome; Ferroptosis; Ischemia/reperfusion; Microglia; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-025-03091-8
  9. Exp Eye Res. 2025 May 19. pii: S0014-4835(25)00208-8. [Epub ahead of print] 110437
    PINK1-mediated mitochondrial autophagy protects lens epithelial cells by reducing ROS and apoptosis.
    Xiangyu Liu, Meiyu Wang, Zhenzhen Ji, Xuanlin Zhu, Jinchang Tian, Yingxin Chen, Jun Cai, Mei Dong, Zhijian Li.
      Cataracts are one of the primary causes of blindness worldwide; however, their pathogenesis remains unclear. Oxidative stress and apoptosis are two dominant inducers in the progression of cataracts; however, little is known about the specific mechanisms associated with mitophagy. This study aimed to investigate the role of PTEN-induced putative kinase 1(PINK1)-mediated mitophagy in cataract development. Initially, we induced a rat cataract model using sodium selenite and observed the upregulated expression of PINK1 and other autophagy-related proteins within lens epithelial cells, accompanied by apoptosis. Furthermore, the survival rate of human lens epithelial cells was significantly reduced by H2O2 treatment. However, PINK1 overexpression reduced ROS levels, allowing cells to survive. This reduction in reactive oxygen species (ROS) levels led to a decrease in cleaved caspase-3 and Bcl-2-associated X protein (Bax) expression and an increase in B-cell lymphoma 2 (Bcl-2) levels. In summary, PINK1 maintains mitochondrial functional stability and inhibits apoptosis by activating mitophagy, thus potentially playing a crucial protective role in cataract pathogenesis.
    Keywords:  Apoptosis; Cataract; Mitophagy; PINK1; ROS
    DOI:  https://doi.org/10.1016/j.exer.2025.110437
  10. Discov Oncol. 2025 May 23. 16(1): 883
    Machine learning explores the prognostic and immuno-oncological impact of mitochondrial unfolded protein response in CESC.
    Keh-Sen Liu, Yen-Hsiang Chang, Hsing-Ju Wu, Hung-Yu Lin.
       BACKGROUND: Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) pose significant global health challenges. While the mitochondrial unfolded protein response (UPRmt) is known to influence cancer biology, its specific role in CESC remains unclear.
    METHODS: We employed machine learning to analyze UPRmt genes in CESC using TCGA multi-omics data. Our comprehensive analysis included genetic alterations, prognostic significance, tumor-immune interactions, single-cell transcriptomics, pathway enrichment, and drug sensitivity assessments.
    RESULTS: ATF5 emerged as the most significant prognostic factor among UPRmt genes, with high expression correlating with better overall survival. High ATF5 expression was associated with an immunologically active tumor microenvironment, characterized by enhanced immune cell infiltration, increased immune checkpoint expression, and higher tumor mutational burden. Single-cell RNA sequencing revealed ATF5's distinct expression patterns in stromal cells, particularly in endometrial stromal and smooth muscle cells. Gene set enrichment analysis provided mechanistic insight, revealing ATF5's connection to the immune response via the regulation of P-stalk ribosome functions, a finding that underscores a novel aspect of UPRmt's role in shaping the tumor immune landscape. Drug sensitivity analysis showed that low ATF5 expression correlated with resistance to conventional chemotherapeutics (cisplatin, paclitaxel, and etoposide) but increased sensitivity to imatinib, potentially through EP300-dependent mechanisms.
    CONCLUSIONS: Our findings establish ATF5 as both a favorable prognostic marker and a key immune response regulator in CESC. Its influence on the tumor microenvironment and treatment response suggests potential therapeutic applications. These insights into UPRmt's role in CESC provide new directions for developing personalized treatment strategies.
    Keywords:  Activating transcription factor 5; Cervical cancer; Drug sensitivity; Machine learning; Mitochondrial unfolded protein response; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-025-02723-9
  11. J Biochem Mol Toxicol. 2025 Jun;39(6): e70273
    Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp-1 Signaling Pathway in Ovarian Cancer Cells.
    Xun Gao, Qinghua Yin, Zhilian Wang.
      Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Alterations in mitochondrial metabolism are considered defining characteristics and therapeutic targets of OC. Olaparib, an oral inhibitor of poly (ADP-ribose) polymerase, has been approved for the treatment of OC. However, the precise mechanisms by which it exerts its effects remain unclear. In this study, we uncover a novel pharmacological function of Olaparib by demonstrating that it induces mitochondrial dysfunction in human SKOV3 ovarian cancer cells. Our findings revealed that Olaparib exposure induced mitochondrial oxidative stress by elevating mitochondrial ROS levels and diminishing GPx activity. Additionally, treatment with Olaparib led to mitochondrial dysfunction, as evidenced by decreased complex I and complex IV activity and reduced ATP production. We observed that Olaparib induced mitochondrial fission by decreasing the average length of mitochondria. Olaparib did not affect the levels of Mfn1, Mfn2, or the total expression of Drp-1. Intriguingly, Olaparib increased the levels of phosphorylated Drp-1 at Ser616. Further investigation revealed that Olaparib facilitated the activation of the CDK5 signaling pathway and induced Caspase 3 activation. Notably, inhibition of CDK5 signaling using roscovitine mitigated the effects of Olaparib on mitochondrial fission and dysfunction, indicating a role for CDK5 in this process. In summary, our research identifies that CDK5/Drp-1-mediated mitochondrial fission may represent a novel mechanism through which Olaparib exerts its anticancer effects in OC.
    Keywords:  CDK5; Drp‐1; mitochondrial fission; olaparib; ovarian cancer
    DOI:  https://doi.org/10.1002/jbt.70273
  12. Transl Lung Cancer Res. 2025 Apr 30. 14(4): 1320-1339
    FOXO3a regulation of non-small cell lung cancer radiotherapy resistance through the PINK1/Parkin pathway of protective mitophagy.
    Xiaoting Wu, Litang Huang, Lu Meng, Shilan Luo, Paola Anna Jablonska, Chi Zhang, Anqi Zhang, Peng Li, Xiaomei Gong.
       Background: Radiotherapy resistance has become one of the major causes of radiotherapy failure among patients with non-small cell lung cancer (NSCLC), but its underlying mechanism remains unclear. In recent years, the influence of mitochondrial autophagy on the radiotherapy resistance in treated tumor cells and its regulatory mechanism has become a hotspot in research, which is also the subject of our group research effort. The primary objective of our study is to investigate the mitophagy-associated pathway and the regulatory mechanisms underlying radiotherapy resistance in NSCLC.
    Methods: We developed biologically stable radiotherapy-resistant NSCLC cell models A549/X and H520/X and verified the radioresistance of these cells. Subsequently, through high-throughput transcriptomic sequencing analysis and experimental verification, we found that the Forkhead box O 3a (FOXO3a) gene and the PINK1/Parkin mitochondrial autophagy pathway in NSCLC radiotherapy-resistant cell lines were consistent and upregulated more reactively than those of parent cells. The effect of gene expression status of the FOXO3a-PINK1/Parkin pathway on the survival outcomes of NSCLC was analyzed in The Cancer Genome Atlas (TCGA) database. Next, we inoculated nude mouse xenografts with small interfering RNA to interfere with the FOXO3a gene and short hairpin RNA to construct radiotherapy-resistant stable strains of NSCLC with stable knockdown of FOXO3a gene. Subsequently, the association and regulation of FOXO3a gene expression levels with radioresistance and mitochondrial autophagy PINK1/Parkin pathway at the cellular and animal levels were determined.
    Results: The expression level of FOXO3a gene in NSCLC radioresistant cells was significantly positively correlated with the level of mitophagy and the expression level of PINK1/Parkin pathway. Higher expression levels of genes in the FOXO3a-PINK1/Parkin pathway had a negative effect on survival outcomes in NSCLC and were positively correlated with the radioresistance of cells.
    Conclusions: FOXO3a regulates NSCLC radioresistance by modulating the mitochondrial autophagy PINK1/Parkin pathway, which may serve as a new molecular intervention target and therapeutic entry point for intervening and improving the radioresistance of patients with NSCLC in clinical practice.
    Keywords:  FOXO3a; Non-small cell lung cancer (NSCLC); PINK1/Parkin pathway; mitochondrial autophagy; radiotherapy resistance
    DOI:  https://doi.org/10.21037/tlcr-2025-181
  13. Int J Biol Sci. 2025 ;21(7): 3061-3080
    Macrophage-derived S100A9 promotes diabetic cardiomyopathy by disturbing mitochondrial quality control via STAT3 activation.
    Shengqi Huo, Moran Wang, Min Du, Bowen Ren, Tianshu Yang, Lulu Peng, Yue Jiang, Dewei Peng, Lintong Men, Wei Shi, Junyi Guo, Cuntai Zhang, Jiagao Lv, Sheng Li, Li Lin.
      The macrophage-cardiomyocyte crosstalk as a potential intervention target for diabetic cardiomyopathy (DCM) remains deeper exploration. We found S100A9, as an immunoinflammatory mediator, was up-regulated in cardiomyocytes and macrophages in diabetic heart by single-cell analysis. Furthermore, F4/80+CCR2+S100A9+ macrophages in peripheral blood and heart both increased in diabetic mice. S100A9 blocking by paquinimod or macrophage depletion (clodronate) alleviated diabetes-induced cardiac dysfunction, inflammatory macrophage infiltration, serum pro-inflammatory cytokines. More importantly, diabetic cardiac dysfunction, myocardial remodeling, and inflammation could be suppressed by macrophage specific S100A9 knockout (S100a9flox/floxLyz2-Cre). S100A9 activation led to excessive mitochondrial fission, decreased mitophagy flux, and elevated mitochondrial oxidative stress. In addition, proteomics and transcription factor profiling array unveiled S100A9 activated STAT3 in cardiomyocytes. Nevertheless, these effects were mitigated by STAT3(Y705F) mutation, STAT3 knockdown, or paquinimod. Our study highlights macrophage-derived S100A9 as a critical mediator for impaired mitochondrial quality control in diabetic cardiac dysfunction, and targeting S100A9 represents a promising therapeutic target.
    Keywords:  S100A9; STAT3; diabetic cardiomyopathy; macrophage; mitochondrial quality control
    DOI:  https://doi.org/10.7150/ijbs.111128
  14. JCI Insight. 2025 May 22. pii: e175422. [Epub ahead of print]10(10):
    DAZAP1 maintains gastric cancer stemness by inducing mitophagy.
    Peiling Zhang, Wei Wang, Hong Xiang, Yun Zhou, Qian Peng, Guolong Liu, Zhi-Xiang Xu, Lin Lu.
      Stem cells play a pivotal role in the malignant behavior of gastric cancer (GC), complicating its treatment and prognosis. However, the regulatory mechanisms of GC stem cells (GCSCs) remain poorly understood. DAZ-associated protein 1 (DAZAP1), a splicing regulator linked to various malignancies, has an unclear role in GC. This study investigated DAZAP1's impact on GC stemness and its mechanisms. DAZAP1 promoted tumor progression in GCSCs, as shown by sphere formation assays and stemness marker analysis. Functional enrichment analysis suggested that DAZAP1 enhanced tumor stemness by promoting oxidative phosphorylation (OXPHOS), which was validated through Seahorse assays and measurements of mitochondrial potential. Transmission electron microscopy and immunofluorescence analyses demonstrated that DAZAP1 promoted mitophagy. RNA immunoprecipitation and PCR analysis revealed that DAZAP1 regulated the splicing and expression of the mitophagy-related gene ULK1 through nonsense-mediated mRNA decay. Rescue experiments showed that overexpression of ULK1 reversed the suppression of GC stemness and OXPHOS levels induced by DAZAP1 silencing. Our findings indicate that DAZAP1 reduces ULK1 decay, thereby activating mitophagy and enhancing OXPHOS to fulfill the metabolic demands of cancer stem cells. These findings highlight the therapeutic potential of DAZAP1 as a target for treating GC.
