bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–04–06
sixty-one papers selected by
Gavin McStay, Liverpool John Moores University
  1. DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
  2. Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.
  3. α‑ketoglutarate protects against septic cardiomyopathy by improving mitochondrial mitophagy and fission.
  4. Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress.
  5. Fibroblast growth factor 8 (FGF8) induces mitochondrial remodeling in chondrocytes via ERK/AMPK signaling pathway.
  6. Pre-clinical evidence for mitochondria as a therapeutic target for luteolin: A mechanistic view.
  7. tsRNA-12391-Modified Adipose Mesenchymal Stem Cell-Derived Exosomes Mitigate Cartilage Degeneration in Osteoarthritis by Enhancing Mitophagy.
  8. Novel insights into copper-induced Chinese mitten crab hepatopancreas mitochondrial toxicity: Oxidative stress, apoptosis and BNIP3L-mediated mitophagy.
  9. Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1 modulation.
  10. LncRNA XIST inhibits mitophagy and increases mitochondrial dysfunction by promoting BNIP3 promoter methylation to facilitate the progression of KBD.
  11. Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
  12. Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem cells.
  13. Ischemic preconditioning attenuates ischemia/reperfusion-induced acute kidney injury dependent on mitochondrial protease CLPP.
  14. Irisin Alleviates Impaired Mitochondrial Fusion via Enhancing PKA/SIRT3/mTOR Pathway in Hepatic Steatosis.
  15. Inhibition of ERK1/2 mediated activation of Drp1 alleviates intervertebral disc degeneration via suppressing pyroptosis and apoptosis in nucleus pulposus cells.
  16. Mitochondrial fusion protein: a new therapeutic target for lung injury diseases.
  17. Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.
  18. Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.
  19. Representing Mitochondrial Dynamics with Abstract Algebra.
  20. Targeting LKB1-AMPK-SIRT1-induced autophagy and mitophagy pathways improves cerebrovascular homeostasis in APP/PS1 mice.
  21. SIRT1 and SIRT3 Impact Host Mitochondrial Function and Host Salmonella pH Balance during Infection.
  22. HTLV-1 Tax induces PINK1-Parkin-dependent mitophagy to mitigate activation of the cGAS-STING pathway.
  23. MK-4 Ameliorates Diabetic Osteoporosis in Angiogenesis-Dependent Bone Formation by Promoting Mitophagy in Endothelial Cells.
  24. Enhancing anti-CD3 mAb-mediated diabetes remission in autoimmune diabetes through regulation of dynamin-related protein 1(Drp1)-mediated mitochondrial dynamics in exhausted CD8+T-cell subpopulations.
  25. Regulation of pyroptosis and ferroptosis by mitophagy in chronic kidney disease.
  26. Screening of patient-derived organoids identifies mitophagy as a cell-intrinsic vulnerability in colorectal cancer during statin treatment.
  27. Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson's Disease therapy.
  28. A dynamin-like protein in Plasmodium falciparum plays an essential role in parasite growth, mitochondrial development and homeostasis during asexual blood stages.
  29. Mitochondrial fission regulates midgut muscle assembly and tick feeding capacity.
  30. Esculetin and Phloretin Combination Mitigates Acute Kidney Injury-Diabetes Comorbidity via Regulating Mitophagy and Inflammation: A Dual-Pronged Approach.
  31. Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.
  32. Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells.
  33. What Is the Role of Inner Membrane Metalloproteases in Mitochondrial Quality Control and Disease?
  34. Voluntary Exercise Attenuates Tumor Growth in a Preclinical Model of Castration-Resistant Prostate Cancer.
  35. Cardioprotective effects of Dendrobium officinale polysaccharides on thiacloprid-induced cardiac injury via modulating mitochondrial dynamics.
  36. Obesity prevention by different exercise protocols (HIIT or MICT) involves beige adipocyte recruitment and improved mitochondrial dynamics in high-fat-fed mice.
  37. SIRT5 Inhibits Mitophagy and Inflammation of Hypoxia-Induced Pulmonary Hypertension by Regulating the Desuccinylation of PDK1.
  38. Analysis and Validation of Mitophagy-Related Genes in Diabetic Foot Ulcers.
  39. Understanding mitochondrial protein import: a revised model of the presequence translocase.
  40. Diet-induced obesity dampens the temporal oscillation of hepatic mitochondrial lipids.
  41. Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.
  42. Gold Nanoparticles Enhance TRAIL Sensitivity Through Drp1-Mediated Apoptotic and Autophagic Mitochondrial Fission in NSCLC Cells [Retraction].
  43. HELLS controls mitochondrial dynamics and genome stability in liver cancer by collusion with MIEF1.
  44. Author Correction: DELE1 oligomerization promotes integrated stress response activation.
  45. [Protein C activator derived from snake venom protects human umbilical vein endothelial cells against hypoxia-reoxygenation injury by suppressing ROS via upregulating HIF-1α and BNIP3].
  46. Environmental NaCl affects C. elegans development and aging.
  47. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms including sleep.