    Keywords:  Autophagy; Cell biology; Gastric cancer; Mitochondria; Oncology; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.175422
  15. Kidney Int. 2025 Jun;pii: S0085-2538(25)00266-2. [Epub ahead of print]107(6): 974-976
    Osteocytes burn out, give bone a break.
    Aline Martin.
      The pathogenic mechanisms of chronic kidney disease-induced osteoporosis are not well understood and might involve metabolic alterations and apoptosis of osteocytes. In this issue, Hsu et al. present experimental work in uremic mice and cultured mouse osteoblasts showing that impaired mitochondrial function and mitophagy in osteocytes contribute to chronic kidney disease-associated osteoporosis. They investigate new therapeutic approaches to improve mitochondrial function in the setting of increased uremic toxin levels.
    DOI:  https://doi.org/10.1016/j.kint.2025.03.015
  16. Prostaglandins Other Lipid Mediat. 2025 May 14. pii: S1098-8823(25)00050-4. [Epub ahead of print]178 106997
    Magnoflorine alleviates nonalcoholic fatty liver disease by modulating lipid metabolism, mitophagy and inflammation.
    Liming Wang, Yan Yang, Haibing Sun, Mengxue Fei.
       BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver condition associated with metabolic syndrome, often aggravated by inflammation and mitochondrial dysfunction. This study aims to explore the therapeutic potential of magnoflorine, an alkaloid with known anti-inflammatory properties, in ameliorating NAFLD by modulating mitochondrial autophagy and inhibiting the NLRP3 inflammasome.
    METHODS: Male C57BL/6 J mice were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Magnoflorine (5 and 10 mg/kg) was administered by gavage daily for 16 weeks. Liver and serum samples were analyzed for lipid profiles, inflammation markers, and autophagy-related proteins, and liver histology was examined to assess changes.
    RESULTS: Magnoflorine treatment improved dyslipidemia in NAFLD mice, shown by decreased serum triglycerides, total cholesterol, and LDL-C, and increased HDL-C. Histological analysis showed reduced hepatic steatosis and inflammation, with less lipid droplet accumulation and hepatocyte ballooning. Western blot results indicated upregulation of Parkin and PINK1, and downregulation of NLRP3, ASC, and caspase-1, with lower serum IL-1β levels, reflecting reduced inflammation.
    CONCLUSIONS: Magnoflorine offers a promising approach for mitigating NAFLD progression through modulating mitochondrial autophagy and inhibiting inflammation.
    Keywords:  Lipid metabolism; Magnoflorine; Mitophagy; NLRP3 inflammasome; Nonalcoholic fatty liver disease
    DOI:  https://doi.org/10.1016/j.prostaglandins.2025.106997
  17. J Ethnopharmacol. 2025 May 17. pii: S0378-8741(25)00673-7. [Epub ahead of print] 119988
    Chuanxiong-Danggui herb pair alleviated cognitive deficits of APP/PS1 mice by promoting mitophagy.
    Keting Pu, Simin Yang, Ruilin Sheng, Jie Chen, Yuan Dai, Ian C Wood, Zhanqiong Zhong, Shijun Xu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Disruption of receptor-mediated mitophagy contributes to neuronal damage in Alzheimer's disease (AD). Chuanxiong-Danggui herb pair (CDHP) is classic herbal pair applied to treating neurodegenerative diseases including AD, Amyotrophic Lateral Sclerosis, Parkinson's disease. Though studies have demonstrated the neuroprotective effects of CDHP, the underlying mechanisms by which CDHP attenuates neuronal impairment of AD remains to be elucidated.
    AIM OF THE STUDY: The objective of this work was to investigate the anti-AD mechanism of CDHP in APP/PS1 mice.
    MATERIALS AND METHODS: Behavioral assessments were conducted on C57BL/6J and APP/PS1 mice following CDHP treatment, alongside an evaluation of neuronal morphology in the hippocampal region. In vitro, HT-22 cells were induced by Aβ25-35 before being treated with CDHP. The mechanisms of CDHP were investigated using transmission electron microscopy, Golgi staining, immunofluorescence, siRNA, and Western blot analysis.
    RESULTS: Results from the passive avoidance test and the Morris water maze (MWM) indicated that CDHP significantly mitigated cognitive deficits of APP/PS1 mice, accompanied by a reduction of pathological damage in the CA1 and CA3 regions of hippocampus. Further testing found that a significant reduction in dendritic spines density was rescued by CDHP. Synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) were elevated in the CDHP group, while Aβ (β-amyloid) plaques deposition was significantly reduced. Simultaneously, CDHP markedly inhibited neuronal apoptosis through a decrease of the levels of Cleaved Caspase-12 and enhanced expression of Bcl-2/Bax, both in vivo and in vitro. Additionally, CDHP improved mitochondrial morphology and function in the AD model by decreasing abnormal mitochondria and increasing the expression of COXIV. Transmission electron microscopy (TEM) revealed that clear mitophagy-autophagosomes were nearly absent in APP/PS1 mice, while the expression of p62 and LC3B were elevated following CDHP treatment. Furthermore, CDHP increased the expression of the FUNDC1 and PGAM5 in APP/PS1 mice and AD-like cell models.
    CONCLUSION: These findings suggest that CDHP mitigated cognitive dysfunction in APP/PS1 mice by enhancing mitophagy to reduce neuronal injury.
    Keywords:  Alzheimer's disease; CDHP; FUNDC1,PGAM5; Mitophagy
    DOI:  https://doi.org/10.1016/j.jep.2025.119988
  18. Autophagy Rep. 2024 ;3(1): 2314361
    Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.
    Rebeca Martín-Jiménez, Olivier Lurette, Etienne Hebert-Chatelain.
      Accumulation of Lewy bodies in dopaminergic neurons is associated to Parkinson disease (PD). The main component of Lewy bodies appears to be aggregates of alpha-synuclein (α-syn). Several mutations of the gene encoding this protein promote its aggregation. Thus, clustering of α-syn is considered a central event in the onset of PD. An old theory also postulates that mitochondrial dysfunction represents another cause of PD pathogenesis. However, the impact of α-syn aggregates on mitochondria remains poorly understood considering the technical difficulties to discriminate between the different forms of α-syn. In this punctum, we describe our recent work in which we used a newly developed optogenetic tool to control the aggregation of α-syn and examine the impact on mitochondria. This work revealed that α-syn aggregates dynamically interact with mitochondria, triggering their depolarization and leading to cardiolipin translocation to the surface of mitochondria and mitophagy. Abbreviations: α-syn: alpha-synuclein; BNIP3L: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; FUNDC1: FUN14 domain-containing protein 1; IMM: inner mitochondrial membrane; LIPA: light-induced protein aggregation; OMM: outer mitochondrial membrane; PD: Parkinson disease; SNc: substantia nigra par compacta.
    Keywords:  Lewy bodies; PLSCR3; mitochondrial fission; mitochondrial membrane potential; parkinson disease; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1080/27694127.2024.2314361
  19. Int J Surg. 2025 May 16.
    A commentary on "SIRT1-Rab7 axis attenuates NLRP3 and STING activation through late endosomal-dependent mitophagy during sepsis-induced acute lung injury".
    Chang'An Zhao, Yani Li, Shibiao Fu, Lan Shen.
      
    DOI:  https://doi.org/10.1097/JS9.0000000000002509
  20. Mol Biol Rep. 2025 May 20. 52(1): 470
    Mitochondrial dysfunction in epilepsy: mechanistic insights and clinical strategies.
    Xiaolu Zhang, Zhengjuan Wu, Xu Zhou, Hua Tao.
      Epilepsy is a common neurological disorder that is increasingly recognized for its significant association with mitochondrial dysfunction. This review explores the intricate relationship between mitochondrial dysfunction and epilepsy, highlighting the molecular mechanisms, diagnostic strategies, and therapeutic approaches involved. Mitochondrial abnormalities, including defects in the electron transport chain, impaired mitochondrial dynamics, disrupted autophagy, and increased oxidative stress, are implicated in epilepsy pathogenesis. The molecular mechanisms involve respiratory chain impairments, fission-fusion imbalances, inadequate mitophagy, and oxidative stress-induced neuronal excitability. The diagnosis of mitochondrial epilepsy requires a multifaceted approach, combining clinical assessment, biochemical testing, imaging, and genetic analysis, with a particular focus on mtDNA mutations. Therapeutic strategies include antiepileptic drugs with variable mitochondrial effects, the ketogenic diet, and emerging potential approaches such as antioxidants and mitochondrial-targeted therapies. Despite advances in understanding and treatment, challenges persist due to the complexity of mtDNA mutations and treatment resistance. Future directions involve gene-editing technologies, mitochondrial transplantation, and induced pluripotent stem cells, which hold promise for addressing the underlying defects and improving epilepsy management.
    Keywords:  Epilepsy; Ketogenic diet; Mitochondria; Mutation; Oxidative stress
    DOI:  https://doi.org/10.1007/s11033-025-10577-1
  21. Phytomedicine. 2025 May 01. pii: S0944-7113(25)00413-1. [Epub ahead of print]143 156774
    Brevilin A, a novel BNIP3 inhibitor suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss via impairing mitophagy and mitochondrial metabolism.
    Rui Zhou, Yiyuan Wang, Siyi Liu, Yuangang Su, Zhijuan Liu, Baihui Yang, Xiangde Li, Jinmin Zhao, Jiake Xu, Qian Liu, Fangming Song.
       BACKGROUND: The mitochondrial dysfunction and overactive osteoclasts is involved in the progress of osteoporosis. Brevilin A (BA), a sesquiterpene lactone, is a compound extracted and purified from Centipeda minima. It exhibits a range of pharmacological activities, such as anti-inflammatory and antioxidant effects. However, its specific impact on osteoporosis remains unclear. The present study is designed to explore BA as a novel osteoclast inhibitor for the treatment of osteoporosis as well as its molecular mechanisms of action via BNIP3-mediated mitophagy.
    METHODS: The cytotoxicity of BA in vitro was evaluated using the CCK8 assay, while tartrate-resistant acid phosphatase (TRAcP) staining and bone resorption assays were conducted to examine its effects on osteoclastogenesis and osteoclast function. To elucidate the molecular mechanisms by which BA targets BNIP3 in osteoclasts, RNA-seq, molecular docking analysis, Surface plasmon resonance (SPR), qPCR, western blot, mitochondrial oxygen consumption rate (OCR), transmission electron microscopy (TEM), Single cell sequencing and immunofluorescence staining were employed. In addition, a specific BNIP3 agonist IOX5, was used to revalidate the inhibitory effect of BA on BNIP3. To investigate the effects and protective role of BA in modulating BNIP3 on bone loss in osteoporotic mice induced by ovariectomy (OVX), we employed in vivo micro-CT scanning and histological immunostaining techniques.
    RESULTS: Our study demonstrated that BA inhibited RANKL-induced osteoclastogenesis in a concentration-dependent manner without any cell cytotoxicity. Further, BA abrogated MAPK-related proteins and intracellular and mitochondrial ROS level, subsequently inhibiting NFATc1 activity. RNA-seq analysis revealed that the molecular mechanism by which BA inhibited osteoclasts is closely related to mitophagy and mitochondrial function. Here, we found that BA suppressed oxygen consumption rate and mitochondrial oxidative phosphorylation during osteoclastogenesis. This compound abolished expression of ATG5, SIRT3, Beclin1 and LC3B. RANKL-induced mitophagy associated protein (PINK1 and Parkin) were also suppressed by BA. BA interacted with BNIP3 and IOX5 treatment further verified the targeted inhibition effect of BA on BNIP3. In addition, we found that BNIP3 deficient inhibited osteoclast differentiation related with mitophagy and mitochondrial function. In vivo experiments confirmed that BA significantly prevent OVX-induced bone loss associated with BNIP3-mediated mitophagy.
    CONCLUSIONS: Our study reveals for the first time that BA acts as a novel inhibitor of BNIP3, which ameliorates osteoclast activity and OVX-induced osteoporosis via limiting mitophagy and mitochondrial energy production, suggesting that it could be a novel therapeutic strategy for osteoporosis.
    Keywords:  BNIP3; Brevilin A; Mitochondrial function; Mitophagy; Osteoclast; Osteoporosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.156774
  22. Int J Biol Macromol. 2025 May 20. pii: S0141-8130(25)04861-5. [Epub ahead of print] 144309
    Autophagy receptor optineurin promotes spring viremia of carp virus replication via mitophagy and innate immune pathways in Cyprinus carpio.
    Yunli Zhang, Chen Li, Mengxi Zhang, Songjie Qi, Xianghui Kong.
      Optineurin (OPTN), an important biological macromolecule protein, functions as a selective autophagy receptor that is essential for mitophagy induction and innate immune regulation. This study identified and characterized two OPTN genes from common carp (Cyprinus carpio), demonstrating that CcOPTNs promoted mitophagy while downregulating the interferon pathway and inflammatory response. Spring viremia of carp virus (SVCV), an RNA virus, poses a significant threat to Cyprinidae fish health. A comprehensive analysis of its interaction with the host can provide valuable insights for fish disease prevention and control. Therefore, we established an SVCV infection model and observed that SVCV stimulation significantly altered the expression of CcOPTNs. Furthermore, CcOPTNs facilitated SVCV replication by promoting mitophagy and impairing innate antiviral immunity. Collectively, our findings indicated that CcOPTNs serve as critical regulators of mitophagy and innate immunity, playing a pivotal role in the immune response to SVCV infection.
    Keywords:  Mitophagy; Optineurin; Spring viremia of carp virus
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144309
  23. Autophagy Rep. 2024 ;3(1): 2422214
    PINK1/PARKIN-mediated mitophagy inhibits the interferon response and promotes viral replication during Pseudorabies virus infection.
    Yuan Zhao, Zhenbang Zhu, Wenqiang Wang, Zhendong Zhang, Wei Wen, Xiangdong Li.
      Pseudorabies virus (PRV) poses a significant threat to the global swine industry, characterized by high morbidity and a range of sequelae in infected pigs. Mitochondria serve as a crucial platform for innate immunity, playing a pivotal role in a wide array of antiviral responses. In our recent study, we revealed that PRV infection induces mitochondrial disruption, which in turn triggers PINK1/PARKIN-mediated mitophagy. We also show that this process leads to the degradation of the mitochondrial antiviral signaling protein (MAVS) and the inhibition of antiviral interferon production and signaling, ultimately facilitating viral replication.
    Keywords:  Interferons; MAVS; Pseudorabies virus; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/27694127.2024.2422214
  24. J Steroid Biochem Mol Biol. 2025 May 20. pii: S0960-0760(25)00115-3. [Epub ahead of print]252 106787
    1,25(OH)2D3 up-regulated mitochondrial dynamics and biogenesis to modulate steroidogenesis in the scent glands of muskrats (Ondatra zibethicus).
    Qingjing Gao, Ke Shi, Xinjing Shi, Yuning Liu, Haolin Zhang, Qiang Weng.
      Vitamin D3 plays a crucial regulatory role in steroid hormone production, but the specific mechanism remains not fully understood. In this study, we investigated the expression and distribution patterns of Vitamin D receptor (VDR), vitamin D3 metabolic enzymes (CYP2R1, CYP27B1 and CYP24A1), mitochondrial dynamics and biogenesis (proteins and genes), and steroidogenic enzymes in the scent glands of muskrats during the breeding and non-breeding periods. VDR, vitamin D3 metabolic enzymes, mitochondrial dynamics and biogenesis-related proteins, and steroidogenic enzymes were immunolocalized in the scent glandular cells in both breeding and non-breeding seasons, with stronger immunostaining in the breeding season. The mRNA expression levels of Cyp27b1, Cyp24a1, Vdr, Mfn1, Opa1, Vdac, Tfam, Pgc1b, Star, Cyp11a1, Cyp17a1, and Cyp19a1 were higher in the scent glands during the breeding season than those of the non-breeding season. 1,25(OH)₂D₃ concentration were positively correlated with the mean mRNA expression levels of mitochondrial dynamics and biogenesis marker genes and steroidogenic enzymes in the scent glands. The concentrations of circulating testosterone (T) and 17β-estradiol (E2), and 1,25(OH)₂D₃ of the scent glands were also significantly higher in the breeding season. Additionally, the addition of 1,25(OH)2D3 to the primary scent glandular cells in vitro increased the expression levels of mitochondrial dynamics and biogenesis-related genes and steroidogenic enzymes in the scent glands of muskrats. These findings suggested that 1,25(OH)₂D₃ might promote the secretion of steroid hormones by upregulating the mitochondrial dynamics and biogenesis in the scent glands of muskrats.
    Keywords:  1,25(OH)₂D₃; Mitochondrial biogenesis; Mitochondrial dynamics; Muskrat; Scent gland; Steroidogenic enzyme; Vitamin D receptor
    DOI:  https://doi.org/10.1016/j.jsbmb.2025.106787
  25. Adv Sci (Weinh). 2025 May 19. e15691
    Apoptotic Bodies Restore NAD and Mitochondrial Homeostasis in Fibroblasts.
    Shutong Qian, Siya Dai, Chunyi Guo, Wenjun Wang, Jiajia Pang, Yichen Shen, Mingyuan Xu, Jie Hu, Wenguo Cui, Xiaoming Sun, Jinghong Xu.
      Fibrotic skin diseases are characterized by excessive fibroblast proliferation and pathological extracellular matrix deposition. As a pivotal coenzyme in cellular energetics, NAD homeostasis perturbation is implicated in fibrosis. Multiple studies have demonstrated the therapeutic potential of mesenchymal stem cells (MSCs) against cutaneous fibrosis, while the specific mechanism remains elusive. Herein, this work finds that although almost all MSCs undergo in situ apoptosis within 24 h post-subcutaneous administration, MSC-derived apoptotic bodies (ABs) mediated potent anti-fibrotic effects. Mechanistically, ABs can restore NAD and mitochondrial homeostasis through NAMPT transfer, FOXO1 deacetylation enhancement, and PINK1/PARKIN-dependent mitophagy activation. To achieve penetration into the hard matrix of fibrotic skin, permeable apoptotic bodies (pABs) are constructed via metabolic glycoengineering and copper-free click chemistry techniques. In both keloid xenograft and scleroderma murine models, pABs can significantly penetrate collagen matrix and reduce skin fibrosis. In summary, this research establishes a highly promising strategy for reversing skin fibrosis with hard fibrotic matrix.
    Keywords:  NAD homeostasis; apoptotic body; mitophagy; skin fibrosis
    DOI:  https://doi.org/10.1002/advs.202415691
  26. Nat Microbiol. 2025 May 22.
    Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.
    Qing Zhu, Robert McElroy, Janvhi Suresh Machhar, Joel Cassel, Zihan Zheng, Behzad Mansoori, Hongrui Guo, Sen Guo, Christian Pangilinan, Jinghui Liang, Dongliang Shen, Lu Zhang, Qin Liu, Andrew V Kossenkov, Dario C Altieri, Paul M Lieberman, Shou-Jiang Gao, Pinghui Feng, Maureen E Murphy, Jikui Song, Joseph M Salvino, Qiming Liang, Jae U Jung, Chengyu Liang.
      Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defence and enhance viral fitness remains unclear. Here we show that Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprogrammes mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signalling protein (MAVS) aggregation and impairs interferon responses in cell lines. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS-IFN signalling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2-NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly and shows that targeting the virus-mitochondria interface represents a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41564-025-02018-3
  27. Free Radic Biol Med. 2025 May 20. pii: S0891-5849(25)00683-5. [Epub ahead of print]
    SIRT1 and its SUMOylation attenuate hyperoxia-induced lung injury by improving mitochondrial biogenesis and fusion.
    Kun Yang, Qinxin Zheng, Mei Luo, Rong Zhang, Shuai Zhao, Lan Kang, Xiaoping Lei, Wenbin Dong.
       OBJECTIVE: To investigate the role of silencing information regulator 2 related enzyme 1 (SIRT1) and its small ubiquitin-like modifier (SUMO) modification (SUMOylation) in hyperoxia lung injury in preterm infants.
    METHODS: The roles of SIRT1 and its SUMOylation in hyperoxia-induced damage to HAECs were explored from the cellular level using CCK-8, MTT, scratch assay, reactive oxygen species (ROS), Mito SOX™, BeyoClick™ EdU-488, immunofluorescence and Western-blot, mitochondrial membrane potential, malondialdehyde and superoxide dismutase assays, MitoTracker® Red CMXRos, transmission electron microscopy, and SIRT1 activity assay. Type II alveolar epithelial cell-specific knockout SENP1 mice were constructed. The role of SUMOylation of SIRT1 in hyperoxia lung injury in mice was explored in vivo by HE staining, immunohistochemistry, immunofluorescence, Western-blot and transmission electron microscopy.
    RESULTS: (1) Hyperoxia increased ROS in HAECs and decreased cell proliferation levels and survival, as well as reduced the expression of peroxisome-proliferator-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), optic atrophy protein 1 (OPA1), mitofusins 1 (MFN1), and mitofusins 2 (MFN2) proteins. (2) N-Acetylcysteine inhibited SIRT1 nucleoplasmic shuttling and reversed the hyperoxia-induced decrease in SUMO1 and increase in SENP1. (3) SRT1720 reversed the hyperoxia-induced decrease of PGC-1α, NRF1, TFAM, MFN1, MFN2 and OPA1 proteins. (4) Overexpression of SUMO1 increased total SIRT1 and nuclear SIRT1 but decreased cytoplasmic SIRT1 protein expression levels, attenuated hyperoxia-induced mitochondrial injury. (5) On day 14 of hyperoxia exposure, type II alveolar epithelial cell-specific knockout SENP1 mice showed reduced lung injury, increased lung tissue total SIRT1 and nuclear SIRT1 but decreased cytoplasmic SIRT1 protein expression, and reduced mitochondrial injury.
    CONCLUSION: Hyperoxia increases ROS levels to decrease SIRT1 and SUMO1 levels, thereby inhibiting mitochondrial biogenesis and fusion, and promotion of SIRT1 and its SUMOylation improves mitochondrial biogenesis and fusion, thereby attenuating hyperoxia lung injury.
    Keywords:  SIRT1; SUMOylation; bronchopulmonary dysplasia; hyperoxia; mitochondrial injury; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.400
  28. Nutrition. 2025 Apr 11. pii: S0899-9007(25)00123-6. [Epub ahead of print]137 112805
    Excessive dietary saturated fat or fructose and their combination (found in ultra-processed foods) impair mitochondrial dynamics markers and cause brown adipocyte whitening in adult mice.
    Jade Sancha de Oliveira Glauser, Daiana Araujo Santana-Oliveira, Flávia Maria Silva-Veiga, Aline Fernandes-da-Silva, Marcia Barbosa Aguila, Vanessa Souza-Mello.
       OBJECTIVE: To investigate the effects of comparable dietary excess of fat or fructose and the combination of these two insults (mimicking ultra-processed foods) on interscapular brown adipose tissue (iBAT) whitening and markers of mitochondrial dynamics in adult male mice.
    METHODS: Male C57BL/6 mice were randomly assigned into four groups according to the diet: control diet (C, following AIN-93M), high-fat diet (HF, 32% energy as lard), high-fructose diet (HFRU, 32% energy as fructose) or for high-fat/high-fructose diet (HF-HFRU, 32% as lard and 32% as fructose) for 12 weeks. Data were tested with one-way ANOVA and Dunnet T3 post-test (n=5 per analysis, significance level P < 0.05).