  48. Upstream Stimulatory Factor 2 Protects Cardiomyocytes by Regulating Mitochondrial Homeostasis.
  49. Mitochondrial and peroxisomal fission in cortical neurogenesis.
  50. PM2.5 from automobile exhaust induces apoptosis in male rat germ cells via the ROS-UPRmt signaling pathway.
  51. Coral calcium hydride promotes peripheral mitochondrial division and reduces AT-II cells damage in ARDS via activation of the Trx2/Myo19/Drp1 pathway.
  52. Cardioprotective role of SIRT1 activation on mitochondrial function in insulin-resistant H9c2 cells.
  53. Rhynchophylline as an agonist of sirtuin 3 ameliorates endothelial dysfunction via antagonizing mitochondrial damage of endothelial progenitor cells.
  54. Roles of Autophagy, Mitophagy, and Mitochondria in Left Ventricular Remodeling after Myocardial Infarction.
  55. Identification of necroptosis & mitophagy-related key genes and their prognostic value in colorectal cancer.
  56. Engineered Extracellular Vesicles Derived from Juvenile Mice Enhance Mitochondrial Function in the Aging Bone Microenvironment and Achieve Rejuvenation.
  57. The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.
  58. Cellular Discrepancy of Platinum Complexes in Interfering with Mitochondrial DNA.
  59. Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway.
  60. DNMT1 targets SRD5A2 to induce mitochondrial homeostasis and EMT in urothelial cells of hypospadias.
  61. Retromer promotes the lysosomal turnover of mtDNA.
  1. Cell Commun Signal. 2025 Apr 01. 23(1): 158
    DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
    Fasih A Rahman, Jasmine M Friedrich Yap, Tyler M Joseph, Amanda M Adam, Sarah M Chapman, Joe Quadrilatero.
       BACKGROUND: Remodeling of the mitochondrial network is implicated in myogenesis. Remodeling processes including mitochondrial fission, mitophagy, and biogenesis are important as they finetune the mitochondrial network to meet the increased energetic demand of myotubes. Evidence suggests that mitochondrial fission governs other mitochondrial remodeling processes; however, this relationship is unclear in the context of myogenesis.
    METHODS: We used C2C12 myoblasts to study changes in mitochondrial remodeling processes and their role in regulating myogenesis. To investigate this, we employed genetic manipulation with adenoviruses to modify the levels of key molecules involved in mitochondrial remodeling, including DNM1L, BNIP3, and PPARGC1A.
    RESULTS: We demonstrate that overexpression of fission protein DNM1L accelerated mitophagic flux, but reduced myotube size without affecting mitochondrial biogenesis. Conversely, DNM1L knockdown reduced mitophagic flux, impaired myoblast differentiation, and suppressed mitochondrial biogenesis signaling. Additionally, DNM1L knockdown increased mitochondrial apoptotic signaling through CASP9 and CASP3 activation. Attempts to rescue myogenesis through overexpression of the mitophagy receptor BNIP3 or the biogenesis regulator PPARGC1A were unsuccessful in the absence of proper mitochondrial fission. Furthermore, DNM1L overexpression in BNIP3-deficient cells enhanced mitophagic flux, but did not promote myogenesis.
    CONCLUSION: These results underscore the complex interdependencies among mitochondrial remodeling processes and highlight the necessity for sequential activation of mitochondrial fission, mitophagy, and biogenesis.
    Keywords:  Apoptosis; Mitochondrial biogenesis; Mitochondrial fission; Mitophagy; Myogenesis; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12964-025-02142-x
  2. Mitochondrion. 2025 Mar 28. pii: S1567-7249(25)00033-9. [Epub ahead of print]83 102036
    Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.
    Sudhir Kshirsagar, Rainier Vladlen Alvir, Jangampalli Adi Pradeepkiran, Arubala P Reddy, P Hemachandra Reddy.
      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; Behavioral tests; Cognitive function; DDQ; Mitochondrial biogenesis; Mitochondrial dysfunction; Mitophagy; Neurodegenerative disorders; Neuroinflammation; Neuroprotection; Transmission electron microscopy; hAbKI mouse model
    DOI:  https://doi.org/10.1016/j.mito.2025.102036
  3. Mol Med Rep. 2025 Jun;pii: 146. [Epub ahead of print]31(6):
    α‑ketoglutarate protects against septic cardiomyopathy by improving mitochondrial mitophagy and fission.
    Wei Wu, Qiong Ma, Bo-Tao Li, Shuang Shi, Gong-Chang Guan, Jun-Kui Wang, Bao-Yao Xue, Zhong-Wei Liu.
      Septic cardiomyopathy is a considerable complication in sepsis, which has high mortality rates and an incompletely understood pathophysiology, which hinders the development of effective treatments. α‑ketoglutarate (AKG), a component of the tricarboxylic acid cycle, serves a role in cellular metabolic regulation. The present study delved into the therapeutic potential and underlying mechanisms of AKG in ameliorating septic cardiomyopathy. A mouse model of sepsis was generated and treated with AKG via the drinking water. Cardiac function was assessed using echocardiography, while the mitochondrial ultrastructure was examined using transmission electron microscopy. Additionally, in vitro, rat neonatal ventricular myocytes were treated with lipopolysaccharide (LPS) as a model of sepsis and then treated with AKG. Mitochondrial function was evaluated via ATP production and Seahorse assays. Additionally, the levels of reactive oxygen species were determined using dihydroethidium and chloromethyl derivative CM‑H2DCFDA staining, apoptosis was assessed using a TUNEL assay, and the expression levels of mitochondria‑associated proteins were analyzed by western blotting. Mice subjected to LPS treatment exhibited compromised cardiac function, reflected by elevated levels of atrial natriuretic peptide, B‑type natriuretic peptide and β‑myosin heavy chain. These mice also exhibited pronounced mitochondrial morphological disruptions and dysfunction in myocardial tissues; treatment with AKG ameliorated these changes. AKG restored cardiac function, reduced mitochondrial damage and corrected mitochondrial dysfunction. This was achieved primarily through increasing mitophagy and mitochondrial fission. In vitro, AKG reversed LPS‑induced cardiomyocyte apoptosis and dysregulation of mitochondrial energy metabolism by increasing mitophagy and fission. These results revealed that AKG administration mitigated cardiac dysfunction in septic cardiomyopathy by promoting the clearance of damaged mitochondria by increasing mitophagy and fission, underscoring its therapeutic potential in this context.
    Keywords:  AKG; fission; mitochondria; mitophagy; septic cardiomyopathy
    DOI:  https://doi.org/10.3892/mmr.2025.13511
  4. Open Biol. 2025 Apr;15(4): 240358
    Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress.
    Alexa Di Pede, Bokang Ko, Abdelrahman AlOkda, Aura A Tamez González, Shusen Zhu, Jeremy M Van Raamsdonk.
      The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that responds to mitochondrial insults by altering gene expression to recover mitochondrial homeostasis. The mitoUPR is mediated by the stress-activated transcription factor ATFS-1 (activating transcription factor associated with stress 1). Constitutive activation of ATFS-1 increases resistance to exogenous stressors but paradoxically decreases lifespan. In this work, we determined the optimal levels of expression of activated ATFS-1 with respect to lifespan and resistance to stress by treating constitutively active atfs-1(et17) worms with different concentrations of RNA interference (RNAi) bacteria targeting atfs-1. We observed the maximum lifespan of atfs-1(et17) worms at full-strength atfs-1 RNAi, which was significantly longer than wild-type lifespan. Under the conditions of maximum lifespan, atfs-1(et17) worms did not show enhanced resistance to stress, suggesting a trade-off between stress resistance and longevity. The maximum resistance to stress in atfs-1(et17) worms occurred on empty vector. Under these conditions, atfs-1(et17) worms are short-lived. This indicates that constitutive activation of ATFS-1 can increase lifespan or enhance resistance to stress but not both, at the same time. Overall, these results demonstrate that constitutively active ATFS-1 can extend lifespan when expressed at low levels and that this lifespan extension is not dependent on the ability of ATFS-1 to enhance resistance to stress.
    Keywords:  ATFS-1; Caenorhabditis elegans; ageing; genetics; mitochondrial unfolded protein response; stress resistance
    DOI:  https://doi.org/10.1098/rsob.240358
  5. FASEB J. 2025 Apr 15. 39(7): e70501
    Fibroblast growth factor 8 (FGF8) induces mitochondrial remodeling in chondrocytes via ERK/AMPK signaling pathway.
    Hongcan Huang, Mengmeng Duan, Jieya Wei, Yang Liu, Siqun Xu, Minglei Huang, Ying Tu, Jing Xie, Wei Du.
      Osteoarthritis (OA) is a disease characterized by articular cartilage degeneration, and its pathogenic mechanisms are associated with mitochondrial homeostasis disorders. Fibroblast growth factor 8 (FGF8) is a multipotent protein ligand which is upregulated in OA cartilage. However, the molecular mechanisms by which FGF8 regulates mitochondria in chondrocytes are not yet fully understood. Here, we treated chondrocytes with FGF8 and detected the effects of FGF8 on mitochondrial morphology in the cytoplasm using transmission electron and confocal laser scanning microscopy. ATP levels were measured to determine the cellular energy status. Western blotting and immunofluorescence staining experiments were employed to detect the fusion-fission proteins mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (DRP1), mitochondrial fission 1 protein (FIS1), and related signaling pathways. The FGF receptor (FGFR) inhibitor, AZD4547, and the ERK inhibitor, U0126, were used to verify the specific effects of the FGFR and ERK pathways. We found that FGF8 regulated mitochondrial morphology and dynamics in chondrocytes by inducing mitochondrial elongation. While it upregulated fusion proteins MFN1, MFN2, and OPA1, FGF8 downregulated fission proteins DRP1 and FIS1. ERK and AMPK pathways were activated in chondrocytes after FGF8 treatment. In contrast, both AZD4547 and U0126 inhibitors abolished mitochondrial elongation as well as the alteration of fusion-fission proteins induced by FGF8, and U0126 also inhibited the FGF8-triggered activation of AMPK. This study is the first to reveal that FGF8 remodels mitochondria through ERK/AMPK signaling in chondrocytes, offering novel insights into the potential role of FGF8 in OA.