    RESULTS: All diets caused insulin resistance and iBAT whitening, albeit with overweight only in the HF and HF-HFRU groups. Principal component analysis indicated that the HFRU scores loaded next to inflammation (Nlrp3) and adipogenesis markers (Pparg), and the HF diet influenced more a mitochondrial gene (Tomm20). However, iBAT whitening in all groups was associated with deficits in mitochondrial dynamics (Ppargc1a, Dnml1, and Pink1), vascularization (Vegfa), and thermogenic markers (Bmp8b, and Ucp1).
    CONCLUSION: Similar increases in dietary saturated fat or fructose (32% as energy) and the combination of these two insults (32% / 32%) caused insulin resistance and brown adipocyte dysfunction (whitening) in adult mice after 12 weeks independent of being overweight. In comparison, the PC scores of the HFRU groups were closer to the HF-HFRU group than the HF group, implying a worse outcome and highlighting the importance of limiting saturated fat and fructose intake from ultra-processed foods.
    Keywords:  Brown adipose tissue; Fructose; Mitochondria; Saturated fat; Whitening
    DOI:  https://doi.org/10.1016/j.nut.2025.112805
  29. Cell Death Dis. 2025 May 19. 16(1): 402
    Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos.
    Beatriz Villarejo-Zori, Juan Zapata-Muñoz, Elena Sierra-Filardi, Ignacio Ramírez-Pardo, Lambert Montava-Garriga, Ian G Ganley, Patricia Boya.
      Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition. Olaparib and DFP rescue parthanatos induced cell death after MNU-induced retinal degeneration. High doses of MNU induce lysosomal damage and mitophagy inhibition. In addition, MNU produces DNA damage and increases oxidative stress, resulting in PAR polymer formation and retinal degeneration (orange panel). DFP and Olaparib are able to rescue retinal degeneration downstream of lysosomal damage (green panel). Sub-lethal doses of MNU induce a peak in mitophagy that is BNIP3L-BNIP3 dependent (blue panel).
    DOI:  https://doi.org/10.1038/s41419-025-07686-x
  30. J Anim Sci Biotechnol. 2025 May 21. 16(1): 71
    High fat diet (HFD) induced hepatic lipogenic metabolism and lipotoxicity via Parkin-dependent mitophagy and Errα signal of Pelteobagrus fulvidraco.
    Angen Yu, Zhiwei Hao, Xiaolei Wei, Xiaoying Tan, Ester Zito, Hua Zheng, Zhi Luo.
       BACKGROUND: Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis, but its role in high fat diet (HFD)-induced lipid accumulation is unclear in the yellow catfish. Thus, this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.
    RESULTS: In the present study, yellow catfish were fed three diets with dietary fat at 6.31% (low fat; LFD, control), 12.03% (middle fat; MFD) and 15.32% (high fat; HFD), respectively, for 8 weeks. High dietary fat addition raised hepatic lipid accumulation, and declined mRNA and protein levels of Parkin-dependent mitophagy, down-regulated the Parkin protein expression and the estrogen-related receptor alpha (Errα) ubiquitination, and induced Errα protein levels; fatty acid (FA) incubation reduced Parkin-dependent mitophagy, inhibited Errα ubiquitination and increased Errα protein expression, and raised TG accumulation. Furthermore, yellow catfish hepatocytes were isolated and cultured. Nicotinamide mononucleotide, N-acetyl-L-cysteine, Parkin and errα siRNA knockdown were used under FA incubation, respectively. Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition; Parkin ubiquitinated Errα, and K63 was an important ubiquitination site for deubiquitinating Parkin activity; Errα targets fas, acca and pparγ genes, whose activation contributed to FA-induced lipogenesis and lipid accumulation. Thus, high fat diet (HFD) and FA incubation inhibited Parkin activity, suppressed mitophagy and activated Errα pathway, and induced hepatic lipogenic metabolism and lipotoxicity.
    CONCLUSIONS: Overall, our study provided new targets against HFD-induced hepatic lipid accumulation and non-alcoholic fatty liver disease in the vertebrates.
    Keywords:  Errα; Hepatocytes; High fat diet; Lipid accumulation; Mitophagy; Parkin
    DOI:  https://doi.org/10.1186/s40104-025-01200-1
  31. Cell Signal. 2025 May 15. pii: S0898-6568(25)00288-8. [Epub ahead of print]133 111873
    METTL14 promotes TBK1 mRNA stability through IGF2BP3-recognized m6A modification and enhances mitophagy in BMSCs.
    Yue Shen, Long Wang, Zixiang Guo, Jiaohong Wang, Runzi Zhang, Chunbo Tang, Jin Wu.
      Osteoporosis, particularly postmenopausal osteoporosis, represents a growing global health challenge characterized by impaired bone remodeling and increased fracture risk. The impairment of bone regeneration manifests in the field of oral and maxillofacial medicine as delayed alveolar bone healing after tooth extraction and poor osseointegration of dental implants, significantly compromising oral functional rehabilitation. This study investigates the role of METTL14 in osteogenic differentiation and its potential regulatory mechanisms in bone metabolism. We identified differential expression patterns of METTL14 in bone marrow-derived mesenchymal stem cells (BMSCs) between osteoporotic patients and healthy controls. Through loss-of-function experiments, we further demonstrated the critical role of METTL14 in promoting osteogenic differentiation, providing direct evidence for its functional importance in bone metabolism regulation. Transcriptome sequencing analysis revealed a significant association between METTL14 and mitophagy. JC-1 assay, Mitosox assay, mt-Keima assay, western blotting and immunofluorescence demonstrated METTL14's positive regulatory role in mitophagy, with TBK1 identified as the most significantly altered downstream target through qRT-PCR and rescue experiments. We further elucidated that IGF2BP3, an m6A reader, promotes osteogenesis and regulates TBK1 mRNA stability, as evidenced by Actinomycin D treatment and mitochondrial-lysosomal colocalization assays. In vivo experiments showed that METTL14 overexpression enhanced alveolar bone healing in ovariectomized osteoporotic mice. These findings provide novel evidence supporting METTL14 as a potential therapeutic target for osteoporosis.
    Keywords:  Bone marrow mesenchymal stem cells; METTL14; Mitophagy; Osteoporosis; m6A methylation
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111873
  32. FEBS Open Bio. 2025 May 22.
    Short peptide perturbs spermatogenesis via immune microenvironment dysregulation and mitochondrial imbalance.
    Heng Wang, Xiaofang Tan, Deyu Chen.
      A short peptide derived from the occludin protein regulates tight junctions (TJ) of the blood-testis barrier and impairs germ cell development. However, the mechanism behind how this peptide regulates TJ and induces cell apoptosis remains unclear. In the present study, an animal model with induced TJ disruption via the short peptide was used to evaluate its impact on spermatogenesis. Here, we demonstrate that the short peptide promoted the infiltration of immune cells into the testicular interstitial tissue, accompanied by upregulation expression of the pro-inflammatory factors interleukin-6 and tumor necrosis factor-α. Moreover, mitochondrial fragmentation and mitophagy were upregulated in Sertoli cells and Leydig cells. Consistently, terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed extensive apoptosis in the testes during spermatogenesis. Notably, the severity of these disruptions began to attenuate after 27 days, although full functional recovery was not observed. Our findings reveal a novel mechanism wherein peptide-induced immune dysregulation and mitochondrial dysfunction synergistically impair spermatogenesis, potentially via microenvironmental perturbation of the TJ. Overall, these findings could hold valuable insights for the development of non-hormonal male contraceptives.
    Keywords:  apoptosis; blood–testis barrier; inflammation; mitophagy; spermatogenesis; tight junctions
    DOI:  https://doi.org/10.1002/2211-5463.70058
  33. Autophagy Rep. 2024 ;3(1): 2396696
    A liver-fat crosstalk for iron flux during healthy beiging of adipose tissue.
    Jinying Yang, Limin Shi, Anna L Cubito, James F Collins, Zhiyong Cheng.
      Beiging of adipocytes is characteristic of a higher number of mitochondria, the central hub of metabolism in the cell. However, studies show that beiging can improve metabolic health or cause metabolic disorders. Here we discuss a liver-fat crosstalk for iron flux associated with healthy beiging of adipocytes. Deletion of the transcription factor FoxO1 in adipocytes (adO1KO mice) induces a higher iron flux from the liver to white adipose tissue, concurrent with augmented mitochondrial biogenesis that increases iron demands. In addition, adO1KO mice adopt an alternate mechanism to sustain mitophagy, which enhances mitochondrial quality control, thereby improving mitochondrial respiratory capacity and metabolic health. However, the liver-fat crosstalk is not detectable in adipose Atg7 knockout (ad7KO) mice, which undergo beiging of adipocytes but have metabolic dysregulation. Autophagic clearance of mitochondria is blocked in ad7KO mice, which accumulates dysfunctional mitochondria and elevates mitochondrial content but lowers mitochondrial respiratory capacity. Mitochondrial biogenesis is comparable in the control and ad7KO mice, and the iron influx into adipocytes and iron efflux from the liver remain unchanged. Therefore, activation of the liver-fat crosstalk is critical for mitochondrial quality control that underlies healthy beiging of adipocytes.
    Keywords:  Adipose beiging; Atg7; FoxO1; iron flux; liver-fat crosstalk
    DOI:  https://doi.org/10.1080/27694127.2024.2396696
  34. Sci Bull (Beijing). 2025 May 06. pii: S2095-9273(25)00491-8. [Epub ahead of print]
    β-hydroxybutyrate enhances mitochondrial function via mitochondrial-derived vesicles.
    Feixiang Bao, Dingxin Zeng, Jiahui Xiao, Lingyan Zhou, Xingguo Liu.
      
    DOI:  https://doi.org/10.1016/j.scib.2025.05.011
  35. Invest New Drugs. 2025 May 22.
    Peptide YY fragment PYY1-36 disrupts mitochondrial biogenesis via RBM43-dependent PGC-1α translation inhibition.
    Benkun Liu, Fucheng Zhou, Bowen Shi, Yubo Yan, Yanbo Wang, Junfeng Wang, Yaoguo Lang, Shidong Xu.
      Mitochondrial dysfunction is a key driver of cancer progression, with therapies increasingly targeting metabolic weaknesses. Peptide YY (PYY), a gastrointestinal hormone, regulates cellular activity, but its influence on mitochondrial health in lung cancer remains poorly understood. We explored how PYY1-36, a bioactive fragment of PYY, affects mitochondrial stability in NCI-H1581 lung cancer cells. Using dose-response experiments, we measured oxidative stress by tracking lactate dehydrogenase (LDH) release, mitochondrial ROS levels, and oxidative DNA damage (8-OHdG). Energy production was evaluated through ATP levels, oxygen consumption rates (OCR), and Complex I activity. We also analyzed mitochondrial biogenesis markers (NRF1, TFAM, PGC-1α) and the RNA-binding protein RBM43 via qPCR and immunoblotting. Dose-dependent tests showed that PYY1-36 triggers mitochondrial oxidative damage, marked by higher LDH release and ROS spikes. These changes aligned with sharp drops in ATP production and disrupted respiratory function. Notably, PYY1-36 reduced mitochondrial mass and biogenesis, supported by weaker MitoTracker Red signals and lower mtDNA/nDNA ratios. Key regulators NRF1 and TFAM were strongly suppressed, pointing to widespread mitochondrial failure. Intriguingly, PYY1-36 blocked PGC-1α protein synthesis without altering mRNA levels, suggesting a post-transcriptional control mechanism. PYY1-36 also boosted RBM43 levels. Knocking down RBM43 reversed PYY1-36's effects on PGC-1α and mitochondrial health. Our findings reveal RBM43 as a central player in PYY1-36-induced mitochondrial dysfunction through its suppression of PGC-1α translation. Targeting RBM43 could unlock new strategies to tackle metabolic chaos in lung cancer.