    Keywords:  AMPK; ERK; FGF8; chondrocytes; mitochondria; osteoarthritis
    DOI:  https://doi.org/10.1096/fj.202500186R
  6. Chem Biol Interact. 2025 Mar 26. pii: S0009-2797(25)00122-X. [Epub ahead of print]413 111492
    Pre-clinical evidence for mitochondria as a therapeutic target for luteolin: A mechanistic view.
    Marcos Roberto de Oliveira.
      Pre-clinical evidence indicates that mitochondria may be a therapeutic target for luteolin (3',4',5,7-tetrahydroxyflavone; LUT) in different conditions. LUT modulates mitochondrial physiology in in vitro, ex vivo, and in vivo experimental models. This flavone exerted mitochondria-related antioxidant and anti-apoptotic effects, stimulated mitochondrial fusion and fission, induced mitophagy, and promoted mitochondrial biogenesis in human and animal cells and tissues. Moreover, LUT modulated the activity of components of the oxidative phosphorylation (OXPHOS) system, improving the ability of mitochondria to produce adenosine triphosphate (ATP) in certain circumstances. The mechanism of action by which LUT promoted mitochondrial benefits and protection are not completely clear yet. Nonetheless, LUT is a potential candidate to be utilized in mitochondrial therapy in the future. In this work, it is explored the mechanisms of action by which LUT modulates mitochondrial physiology in different pre-clinical experimental models.
    Keywords:  Bioenergetics; Luteolin; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy
    DOI:  https://doi.org/10.1016/j.cbi.2025.111492
  7. Biotechnol J. 2025 Apr;20(4): e202400611
    tsRNA-12391-Modified Adipose Mesenchymal Stem Cell-Derived Exosomes Mitigate Cartilage Degeneration in Osteoarthritis by Enhancing Mitophagy.
    Jingsheng Shi, Guanglei Zhao, Siqun Wang, Yibing Wei, Jianguo Wu, Gangyong Huang, Jie Chen, Jun Xia.
      Osteoarthritis (OA) is a cartilage-degenerative joint disease. Mitophagy impacts articular cartilage damage. tRNA-derived small RNAs (tsRNAs) are one of the contents of adipose mesenchymal stem cell (AMSC)-derived exosomes (AMSC-exos) and are involved in disease progression. However, whether tsRNAs regulate mitophagy and whether tsRNA-modified AMSC-exos improve OA via mitophagy remain unclear. We performed small RNA sequencing to identify OA-related tsRNAs, which were then loaded into AMSC-exos, exploring the function and mechanisms related to mitophagy in vitro and in vivo. Overall, 53 differentially expressed tsRNAs (DEtsRNAs) were identified between OA and normal cartilage tissues, among which 42 DEtsRNAs, including tsRNA-12391, were downregulated in the OA group. Target genes of tsRNA-12391 mainly participated in mitophagy-related pathways such as Rap1 signaling pathway. Compared to the control group, tsRNA-12391 mimics significantly promoted mitophagy, as shown by the upregulated expression of PINK1 and LC3 and the co-localization of Mito-Tracker Green and PINK1. Furthermore, tsRNA-12391 mimics effectively enhanced chondrogenesis in chondrocytes, as demonstrated by the elevated expression of collagen II and ACAN. AMSC-exos with tsRNA-12391 overexpression also facilitated mitophagy and chondrogenesis in vitro and in vivo. Mechanistically, tsRNA-12391 bound to ATAD3A restricted ATAD31 from degrading PINK1, leading to PINK1 accumulation. ATAD31 overexpression reversed the effects of tsRNA-12391 mimics on mitophagy and chondrogenesis. AMSC-exos loaded with tsRNA-12391 promoted mitophagy and chondrogenesis by interacting with ATAD31; this may be a novel therapeutic strategy for OA.
    Keywords:  adipose mesenchymal stem cells; exosomes; mitophagy; osteoarthritis; tsRNA‐12391
    DOI:  https://doi.org/10.1002/biot.202400611
  8. Aquat Toxicol. 2025 Mar 22. pii: S0166-445X(25)00100-6. [Epub ahead of print]283 107335
    Novel insights into copper-induced Chinese mitten crab hepatopancreas mitochondrial toxicity: Oxidative stress, apoptosis and BNIP3L-mediated mitophagy.
    Xinping Guo, Minghao Shen, Su Jiang, Xiumei Xing, Cong Zhang, Shaowu Yin, Kai Zhang.
      Copper (Cu) is an important metal pollutant commonly found in aquatic environment. Cu-based nanoparticles (NPs) have been increasingly fabricated, and led to cytotoxicity in aquatic animals. Herein, the mechanisms underlying the CuSO4/Cu-NPs-mediated perturbation of the hepatopancreatic mitochondrial function at different concentrations were investigated and compared. After exposing Eriocheir sinensis to 0 (control), 5, 50, and 500 μg/L CuSO4 and 10 μg/L Cu-NPs for 21 days, hepatopancreases were retrieved. The results revealed that Cu-NPs or excess CuSO4 induced ultrastructural damage following a time-dose effect, as indicated by swelling and degeneration of the lumen of hepatic tubules. Cu-NPs or excess CuSO4 exposure decreased the antioxidative capacity and led to the over-accumulation of reactive oxygen species (ROS). Moreover, the mitochondrial membrane potential (MMP) was reduced and apoptosis induced. Additionally, both CuSO4 and Cu-NPs increased the numbers of mitophagosomes and the mRNA and protein levels of microtubule associated protein 1 light chain 3 beta (LC3B), and triggered mitophagy through BCL2 interacting protein 3 like (BNIP3L)/Beclin1 pathway. Altogether, this study provides a basis for exploring Cu-mediated potential mitochondrial autophagy activation mechanisms, uncovered the difference between CuSO4 and Cu-NPs.
    Keywords:  Apoptosis; Cu-NPs; CuSO(4); Eriocheir sinensis; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.aquatox.2025.107335
  9. Cell Commun Signal. 2025 Apr 02. 23(1): 166
    Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1 modulation.
    Gee Euhn Choi, Ji Yong Park, Mo Ran Park, Chang Woo Chae, Young Hyun Jung, Jae Ryong Lim, Jee Hyeon Yoon, Ji Hyeon Cho, Ho Jae Han.
       BACKGROUND: Prenatal stress exposure irreversibly impairs mitochondrial dynamics, including mitochondrial trafficking and morphology in offspring, leading to neurodevelopmental and neuropsychiatric disorders in adulthood. Thus, understanding the molecular mechanism controlling mitochondrial dynamics in differentiating neurons is crucial to prevent the prenatal stress-induced impairments in behavior. We investigated the interplay between mitochondrial transport and fusion/fission in differentiating neurons exposed to prenatal stress, leading to ensuing behavior impairments, and then tried to identify the primary regulator that modulates both phenomena.
    METHODS: We used primary hippocampal neurons of mice exposed to prenatal stress and human induced-pluripotent stem cell (hiPSC)-derived neurons, for investigating the impact of glucocorticoid on mitochondrial dynamics during differentiation. For constructing mouse models, we used AAV vectors into mouse pups exposed to prenatal stress to regulate protein expressions in hippocampal regions.
    RESULTS: We first observed that prenatal exposure to glucocorticoids induced motility arrest and fragmentation of mitochondria in differentiating neurons derived from mouse fetuses (E18) and human induced pluripotent stem cells (hiPSCs). Further, glucocorticoid exposure during neurogenesis selectively downregulated Miro1 and increased Drp1 phosphorylation (Ser616). MIRO1 overexpression restored mitochondrial motility and increased intramitochondrial calcium influx through ER-mitochondria contact (ERMC) formation. Furthermore, we determined that the N-terminal GTPase domain of Miro1 plays a critical role in ERMC formation, which then decreased Drp1 phosphorylation (Ser616). Similarly, prenatal corticosterone exposure led to impaired neuropsychiatric and cognitive function in the offspring by affecting mitochondrial distribution and synaptogenesis, rescued by Miro1WT, but not N-terminal GTPase active form Miro1P26V, expression.
    CONCLUSION: Prenatal glucocorticoid-mediated Miro1 downregulation contributes to dysfunction in mitochondrial dynamics through Drp1 phosphorylation (Ser616) in differentiating neurons.
    Keywords:  ER-mitochondria contacts; Miro; Mitochondrial dynamics; Neurodegeneration; Prenatal glucocorticoid
    DOI:  https://doi.org/10.1186/s12964-025-02172-5
  10. Mol Immunol. 2025 Apr 02. pii: S0161-5890(25)00086-0. [Epub ahead of print]182 62-75
    LncRNA XIST inhibits mitophagy and increases mitochondrial dysfunction by promoting BNIP3 promoter methylation to facilitate the progression of KBD.
    Ruoxi Liu, Yi Xiao, Sihua Huang, Hao Wu, Jun Dong, Sixiang Zeng, Yongwei Li, Jintao Ye, Wei Wu, Mengxin Wang, Sanpeng Zhang, Zhaoxing Lin, Huanjin Song.