    Keywords:  Lung Cancer; Mitochondrial Biogenesis; PGC-1α; PYY1-36; RBM43
    DOI:  https://doi.org/10.1007/s10637-025-01545-4
  36. J Transl Med. 2025 May 22. 23(1): 571
    SRSF1-mediated alternative splicing regulates bladder cancer progression and cisplatin sensitivity through HIF1A/BNIP3/mitophagy axis.
    Qikai Wu, Hao Yu, Huanyou Sun, Jiancheng Lv, Juntao Zhuang, Lingkai Cai, Lingjing Jiang, Yuhan Chen, Yiran Tao, Kexin Bai, Haiwei Yang, Xiao Yang, Qiang Lu.
       BACKGROUND: Alternative splicing (AS) is consistently linked to tumor progression. SRSF1, the first identified proto-oncogene in the serine/arginine-rich splicing factor (SRSF) protein family, plays a crucial role. However, the specific functions and potential mechanisms of SRSF1 in advancing bladder cancer (BCa) progression and influencing chemosensitivity remain largely unexplored.
    METHODS: The expression of SRSF1 in BCa tissues and cell lines was investigated using quantitative real-time PCR (RT-qPCR) and western blotting. Survival analysis was employed to examine the association between SRSF1 expression and prognosis of BCa. The functions of SRSF1 were evaluated through proliferation assays, migration assays, IC50 determination assays, and tumorigenesis assays in nude mice. Subsequent RNA sequencing validated the relationship between SRSF1 alternative splicing and the mitophagy pathway. Mitochondrial membrane potential (MMP) was assessed using JC-1 staining. Mitophagy and autophagic flux were quantified using transmission electron microscopy and fluorescence imaging. RNA immunoprecipitation, CUT & RUN assays, and luciferase reporter assays were performed to validate the SRSF1/HIF1A/BNIP3 axis.
    RESULTS: High expression of SRSF1 in BCa was significantly associated with poor prognosis. SRSF1 promoted the progression of BCa cells and conferred resistance to cisplatin both in vitro and in vivo. Mechanistically, SRSF1 interacted with pre-HIF1A via the RRM1/RRM2 domain, thereby enhancing the production of the transcription factor HIF1A through the alternative splicing pathway. This interaction subsequently activated the HIF1A/BNIP3 axis, which promoted mitophagy in BCa. Ultimately, this led to further progression of bladder cancer and a decrease in cisplatin sensitivity.
    CONCLUSIONS: SRSF1 indicated poor prognosis and promoted the progression and cisplatin resistance of BCa cells through the HIF1A/BNIP3/mitophagy axis. It holds significant potential as a novel biomarker for the diagnosis and treatment of BCa, particularly in chemotherapy.
    Keywords:  Alternative splicing; Bladder cancer; Cisplatin resistance; Mitophagy; SRSF1
    DOI:  https://doi.org/10.1186/s12967-025-06547-7
  37. Haematologica. 2025 May 22.
    Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.
    Maria Eugenia Gallo Cantafio, Ilenia Valentino, Roberta Torcasio, Ludovica Ganino, Claudia Veneziano, Pierpaolo Murfone, Maria Mesuraca, Ida Perrotta, Federico Tallarigo, Valter Agosti, Carmela De Marco, Teresa Pasqua, Cesarina Giallongo, Anna Rita Cappello, Marco Fiorillo, Massimo Gentile, Daniele Tibullo, Giuseppe Viglietto, Antonino Neri, Nicola Amodio.
      Proliferating multiple myeloma (MM) cells in the bone marrow fluctuate across various metabolic states to resist cancer treatments. Herein, we investigate how mitochondrial dynamics, which controls mitochondrial fitness via coordinated fission and fusion events, shapes MM cell metabolism impacting growth, survival and drug sensitivity. We identify MFF (Mitochondrial Fission Factor), a pivotal driver of mitochondrial fragmentation, as being highly expressed in MM plasma cells bearing cytogenetic abnormalities predicting poor clinical outcome. In preclinical models, MFF selective inhibition via multiple RNAbased strategies (shRNAs, siRNAs or LNA gapmeR ASOs) reduces MM cell growth both in vitro and in vivo, enabling adaptive metabolic responses consistent with the induction of glycolysis and the inhibition of lactate-mediated OXPHOS. We also demonstrate that lactate supplementation, as well as clinically relevant drugs promoting lactate accumulation, such as AZD3965 and Syrosingopine, trigger MFF-dependent metabolic changes, enhancing the sensitivity of MM cells to strategies targeting mitochondrial fission. Finally, we highlight a novel lactate-MFF axis involved in proteasome inhibitor resistance, and show that combining AZD3965 or Syrosingopine with bortezomib results in synergistic anti-MM activity along with MFF down-regulation. Collectively, these data point to MFF-dependent mitochondrial fragmentation as a key metabolic hallmark of MM, providing a framework for the development of novel therapeutic strategies targeting mitochondrial dynamics and harnessing the metabolic plasticity of malignant plasma cells.
    DOI:  https://doi.org/10.3324/haematol.2025.287526
  38. Nutrition. 2025 Apr 09. pii: S0899-9007(25)00114-5. [Epub ahead of print]137 112796
    Maternal exposure to high-fat diet induces long-term mitochondrial alterations in the offspring heart.
    Mariapia Chindamo, Hassib Chehade, Anthony Sordet, Gaël Humbert-Droz, François Cachat, Claire Mauduit, Mohamed Benahmed, Umberto Simeoni, Benazir Siddeek.
       OBJECTIVES: Heart disease is a leading cause of death worldwide, with its prevalence exacerbated by inadequate nutritional intake. Particularly concerning is the elevated risk induced by imbalanced nutrition during development, which can impact lifelong heart health. Recent research has underscored mitochondrial dysregulation as a pivotal mechanism driving the enduring consequences of nutritional excess. Building upon previous findings wherein a maternal high-fat diet (HFD) led to cardiac hypertrophy and fibrosis, our current study aimed to evaluate the impact of such a challenge on myocardial mitochondrial function.
    METHODS: Female rats were fed a chow diet or HFD during gestation and lactation. The hearts of male offspring were analyzed at adulthood. Mitochondrial DNA abundance was evaluated by quantitative polymerase chain reaction. Proteins involved in mitochondrial biogenesis, fusion, fission, damage to the electron transport chain, metabolism, cell death, proliferation, and inflammation were measured by western blot. Mitochondrial clearance was evaluated by the measurement of mitophagy markers on isolated mitochondria. Lipids were visualized by histologic approaches.
    RESULTS: We detected decreased cardiac mitochondrial fission factor and mitochondrial adenosine triphosphate synthase beta subunit and increased Parkin, pro-tumor necrosis factor alpha, and pro-interleukin 1 beta protein levels associated with decreased microtubule-associated protein 1A/1B light chain 3B levels in cardiac mitochondrial fraction, with a tendency for increased Oil Red O staining in the adult hearts of male offspring exposed to HFD.
    CONCLUSIONS: Maternal exposure to HFD enhanced mitochondrial damage and impaired fission and clearance in offspring hearts at adulthood. These alterations were associated with altered expression of proteins involved in the mitochondrial electron transport chain coupled with a propensity for increased fatty acid accumulation and elevated proinflammatory markers.
    Keywords:  Developmental programming; Diet; Fat; Heart; Mitochondria
    DOI:  https://doi.org/10.1016/j.nut.2025.112796
  39. Cytotherapy. 2025 Apr 25. pii: S1465-3249(25)00682-6. [Epub ahead of print]
    Cold storage effects on mitochondrial bioenergetics and protein expression in human mesenchymal stromal cells.
    Tiffany C Heard, Isaac E Abaasah, Eric Botts, Barbara A Christy, Maj Kennedy S Mdaki, Evan Ross, M Adam Meledeo, Maryanne C Herzig.
       BACKGROUND: A ready-to-use format for cell therapy products, human mesenchymal stromal cells (MSCs) or other progenitor cells, would make their use in acute trauma feasible by the military or in rural community hospitals. In designing a strategy to package MSCs, it was noted that vitality (adenosine triphosphate [ATP] content) fell prior to viability. This study investigated the effects of cold storage on mitochondrial bioenergetics and protein in MSCs.
    METHODS: Commercial MSCs were harvested and resuspended in either a balanced salt solution (PlasmaLyte A) or xeno-free medium (XFM) and then stored at 4°C. Cells were assayed on Days 0, 4, 7, 14, and 21 for cell count, viability, and ATP content, mitochondrial bioenergetics by Seahorse XF24 and Oroboros, and mitochondrial membrane potential by JC1 staining. Levels of proteins involved in mitochondrial function were assayed by Western blots. Proteins assessed included those involved in mitochondrial fusion (OPA1, MFN1, MFN2), fission (FIS1, DRP1, and DRP1 phosphoserine 637), regulation (PINK1 kinase and Parkin ubiquitin-ligase), mitophagy (NDP52 and optineurin), and electron transport chain function (COX IV, SDHB, cytochrome C, and NDUFS1).
    RESULTS: Total counts for cells stored in PlasmaLyte A and XFM were similar through Day 21. However, by Day 4, while viability was modestly decreased for cells stored in PlasmaLyte A compared with those in XFM (68% vs. 83%), ATP content plummeted for cells stored in PlasmaLyte A, with only 9.5% of the initial ATP compared with 86% of the initial ATP levels for cells stored in XFM. Both the Seahorse assays and JC1 staining identified further differences between media. JC1 staining revealed that mitochondria were almost completely depolarized by Day 7 following storage in PlasmaLyte A whereas polarized mitochondria were still evident at Day 21 for cells stored in XFM. By Western blot analyses, significant changes in fusion, fission, and mitophagy proteins were observed both for media and over time whereas the electron transport proteins were generally stable. Significant changes in the phosphorylated form of the fission protein DRP1S637 most closely correlated with the ATP data. All parameters were better preserved over time in the XFM.
    CONCLUSIONS: This study highlighted changes that occur during 4°C storage in the areas of vitality, mitochondrial membrane polarization, and fission. With these targets, research into treatments or additives to a media to improve cold storage and maintain functional cells at 4°C could result in a product that greatly extends the therapeutic use of cellular therapies.
    Keywords:  JC-1; SeaHorse; automated Western; mesenchymal stromal cells; mitochondria; storage
    DOI:  https://doi.org/10.1016/j.jcyt.2025.04.066
  40. J Med Chem. 2025 May 20.
    Unexpected Discovery of a Novel Triphenylphosphonium Alkylalcohol That Triggers Cancer Cell Death via Mitophagy and Ferroptosis.
    Ding Huang, Maojie Zhang, Haibo Yan, Ligang Mei, Aiming Yang, Yun He, Kin Yip Tam, Shao-Lin Zhang.
      Mitochondria-targeted delivery is a promising strategy in anticancer drug development. Triphenylphosphine cation (TPP+) is the most widely used mitochondrial-targeting carrier due to the elevated mitochondrial membrane potential (MMP) in cancer cells. Here, we report the serendipitous discovery of a mitochondrial-targeting carrier, compound 23, which exhibited potent anticancer activity (IC50 = 70 nM, HCC827) with minimal toxicity to normal cells. Compound 23 selectively accumulates in cancer cell mitochondria, induces MMP depolarization, and activates mitophagy via PINK1-Parkin pathway. It also disruptes mitochondrial functions, elevates ROS levels, and inhibits the xCT-GSH-GPX4 axis, leading to lipid peroxidation and ferroptotic cell death. In vivo, 23 significantly suppressed the growth of HCC827 xenograft tumors at 10 mg/kg. These findings support compound 23 as a highly selective and effective mitochondrial-targeting anticancer agent for further investigation.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c00701
  41. Fitoterapia. 2025 May 15. pii: S0367-326X(25)00252-7. [Epub ahead of print]184 106627
    Ganoderma lucidum extract reduces skin aging by reducing mitochondrial stress and controlling mitochondrial numbers.