      The primary mechanisms underlying cartilage destruction in Kashin-Beck disease (KBD) involve excessive chondrocyte death and extracellular matrix (ECM) degradation. While long non-coding RNA XIST (lncRNA XIST) has been implicated in promoting chondrocyte injury in osteoarthritis (OA), its role in KBD-related chondrocyte injury remains poorly understood. In this study, joint tissues were collected from four healthy and four KBD-affected children, as well as five healthy and five KBD-affected adults, to assess the expression of lncRNA XIST. The results revealed a significant upregulation of lncRNA XIST in the cartilage tissues of KBD patients. To model KBD-induced chondrocyte damage in vitro, hypertrophic ATDC5 cells were exposed to 10 ng/ml T-2 toxin for 24 hours, which resulted in increased lncRNA XIST expression. Silencing lncRNA XIST was found to mitigate T-2 toxin-induced ECM degradation and chondrocyte apoptosis by alleviating defects in mitochondrial autophagy and dysfunction. Mechanistically, lncRNA XIST promoted the methylation of the BNIP3 promoter by recruiting DNA methyltransferases (DNMTs) to the BNIP3 promoter region, thereby suppressing BNIP3-mediated mitophagy and exacerbating mitochondrial dysfunction. To establish a KBD rat model, rats were fed a low-selenium diet supplemented with T-2 toxin for four weeks. Knockdown of lncRNA XIST in these rats attenuated articular cartilage damage and apoptosis, while enhancing collagen II expression. In conclusion, lncRNA XIST accelerates KBD progression by inhibiting mitophagy and promoting mitochondrial dysfunction through increased BNIP3 promoter methylation.
    Keywords:  BNIP3; Chondrocyte; DNA methylation; Kashin-Beck disease; LncRNA XIST; Mitophagy
    DOI:  https://doi.org/10.1016/j.molimm.2025.03.016
  11. Free Radic Biol Med. 2025 Apr 01. pii: S0891-5849(25)00196-0. [Epub ahead of print]
    Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
    Arunkumar Venkatesan, Marc Ridilla, Nileyma Castro, J Mario Wolosin, Jessica L Henty-Ridilla, Barry E Knox, Preethi S Ganapathy, Jamin S Brown, Anthony F DeVincentis, Sandra Sieminski, Audrey M Bernstein.
      Exfoliation Syndrome is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG). XFG is a multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from patients without glaucoma (No Glaucoma, NG) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with increased mitochondrial localization to lysosomes and slowed mitophagic flux. Mitochondrial dysfunction in the XFG TFs was associated with hyperdynamic microtubules, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A, and a mitochondrial biogenesis inducer, Nicotinamide Ribose, improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate that XFG TFs have abnormal mitochondria and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.
    Keywords:  Microtubule cytoskeleton; Mitochondria; Mitophagy; ROS; Tenon fibroblast
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.046
  12. bioRxiv. 2025 Mar 13. pii: 2025.03.10.642434. [Epub ahead of print]
    Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem cells.
    Luana Chiquetto, Meg Schuetz, Qian Dong, Mia Warmka, Liana Valin, Ashley Jones, Patrick Hunt, Copper Petermeier, Jie Wang, Nate Roundy, Zev J Greenberg, Wei Yang, Christine R Zhang, Grant A Challen, Cliff J Luke, Robert A J Signer, Wandy L Beatty, Stephen Sykes, Weikai Li, David J Kast, Laura G Schuettpelz.
      Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics via promotion of microtubule catastrophe and sequestration of free tubulin heterodimers. Stathmin 1 is highly expressed in hematopoietic stem cells (HSCs), and overexpressed in leukemic cells, however its role in HSCs is not known. Herein, we found that loss of Stathmin 1 is associated with altered microtubule architecture in HSCs, and markedly impaired HSC function. Transcriptomic studies suggested alterations in oxidative phosphorylation in Stmn1 -/- HSCs, and further mechanistic studies revealed defective mitochondrial structure and function in the absence of Stathmin 1 with increased ROS production. Microtubules associate with mitochondria and lysosomes to facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stathmin 1-deficient HSCs. Finally, stimulation of autophagy improved the colony forming ability of Stmn1 -/- hematopoietic stem and progenitor cells. Together, our data identify Stathmin 1 as a novel regulator of mitophagy and mitochondrial health in HSCs.
    Key Points: The microtubule regulating protein Stathmin 1 is highly expressed in HSPCs and promotes normal microtubule architecture.Loss of Stathmin 1 in HSPCs leads to impaired autophagy with abnormal mitochondrial morphology, decreased respiratory capacity, and impaired cellular function.
    DOI:  https://doi.org/10.1101/2025.03.10.642434
  13. IUBMB Life. 2025 Apr;77(4): e70015
    Ischemic preconditioning attenuates ischemia/reperfusion-induced acute kidney injury dependent on mitochondrial protease CLPP.
    Wenjia Xie, Lingqi Gao, Xinyan Gu, Liu Li, Hui Zheng, Lulu Wang, Ping Wen, Yang Zhou, Lei Jiang, Chunsun Dai, Hongdi Cao.