    Han Wang, Meiling Tai, Wanzhao Li, Yawen Li, Zhimeng Zhang, Dongli Zhang, Lishe Gan, Junhao Li, Xiaojuan Song, Honghong Qiu, Manmei Li, Heyun Zhang, Zhong Liu.
      Mitochondrial dysfunction is one of the important signs of cellular and even individual aging. Ganoderma lucidum is a common edible and medicinal mushroom, widely used as a functional food in Asia. This study investigated the potential anti-aging effects of Ganoderma lucidum extract (GLE). Our results demonstrated that GLE alleviated cellular oxidative stress, reduced the abnormal increase of mitochondrial ROS in aging cells, and maintained mitochondrial membrane integrity and inner membrane potential. Additionally, GLE affected mitochondrial biogenesis in aging cells. In a murine photoaging model, GLE treatment mitigated UVA-induced mitochondrial dysfunction while markedly attenuating UVA-triggered epidermal thickening and dermal protein depletion. These properties may be interrelated with the presence of abundant triterpenoids identified by LC-MS analysis.
    Keywords:  Ganoderma lucidum; Mitochondrial dysfunction; Photoaging; UVA
    DOI:  https://doi.org/10.1016/j.fitote.2025.106627
  42. Spine J. 2025 May 14. pii: S1529-9430(25)00241-4. [Epub ahead of print]
    TBRG4 regulates ubiquitination of Beclin1 and participates in autophagy pathway to inhibit intervertebral disc degeneration.
    Xilong Cui, Feng Zhang, Di Cui, Wei Zhang, Hao Wu, Xi Chen, Haiyang Yu.
       BACKGROUND: IDD is commonly observed in symptomatic spinal disorders and is associated with mitochondrial dysfunction and NPC apoptosis. Current therapeutic targets remain theoretical, highlighting the need to explore alternative molecular targets.
    PURPOSE: To investigate the role of TBRG4 in regulating mitochondrial function, autophagy, and apoptosis in IDD, and to evaluate its therapeutic potential.
    STUDY DESIGN/SETTINGS: This study combines molecular and cellular biology techniques with an in vivo rat model of IDD.
    METHODS: Human NPCs were isolated and characterized from IDD patients and controls. TBRG4 expression was modulated using plasmid transfection. Autophagy, apoptosis, and mitochondrial function were assessed using immunofluorescence, Western blot, and flow cytometry. Co-immunoprecipitation and mass spectrometry identified TBRG4-interacting proteins. A rat IDD model evaluated TBRG4's therapeutic effects in vivo.
    RESULTS: TBRG4 expression was significantly downregulated in degenerated NPCs. TBRG4 knockdown exacerbated mitochondrial dysfunction, increased apoptosis via the BCL2/C-caspase3 pathway, and inhibited autophagy. Mechanistically, TBRG4 interacted with Beclin1 and reduced its ubiquitination, thereby promoting autophagy. Overexpression of TBRG4 in NPCs restored mitochondrial function and suppressed apoptosis. In a rat IDD model, TBRG4 overexpression alleviated disc degeneration, as evidenced by MRI, histological analysis, and decreased Pfirmmann grading.
    CONCLUSIONS: TBRG4 plays a crucial protective role in IDD by promoting autophagy and maintaining mitochondrial homeostasis. It interacts with Beclin1 to enhance autophagy by reducing ubiquitination. TBRG4 shows potential as a novel therapeutic target for IDD.
    CLINICAL SIGNIFICANCE: TBRG4-based therapies may represent a promising strategy to mitigate IDD progression, improve NPC survival, and restore disc function. Future research should focus on the development of TBRG4 activators and large-scale clinical validation.
    Keywords:  Autophagy; Beclin1; Intervertebral disc degeneration; TBRG4; Ubiquitination
    DOI:  https://doi.org/10.1016/j.spinee.2025.05.018
  43. Drug Des Devel Ther. 2025 ;19 3925-3947
    ShenQi ShenKang Granule Alleviates Chronic Kidney Disease by Inhibiting the PI3K/AKT/mTOR Pathway and Restoring Autophagy Flux and Mitochondrial Integrity.
    Chenhui Xia, Jiale Zhang, Huixi Chen, Shaofeng Zhou, Weimin Jiang, Huijuan Zheng, Zaoqiang Lin, Qinxiang Tan, Weiwei Sun.
       Purpose: This study investigates the effect of Shenqi Shenkang granule (SQSKG) on chronic kidney disease (CKD), focusing on regulating the PI3K/AKT/mTOR pathway, autophagy, and mitochondrial homeostasis.
    Methods: The compounds and targets of SQSKG on CKD were identified by network pharmacology and validated by molecular docking. LC-MS/MS was used to verify the compounds screened by network pharmacology. In vitro experiments based on HK-2 cells were used to assess its impact on cell migration, viability, oxidative stress, and key proteins of the PI3K/AKT/mTOR pathway, autophagy, and fibrosis. Mitochondrial function and autophagic flux were evaluated via JC-1, Mito-Tracker, and Ad-mCherry-GFP-LC3B assays. In vivo, an adenine-induced CKD rat model was used to analyze renal function, fibrosis, and autophagy through serum/urine tests, histology, and immunofluorescence.
    Results: Network pharmacology identified 49 compounds and 149 targets associated with SQSKG's therapeutic effects on CKD, highlighting critical targets such as AKT1, MAPK1, EGFR, HSP90AA, and IGF1R. The primary mechanism involves the PI3K/AKT pathway. In vitro experiments demonstrated that SQSKG significantly enhanced cell migration, colony formation, viability in AGEs-treated HK-2 cells, and exhibited robust antioxidant properties by increasing SOD levels and reducing MDA and ROS production. SQSKG effectively inhibited the phosphorylation of PI3K, AKT, and mTOR, and reduced TGF-β fluorescence intensity in kidney tissue. Autophagic flux analysis showed that SQSKG increased autophagic activity and reduced p62 accumulation. Additionally, JC-1 and Mito-Tracker Green assays demonstrated that SQSKG improved mitochondrial membrane potential and morphology. In vivo, SQSKG significantly improved renal function and alleviated renal fibrosis in a dose-dependent manner, reversing fibrosis marker overexpression (Col-I, α-SMA, TGF-β) and activating autophagy.
    Conclusion: Our findings provide novel insights into the therapeutic potential of SQSKG in CKD management, highlighting its ability to modulate PI3K/AKT/mTOR pathway, activating autophagy flux, and restoring mitochondrial integrity, thereby offering a promising complementary or alternative treatment option for patients with CKD.
    Keywords:  PI3K/AKT/mTOR pathway; Shenqi Shenkang Granule; autophagy; chronic kidney disease; network pharmacology; renal fibrosis
    DOI:  https://doi.org/10.2147/DDDT.S513824
  44. Am J Hypertens. 2025 May 17. pii: hpaf084. [Epub ahead of print]
    OGT-mediated O-GlcNAc of PINK1 promotes the progression of obesity-related hypertension via regulating mitophagy.
    Xiaoling Zeng, Shengjiao Liang.
       BACKGROUND: Obesity causes a variety of metabolic diseases, including hypertension. O-linked beta-N-acetylglucosamine (O-GlcNAc), a dynamic post-translational modification, is rapidly cycled on and off proteins by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Our study hypothesized that O-GlcNAc contributes to the progression of obesity-related hypertension (OH). Using in vivo and in vitro approaches, we systematically investigated the role of O-GlcNAc in OH pathogenesis and elucidated its molecular mechanisms.
    METHODS: An in vivo OH rat model was established through feeding with a high-fat diet. Besides, A7r5 cells were treated with oxidized low-density lipoprotein (ox-LDL) to simulate OH in vitro. Western blot was used to detect the protein levels of O-GlcNAc, OGT, OGA, and autophagy-related indicators. CCK-8 was performed to analyze the cell viability. The apoptosis rate was assessed by flow cytometry. Co-immunoprecipitation was performed to verify the endogenous interaction between OGT and PTEN-induced putative kinase (PINK)1.
    RESULTS: OGT-mediated O-GlcNAc was elevated in both in vivo and in vitro OH models. Besides, OGT deficiency inhibited hypertension and inflammation, and increased autophagy in high-fat diet-induced OH rats. Additionally, OGT inhibition increased cell viability and autophagy and inhibited apoptosis in ox-LDL-treated A7r5 cells. Mechanically, OGT-mediated O-GlcNAc of PINK1 at S335 site regulated the phosphorylation of PINK1. Finally, PINK1 inhibition decreased cell viability and autophagy and promoted apoptosis in ox-LDL-treated A7r5 cells.
    CONCLUSION: OGT-mediated O-GlcNAc of PINK1 promoted the progression of OH via regulating mitophagy, which might provide a new insight for OH treatment.
    Keywords:  O-GlcNAc; OGT; PINK1; mitophagy; obesity-related hypertension
    DOI:  https://doi.org/10.1093/ajh/hpaf084
  45. J Agric Food Chem. 2025 May 21.
    Vitamin K2 Attenuates Mitochondrial Damage in Renal Proximal Tubular Cells.
    Hsinjung Ho, Natsumi Aoki, Miki Eguchi, Mingchen Gao, Hirotaka Suzuki, Mao Mikami, Hitoshi Chiba, Shu-Ping Hui.
      Excessive reactive oxygen species (ROS) levels cause oxidative stress, which can lead to various diseases. Renal failure is associated with oxidative stress and mitochondrial dysfunction. Vitamin K1 (phylloquinone) and K2 (menaquinone) are essential for blood coagulation and bone formation. Vitamin K has been shown to have anti-inflammation, glucose metabolism regulation, and antiferroptosis functions. We investigated the impact of menaquinone-4 (MK-4) on oxidative stress and mitochondrial dysfunction in human renal proximal tubular cells. MK-4 protected cells from oxidative damage induced by l-buthionine-(S,R)-sulfoximine (BSO), a selective inhibitor of glutathione metabolism, by inhibiting cell death, mitochondrial ROS production, and lipid peroxidation. MK-4 also reduced lactate production, prevented mitochondrial fragmentation, and improved mitochondrial respiratory function, indicating cytoprotective effects. Moreover, it enhanced intracellular ATP production and respiratory capacity, even in the absence of oxidative stress. Thus, MK-4 plays an important role in mitochondrial function in renal proximal tubular cells.
    Keywords:  ATP; MK-4; mitochondrial oxidative phosphorylation; mitophagy; oxidative stress; renal function
    DOI:  https://doi.org/10.1021/acs.jafc.5c01320
  46. Microbiol Spectr. 2025 May 22. e0010025
    Disrupted host-microbiota crosstalk promotes nonalcoholic fatty liver disease progression by impaired mitophagy.
    Wenjing Yin, Wenxing Gao, Yuwei Yang, Weili Lin, Wanning Chen, Xinyue Zhu, Ruixin Zhu, Lixin Zhu, Na Jiao.