      Ischemic preconditioning (IPC) is a phenomenon in which brief periods of ischemia trigger protective mechanisms that alleviate subsequent ischemia-reperfusion injury (IRI), although the precise protective mechanism remains unclear. This study investigated the mechanism by which IPC protects acute kidney injury (AKI) induced by renal IRI. We found that IPC for 10 min significantly ameliorated IRI-induced AKI, whereas IPC for 5 or 15 min did not have any protective effects. Renal ischemia increased the expression of caseinolytic protease P (CLPP) in tubular epithelial cells. The peak effect was reached after 10 min of renal ischemia, during which no mitochondrial deposition of misfolded/unfolded proteins or signs of AKI were evident. However, after 15 min of renal ischemia, there was no further increase in CLPP levels, which was accompanied by mitochondrial deposition of misfolded/unfolded proteins and signs of AKI. The increase in CLPP levels suggests potential activation of the mitochondrial unfolded protein response (UPRmt), which is a cellular stress response pathway that regulates the expression of mitochondrial chaperones and proteases to maintain protein homeostasis within the mitochondria. Knockdown of Clpp led to the aggregation of mitochondrial unfolded/misfolded proteins and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which indicated integrated stress response (ISR) activation. Clpp knockdown in mice antagonized the protective effects induced by IPC for 10 min during renal IRI. Furthermore, the inhibition of ISR activation by an ISR inhibitor (ISRIB) may also impede the protective effects of IPC for 10 min. This study indicates that IPC can ameliorate renal IRI injury and that its effect is dependent on CLPP.
    Keywords:  CLPP; UPRmt; acute kidney injury; ischemic preconditioning
    DOI:  https://doi.org/10.1002/iub.70015
  14. J Gastroenterol Hepatol. 2025 Apr 02.
    Irisin Alleviates Impaired Mitochondrial Fusion via Enhancing PKA/SIRT3/mTOR Pathway in Hepatic Steatosis.
    Jia Li, Ying Zhao, Zhihong Wang, Anran Ma, Yunzhi Ni, Di Wu, Yue Zhou, Na Zhang, Li Zhang, Yongsheng Chang, Qinghua Wang.
       BACKGROUND AND AIM: Hepatic steatosis, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), arises from disrupted lipid homeostasis. Mitochondrial dysfunction, particularly imbalances in mitochondrial fusion and fission, plays a crucial role in MASLD progression. Irisin, an exercise-induced myokine, is involved in lipid metabolism, though its precise mechanisms of action remain unclear.
    METHODS: An irisin-Fc fusion protein was prophylactically administered to mice with high-fat diet (HFD)-induced MASLD for 12 weeks. Liver tissues were analyzed using oil red O staining and hepatic and serum lipid profiling to evaluate irisin's therapeutic efficacy. Expression levels of proteins involved in fatty acid metabolism and mitochondrial dynamics were assessed. In palmitate (PA)-treated HepG2 cells, mitochondrial morphology was analyzed, and fatty acid uptake was determined through colocalization of fluorescently labeled PA with mitochondria. PKA activity and SIRT3 expression were validated using a PKA agonist/inhibitor and SIRT3 overexpression or knockdown via plasmid transfection and siRNA.
    RESULTS: Irisin significantly reduced lipid accumulation in HFD-induced MASLD mouse models and PA-treated HepG2 cells. These effects were associated with enhanced mitochondrial fusion, indicated by increased expression of mitofusin 2 and optic atrophy type 1 and reduced excessive fission, evidenced by decreased activation of dynamin-related protein 1. These changes were mediated partly through PKA/SIRT3/mTOR pathway activation, which facilitated mitochondrial fatty acid uptake and β-oxidation while inhibiting lipogenesis.
    CONCLUSIONS: Our results demonstrate the protective role of irisin in alleviating hepatic steatosis by regulating mitochondrial dynamics. These findings provide valuable evidence of the antisteatogenic mechanisms of irisin and its therapeutic potential for MASLD management.
    Keywords:  MASLD; hepatic steatosis; irisin; lipid metabolism; mitochondrial dynamics
    DOI:  https://doi.org/10.1111/jgh.16950
  15. J Orthop Translat. 2025 Mar;51 163-175
    Inhibition of ERK1/2 mediated activation of Drp1 alleviates intervertebral disc degeneration via suppressing pyroptosis and apoptosis in nucleus pulposus cells.
    Shenkai Su, Xuanzhang Wu, Bin Li, Fengyu Zhang, Kaiying Zhang, Hui Wang, Yan Lin, Jiaoxiang Chen.
       Objective: Dynamin-related protein 1 (Drp1) plays a crucial role in various inflammatory and degenerative diseases, yet its involvement in intervertebral disc degeneration (IVDD) remains poorly understood. This study aims to elucidate the mechanism by which Drp1 contributes to IVDD and to identify the efficacy of the Drp1 inhibitor Mdivi-1 on IVDD.
    Methods: Tert-butyl hydroperoxide (TBHP) is utilized to induce an oxidative stress microenvironment in vitro. In vivo, IVDD model is constructed in 8-week old rats through puncture operation. The therapeutic effect of Mdivi-1 is evaluated through X-ray, MRI and histological analysis. A comprehensive set of experiments, including single-cell sequencing analysis, western blot, flow cytometry and immunofluorescence staining, are conducted to investigate the role and underlying mechanisms of Drp1 in vitro.