      The intricate interplay between host genes and intrahepatic microbes is vital in shaping the hepatic microenvironment. This study aims to elucidate how host-microbiota interactions contribute to the progression of nonalcoholic fatty liver disease (NAFLD). Hepatic gene and microbial profiles were analyzed from 570 samples across five cohorts, including 72 control, 124 nonalcoholic fatty liver (NAFL), 143 Borderline, and 231 nonalcoholic steatohepatitis (NASH) samples. Least absolute shrinkage and selection operator penalized regression and sparse canonical correlation analysis were utilized to identify host-microbiota interactions and their function. Validation was performed using a bulk transcriptomic data set comprising 1,332 samples and a single-cell transcriptomic data set of seven samples. We observed stage-specific gene expression changes of disrupting energy metabolism and immune responses, alongside microbial shifts shaping the NAFLD microenvironment. Additionally, we identified 5,537, 1,937, 1,485, and 2,933 host-microbiota interactions in control, NAFL, Borderline, and NASH samples, respectively. Escherichia coli and Actinomyces naeslundii dominated the interaction network in control but were replaced by Sphingomonadales and Sphingomonadaceae in disease stages from NAFL, preceding the transcriptomic tipping point observed in Borderline. In NASH, interactions significantly weakened, accompanied by the loss of mutualistic interactions between bacteria such as Bacillales, Ralstonia insidiosa, Sphingomonadaceae, and host mitophagy genes including SQSTM1, OPTN, and BNIP3L. Single-cell data sets confirmed these interactions were co-localized in macrophages and monocytes in control, which shifted to hepatocytes and endothelial cells in NAFLD. Shifts in host-microbial interaction signal early microenvironment changes. Disturbed host-microbiota interactions impacting mitophagy can trigger a pro-inflammatory hepatic microenvironment, potentially driving disease progression.IMPORTANCEThis study integrated multiple cohorts to uncover fundamental and generalizable signals in the progression of nonalcoholic fatty liver disease. Key changes in both liver gene expression and microbiota were identified across disease stages, with microbial composition and interactions with host offering earlier insights into microenvironmental changes. Notably, host-microbiota interactions related to mitophagy, crucial in early stages, were destroyed in nonalcoholic steatohepatitis. This disruption may contribute to the worsening inflammation and disease progression.
    Keywords:  disease progression; hepatic microenvironment; host-microbe interaction; intrahepatic microbiome; mitophagy; nonalcoholic fatty liver disease
    DOI:  https://doi.org/10.1128/spectrum.00100-25
  47. Curr Comput Aided Drug Des. 2025 May 16.
    Validation of the Mechanism of Action of Jiedu Shengji Oil in the Treatment of Radiation Dermatitis based on Network Pharmacology and In Vivo Experiments.
    Weishan He, Guangmei Deng, Wenya Liu, Long Kou, Fasheng Wu.
       BACKGROUND: Radiation Dermatitis (RD) is a common complication of radiation therapy, with approximately 90% of patients experiencing moderate to severe radiation dermatitis injury after radiotherapy. Jiedu Shengji oil (JDSJY) is a commonly used herbal topical preparation in our hospital, with remarkable clinical efficacy in treating radiation dermatitis. However, the mechanism of JDSJY in treating RD is unclear.
    AIMS: The aim of the study is to explore JDSJY's mechanism of action in treating RD through methods, such as network pharmacology and in vivo experiments.
    METHODS: The active components and disease targets of JDSJY were screened and intersected via network pharmacology for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The pharmacodynamics of JDSJY was evaluated by establishing a rat model of RD.
    RESULTS: Network pharmacology showed that the pathway network of JDSJY action involved 64 targets and 6 pathways and might act by targeting key targets, such as C-reactive protein (CRP) and regulating the MAPK signalling pathway. In addition, in vivo experiments showed that JDSJY reduced skin inflammation and inhibited apoptosis, significantly ameliorated mitochondrial damage in keratinocytes, and reduced the levels of antioxidant-related indicators.
    CONCLUSION: Comprehensive network pharmacology and in vivo experiments revealed that JDSJY's therapeutic efficacy in RD is mediated by ameliorating oxidative stress and maintaining mitochondrial homeostasis in keratinocytes.
    Keywords:  Jiedu Shengji Oil; Radiation dermatitis; in vivo experiments; network pharmacology.; traditional Chinese medicine
    DOI:  https://doi.org/10.2174/0115734099370851250512074033
  48. Redox Rep. 2025 Dec;30(1): 2507557
    Varespladib attenuates Naja atra-induced acute liver injury via reversing Nrf2 signaling-mediated ferroptosis and mitochondrial dysfunction.
    Jiahao Liu, Linfeng Wang, Mengxia Xie, Wenjie Zhao, Jiaqi Sun, Yuji Jin, Meiling Liu, Jianqi Zhao, Lixia Cheng, Cheng Wen, Xiaowen Bi, Chunhong Huang.
      Objective: To investigate the protective effects of varespladib against Naja atra-induced acute liver injury (ALI) and to elucidate the toxic mechanism of snake venom phospholipase A2 (SVPLA2)-induced hepatic oxidative stress, with a particular focus on the role of Nrf2 signaling and its downstream pathways.Methods: A combination of in vivo and in vitro models of N. atra envenomation was employed to assess liver injury, oxidative stress, and mitochondrial dysfunction. The interaction between SVPLA2 and Nrf2 was analyzed, and the effects of varespladib treatment on these processes were evaluated using histological analysis, biochemical assays, and molecular techniques targeting oxidative stress, ferroptosis, mitophagy, and apoptosis.Results: Varespladib significantly alleviated N. atra-induced ALI. SVPLA2 was found to directly bind to Nrf2, leading to severe oxidative stress. This oxidative stress initiated a cascade involving Nrf2-mediated ferroptosis, mitochondrial dysfunction, excessive mitophagy, and mitochondria-dependent apoptosis. Treatment with varespladib effectively reversed these pathological events by inhibiting SVPLA2 activity.Conclusion: Varespladib shows strong therapeutic potential for N. atra envenomation by targeting SVPLA2. Nrf2 was identified as a direct toxic target of SVPLA2, and Nrf2-mediated ferroptosis and mitochondrial dysfunction were key mechanisms underlying SVPLA2-induced hepatic injury.
    Keywords:  Naja atra; Nrf2; apoptosis; ferroptosis; mitochondrial dysfunction; mitophagy; snake venom; varespladib
    DOI:  https://doi.org/10.1080/13510002.2025.2507557
  49. Curr Osteoporos Rep. 2025 May 22. 23(1): 22
    Mitochondrial Distribution and Osteocyte Mechanosensitivity.
    Jianfeng Jin, Peter A Nolte.
       PURPOSE OF REVIEW: Mechanical loading of bone is an important physical stimulus for bone tissue remodeling and adaptation. It is transmitted from the extracellular matrix all the way to the osteocyte nucleus via the extracellular matrix-integrin-cytoskeleton-nucleus system. Mitochondria are integral in sensing of mechanical loads to allow the cell to adapt to its environment. This review provides a background of mitochondrial distribution in osteocytes especially during mechanical loading, discussing the importance of mitochondrial distribution in osteocyte mechanosensitivity and mechanotransduction.
    RECENT FINDINGS: Mitochondria throughout the osteocyte are highly dynamic and provide essential metabolic and signal functions to regulate osteocyte morphology and function. They undergo the processes of fission and fusion accompanied by mitochondrial DNA distribution. The mitochondrial network structure and function in osteocytes can be regulated by mechanical loading. Interestingly, mitochondria can be transmitted by osteocytes into adjacent cells to communicate with them via tunneling nanotubes, migrasomes, and blebbisomes, causing changes in cell morphology and/or function. Mitochondrial distribution in or out osteocytes can be rearranged by physical and (bio)chemical signals via fission and fusion, as well as tunneling nanotubes, migrasomes, and blebbisomes. Mechanical loading-induced changes in mitochondria may drive signaling pathways of cell function in aging and diseases. More insights into interactions between neighbouring osteocytes and between osteocytes and other cell types would facilitate the development of new strategies to apply mitochondrial therapy for bone-related diseases.
    Keywords:  Cell communication; Mechanical loading; Mechanotransduction; Mitochondria; Mitochondrial distribution; Osteocytes
    DOI:  https://doi.org/10.1007/s11914-025-00918-1
  50. Cell Mol Immunol. 2025 May 19.
    Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy.
    Shifeng Li, Hong Xu, Shupeng Liu, Jinkun Hou, Yueyin Han, Chen Li, Yupeng Li, Gaigai Zheng, Zhongqiu Wei, Fang Yang, Shuwei Gao, Shiyao Wang, Jing Geng, Huaping Dai, Chen Wang.
      Monocyte-derived macrophages (MoMacs) are the most important effector cells that cause pulmonary fibrosis. However, the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear. Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs, identified as Spp1hiMacs, which remain in an immature transitional state of differentiation during silicosis. This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by Pla2g7)-acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1)-cardiolipin (CL) signaling pathway, which interferes with Spp1hiMac differentiation. We demonstrated that in SiO2-induced MoMacs, Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1, resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects. Simultaneously, lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm, which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways. Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.
    Keywords:  Cardiolipin; Lipoprotein-associated phospholipase A2; Mitophagy; Monocyte-derived macrophages; Pulmonary fibrosis
    DOI:  https://doi.org/10.1038/s41423-025-01288-5
  51. Cryobiology. 2025 May 22. pii: S0011-2240(25)00064-1. [Epub ahead of print]119 105258
    Identification of the hub genes involved in ATF5 mediated stress response in vitrified mouse oocytes based on WGCNA.
    Guizhen Zhou, Aiju Liu, Jiachen Bai, Yixiao Zhu, Xinhua Zou, Yuwen Luo, Yizaitiguli Reyimjan, Yan Ma, Shuaixiang Huang, Yunpeng Hou, Jun Li, Xiangwei Fu.
      Activating transcription factor 5 (ATF5) is a key regulator in the stress response and plays a crucial role in cellular adaptation to the nonphysical environment. Our previous study indicated that a homeostatic state of ATF5 level could improve mitochondrial function in vitrified oocytes. However, the molecular mechanisms underlying the ATF5-mediated gene network in response to oocyte vitrification remain largely unknown. In this study, specific ATF5 siRNA was microinjected into oocytes to suppress ATF5 expression, and oocytes with ATF5 deficiency under normal and vitrification stress conditions were collected for Smart RNA-seq analysis. Weighted gene co-expression network analysis (WGCNA) was used to characterize oocyte co-expression modules involved in the ATF5 mediated response. Our results identified three key gene modules related to ATF5 knockdownRed, Green and, Yellow-using the screening criteria of |R| ≥0.5 and P ≤ 0.05 with WGCNA. Functional enrichment analysis of key gene modules showed that genes in the modules were mainly enriched in apoptosis, ubiquitin mediated proteolysis, the PI3K-Akt signaling pathway, and protein digestion and absorption. STEM and KEGG functional enrichment analysis showed that most genes were involved in protein digestion and absorption, the AMPK signaling pathway, the JAK-STAT signaling pathway, and the apoptosis signaling pathway. Importantly, Diablo, Map3k1, Spta1, and Ubqln4, obtained by sequential scanning of WGCNA and combined functional enrichment analysis, were identified as candidate genes under ATF5 regulation in response to vitrification. These findings demonstrate that the ATF5 mediated gene network exerts regulatory roles in various cellular events and provide novel insights for a deeper understanding of stress response associated impairments in vitrified oocytes.
    Keywords:  ATF5; Mitochondrial unfolded protein responses; Oocytes; Vitrification; WGCNA
    DOI:  https://doi.org/10.1016/j.cryobiol.2025.105258
  52. Front Cell Dev Biol. 2025 ;13 1595121
    Protein misfolding and mitochondrial dysfunction in glaucoma.
    Arunkumar Venkatesan, Audrey M Bernstein.
      Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure caused by restricted outflow of the aqueous humor leads to the degeneration of retinal ganglion cells (RGCs) and their axons. Emerging evidence suggests that pathological mechanisms relating to protein folding and mitochondrial dysfunction are significant factors in the disease onset of different types of open-angle glaucoma. In this review, we discuss these defects in three distinct types of open-angle glaucoma: primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and exfoliation glaucoma (XFG). Genetic mutations linked to the previously mentioned open-angle glaucoma, including those in myocilin (MYOC), optineurin (OPTN), and lysyl oxidase 1 (LOXL1), disrupt protein folding and homeostasis, leading to endoplasmic reticulum stress, activation of the unfolded protein response and impaired autophagic protein degradation. These factors contribute to trabecular meshwork and retinal ganglion cell apoptosis. In addition to protein folding defects, mitochondrial dysfunction is also associated with the progression of trabecular meshwork damage and the death of RGCs. Factors such as oxidative stress, an altered mitochondrial fission-fusion balance, and mitophagy dysregulation make RGCs vulnerable and contribute to optic nerve degeneration. The crosstalk between protein folding and mitochondrial defects in glaucoma underscores the complexity of disease pathogenesis and offers potential targets for therapeutic intervention. Strategies aimed at restoring protein homeostasis, enhancing mitochondrial function, and mitigating cellular stress responses hold promise for neuroprotection in glaucoma.
    Keywords:  NTG; POAG; XFG; autophagy; er stress; glaucoma; mitochondrial dysfunction; upr
    DOI:  https://doi.org/10.3389/fcell.2025.1595121
  53. J Adv Res. 2025 May 21. pii: S2090-1232(25)00359-5. [Epub ahead of print]
    Maternal exposure to urban particulate matter induces cardiac developmental toxicity in zebrafish offspring by disrupting mitochondrial homeostasis.
    Shiqian Liu, Ruiyang Ding, Linyuan Huang, Jianong Lv, Zhiwei Sun, Xiaoxiao Wang, Junchao Duan.
       INTRODUCTION: Urban particulate matter (UPM) is a major air pollutant affecting public health, with maternal exposure potentially leading to cardiac developmental disorders in offspring. However, the exact mechanisms underlying the intergenerational effects of UPM remain unclear.
    OBJECTIVE: This study aimed to investigate the molecular mechanisms involved in cardiac developmental defects caused by maternal UPM exposure in offspring zebrafish.
    METHODS AND RESULTS: Female zebrafish were exposed to UPM for 21 days to examine intergenerational effects. The results indicated that maternal zebrafish in the exposed group exhibited ovarian damage and a reduced number of embryos and fertilization rates. Zebrafish offspring exhibited abnormal cardiac development, including pericardial edema and pathological heart injury. Mechanistically, transcriptomic analysis of the offspring indicated that UPM exposure induced significant modifications in the mitochondrial biogenesis pathway, with altered expression of mitochondrial function-related genes. Maternal UPM exposure impaired respiration in zebrafish embryos and increased angiopoietin-like 4 (ANGPTL4) expression in offspring hearts. In vitro, Angptl4 knockdown alleviated UPM-induced mitochondrial membrane potential reduction and mitochondrial reactive oxygen species overproduction in cardiomyocytes, whereas Angptl4 overexpression exacerbated UPM-induced mitochondrial toxicity.
    CONCLUSION: These findings show that maternal UPM exposure disrupts mitochondrial homeostasis by upregulating ANGPTL4 expression, leading to abnormal cardiac development in zebrafish offspring.
    Keywords:  Heart development; Maternal exposure; Mitochondrial dysfunction; Urban particulate matter; Zebrafish
    DOI:  https://doi.org/10.1016/j.jare.2025.05.041
  54. EMBO Mol Med. 2025 May 23.
    FOXK2 in skeletal muscle development: a new pathogenic gene for congenital myopathy with ptosis.
    Peixuan Wu, Nan Song, Yang Xiang, Zhe Tao, Bing Mao, Ruochen Guo, Xin Wang, Dan Wu, Zhenzhen Zhang, Xin Chen, Duan Ma, Tianyu Zhang, Bingtao Hao, Jing Ma.
      Congenital ptosis, a genetic disorder involving levator palpebrae muscle dysfunction, is often associated with congenital myopathy. The genetic causes of this condition remain poorly understood. In this study, we identified FOXK2 mutations in five pedigrees with congenital myopathy and ptosis through whole exome sequencing and Sanger sequencing. Zebrafish with foxk2 deficiency exhibited underdeveloped skeletal muscles and reduced mobility, while mice with Foxk2 deletion in skeletal muscle stem cells (MuSCs) showed generalized skeletal muscle abnormalities. Further analysis revealed that FOXK2 deficiency impaired myogenic differentiation in C2C12 cells and disrupted mitochondrial homeostasis in both mouse MuSCs and C2C12 cells. Rescue experiments confirmed the loss-of-function effects of FOXK2 mutation. Coenzyme Q10 treatment improved mitochondrial function and alleviated skeletal muscle development defects in Foxk2-deficient mice. Preliminary omics analysis suggested FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites. Our study identifies FOXK2 as a novel pathogenic gene for congenital myopathy with ptosis and highlights its essential role in skeletal muscle development and mitochondrial homeostasis, offering insights for potential diagnostics and therapies.
    Keywords:  Coenzyme Q10; FOXK2; Mitochondrial Homeostasis; Ptosis; Skeletal Muscle Development
    DOI:  https://doi.org/10.1038/s44321-025-00247-x
  55. J Nanobiotechnology. 2025 May 19. 23(1): 360
    Baicalein based nano-delivery system restores mitochondrial homeostasis through PPAR signaling pathway to promote wound healing in diabetes.
    Danlei Qin, Weiting Hu, Yanqin Guo, Rui Cheng, Fengxiang Hao, Bin Zhao.
      Wound healing in diabetes is a substantial clinical challenge due to the hyperglycemic microenvironment, high pH, bacterial infection, persistent inflammation, and impaired cellular functions, attributed to mitochondrial dysfunction. Here, we have developed an injectable photo-crosslinking nanocomposite hydrogel (BA/GOx@ZIF-8@GelMA, BGZ@GelMA) with baicalein (BA) and glucose oxidase (GOx) loaded Zinc metal-organic framework (ZIF-8) based on methacrylated gelatin (GelMA) to accelerate diabetic infected wound healing by regulating subcellular and cellular functions. The combination of ZIF-8 and BA gives the hydrogel excellent antibacterial properties. A high blood sugar environment triggers the release of GOx in BGZ@GelMA, reducing local glucose and pH, producing hydrogen peroxide (H2O2), and releasing BA and Zinc ions (Zn2+). This process provides a suitable microenvironment for wound healing. Zn2+ can significantly inhibit the proliferation of Staphylococcus aureus (S.aureus) and Escherichia coli (E.coli). The released BA can clear ROS in cells and mitochondria, restore mitochondrial function and stability, and make the hydrogel fundamentally improve the cell function damage induced by hyperglycemia, and ultimately promote cell proliferation, migration and angiogenesis. In general, our multifunctional nanocomposite hydrogel provides a new strategy for diabetes wound healing at the subcellular and cellular functional levels.
    Keywords:  Baicalein; Diabetic wound healing; Metal-organic framework; Mitochondrion
    DOI:  https://doi.org/10.1186/s12951-025-03427-6
  56. Autophagy Rep. 2024 ;3(1): 2386194
    Re-exploration of all ATG genes.
    Kentaro Furukawa, Tamara Ginevskaia, Tomotake Kanki.
      Most autophagy-related (ATG) genes have been identified and characterized through studies using the budding yeast Saccharomyces cerevisiae. However, there are no studies that comprehensively compare the contribution of each ATG gene to non-selective bulk autophagy and various types of selective autophagy, including the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy, reticulophagy, and pexophagy. Our recent study quantified these types of autophagy in all atg mutants and showed that (i) autophagy is not completely impaired in specific deletants such as lacking the components of the two ubiquitin conjugation-like (UBL) systems, traditionally regarded as essential for autophagy in yeast, and (ii) residual autophagic activity is especially prominent in mutants of the Atg8 UBL system, which display small autophagic body-like vesicles at a low frequency. Alongside these findings, our comprehensive analysis suggested a link between mitophagy and pexophagy, and a differential contribution of Atg proteins to cargo specificity. We discuss how our datasets are useful for future autophagy research. Abbreviations: Ape1: aminopeptidase I; ATG: autophagy related; Cvt: cytoplasm-to-vacuole targeting; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; PI3K: phosphatidylinositol 3-kinase; UBL: ubiquitin conjugation-like.
    Keywords:  Atg8 conjugation system; Autophagy; Cvt pathway; ER-phagy; core autophagy genes; mitophagy; pexophagy
    DOI:  https://doi.org/10.1080/27694127.2024.2386194
  57. Trends Mol Med. 2025 May 19. pii: S1471-4914(25)00106-6. [Epub ahead of print]
    Powering immunity: mitochondrial dynamics in natural killer cells.
    Tias Verhezen, An Wouters, Evelien Smits, Jorrit De Waele.
      Natural killer (NK) cells are innate lymphocytes that are crucial for eliminating malignant and infected cells, and have significant therapeutic potential against cancer and viral infections. However, their functionality is often impaired under pathological conditions. Emerging evidence identifies mitochondria as key regulators of NK cell metabolism, fitness, and fate. This review examines how mitochondrial dysfunction impacts on NK cell activity in cancer, viral infections, and inflammatory disorders. We discuss strategies to target mitochondrial architecture, dynamics, and function as potential therapies to restore NK cell fitness. Finally, we highlight unanswered questions and future directions to better understand mitochondrial regulation in NK cells and its implications for therapeutic development.
    Keywords:  HIV; cellular therapies; immunometabolism; mitochondria; natural killer cells; oncology
    DOI:  https://doi.org/10.1016/j.molmed.2025.04.004
  58. J Appl Physiol (1985). 2025 May 22.
    Hyperbaric Oxygen Increases Mitochondrial Biogenesis and Function with Oxidative Stress in HL-1 Cardiomyocytes.
    Ha-Yeong Young, Sunchul Lee, Yeo-Eun Choi, Sang-Hoon Nam, Seung-Kuy Cha, Yangsik Jeong, Hyun Kim, Tae-Min Shin, Kyu-Sang Park.
      Hyperbaric oxygen (HBO2) therapy has been used to treat various pathological conditions, including carbon monoxide poisoning and ischemia-reperfusion injury. However, the molecular mechanisms underlying these therapeutic effects remain unclear. We investigated HBO2-induced changes in mitochondrial function and biogenesis in a clonal cardiomyocyte cell line, HL-1. Cells were exposed to HBO2 (3 atmospheres, 2218 mmHg O2, 39 mmHg CO2) in a cell incubation chamber under controlled temperature and humidity conditions. Levels of reactive oxygen species (ROS), gene transcription and translation, mitochondrial membrane potential (ΔΨm), mitochondrial respiration, cellular ATP content, and spontaneous beating foci of HL-1 cells were measured. Exposure (2 or 6 h) to HBO2 increased the cytosolic and mitochondrial ROS production, followed by upregulation of stress responses, including growth differentiation factor 15 and fibroblast growth factor 21. HBO2 augmented antioxidant defence signalling through nuclear factor erythroid-2-related factor 2 and mitochondrial biogenesis through peroxisome proliferator-activated receptor-gamma coactivator-1α. HBO2 exposure also elevated mitochondrial oxygen consumption, ΔΨm, and ATP production. To assess cardiomyocyte function, live cell imaging was performed, and the findings demonstrated an increase in the number of beating clusters in HL-1 cells following exposure to HBO2. Notably, in HL-1 cells pre-treated with sublethal doses of mitochondrial electron transport chain inhibitors, further depolarisation of ΔΨm was observed after HBO2 exposure, implying exacerbation of mitochondrial dysfunction. Collectively, HBO2-induced oxidative stress enhances mitochondrial biogenesis and function, possibly through a stress-mediated response. However, in the presence of defective mitochondrial function, cells may not be able to overcome the stress caused by HBO2.
    Keywords:  Cardiomyocytes; Hyperbaric oxygen; Mitochondrial biogenesis; Mitochondrial respiration; Reactive oxygen species; Stress response
    DOI:  https://doi.org/10.1152/japplphysiol.00428.2024
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