    Results: Our study demonstrates that the expression of Drp1 and phosphorylated Drp1 (p-Drp1) are up-regulated in degenerative nucleus pulposus cells (NPCs), which are accompanied with increased pyroptosis and apoptosis. In vivo, both si-Drp1-mediated Drp1 knockdown and the pharmacological inhibitor Mdivi-1 alleviate puncture-induced IVDD in rats. In vitro, si-Drp1 or Mdivi-1 inhibits mitochondria-dependent apoptosis and pyroptosis triggered by TBHP. Mechanistically, Mdivi-1 reduces p-Drp1 levels, inhibits excessive mitochondrial fission, and mitigates mitochondrial dysfunction. Drp1 phosphorylation-based Drp1 mitochondrial translocation and subsequent apoptosis and pyroptosis are regulated by ERK1/2 phosphorylation in NPCs under oxidative stress condition.
    Conclusion: This study highlights the involvement of Drp1 in the pathological progression of degenerative NPCs in IVDD, which is regulated by ERK1/2. Pharmacological inhibition of Drp1 with Mdivi-1 protects NPCs by promoting mitochondrial function and attenuating apoptosis and pyroptosis. These findings suggest that Mdivi-1 is a promising therapeutic candidate for IVDD treatment.
    Translational Potential: By offering experimental evidence on the role and mechanism of Drp1 in IVDD, this study underscores the potential of Mdivi-1 as a therapeutic strategy for IVDD.
    Keywords:  Apoptosis; Drp1; IVDD; Mitochondria; Pyroptosis
    DOI:  https://doi.org/10.1016/j.jot.2025.01.013
  16. Front Physiol. 2025 ;16 1500247
    Mitochondrial fusion protein: a new therapeutic target for lung injury diseases.
    Guiyang Jia, Erqin Song, Qianxia Huang, Miao Chen, Guoyue Liu.
      Mitochondria are essential organelles responsible for cellular energy supply. The maintenance of mitochondrial structure and function relies heavily on quality control systems, including biogenesis, fission, and fusion. Mitochondrial fusion refers to the interconnection of two similar mitochondria, facilitating the exchange of mitochondrial DNA, metabolic substrates, proteins, and other components. This process is crucial for rescuing damaged mitochondria and maintaining their normal function. In mammals, mitochondrial fusion involves two sequential steps: outer membrane fusion, regulated by mitofusin 1 and 2 (MFN1/2), and inner membrane fusion, mediated by optic atrophy 1 (OPA1). Dysfunction in mitochondrial fusion has been implicated in the development of various acute and chronic lung injuries. Regulating mitochondrial fusion, maintaining mitochondrial dynamics, and improving mitochondrial function are effective strategies for mitigating lung tissue and cellular damage. This study reviews the expression and regulatory mechanisms of mitochondrial fusion proteins in lung injuries of different etiologies, explores their relationship with lung injury diseases, and offers a theoretical foundation for developing novel therapeutic approaches targeting mitochondrial fusion proteins in lung injury.
    Keywords:  lung injury; mitochondria; mitochondrial fusion; mitofusin 1/2; optic atrophy 1
    DOI:  https://doi.org/10.3389/fphys.2025.1500247
  17. Autophagy. 2025 Mar 31.
    Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.
    Yuyuan Zhu, Min Cao, Yancheng Tang, Yifan Liu, Haiji Wang, Jiaqi Qi, Cainian Huang, Chenghao Yan, Xu Liu, Sijia Jiang, Yufei Luo, Shaogui Wang, Bo Zhou, Haodong Xu, Ying-Ying Lu, Liming Wang.
      Mitochondria serve as the primary source of intracellular reactive oxygen species (ROS), which play a critical role in orchestrating cell death pathways such as pyroptosis in various types of cancers. PINK1-mediated mitophagy effectively removes damaged mitochondria and reduces detrimental ROS levels, thereby promoting cell survival. However, the regulation of pyroptosis by PINK1 and ROS in neuroblastoma remains unclear. In this study, we demonstrate that inhibition or deficiency of PINK1 sensitizes ROS signaling and promotes pyroptosis in neuroblastoma cells via the BAX-caspase-GSDME signaling pathway. Specifically, inhibition of PINK1 by AC220 or knockout of PINK1 impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Activated BAX facilitates the release of CYCS (cytochrome c, somatic) from the mitochondria into the cytosol, activating CASP3 (caspase 3). Subsequently, activated CASP3 cleaves and activates GSDME, inducing pyroptosis. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression in vivo. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.
    Keywords:  Cell death; GSDME; PINK1; mitochondrial ROS; mitophagy; neuroblastoma
    DOI:  https://doi.org/10.1080/15548627.2025.2487037
  18. Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 31.
    Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.
    Al-Hassan Soliman Wadan, Ahmed H Shaaban, Mohamed Z El-Sadek, Salah Abdelfatah Mostafa, Ahmed Sherief Moshref, Ahmed El-Hussein, Doha El-Sayed Ellakwa, Samah S Mehanny.
      Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.
    Keywords:  Mitochondria-focused therapies; Mitochondrial dysfunction; Neurodegenerative diseases; Oxidative stress; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s00210-025-04014-0
  19. bioRxiv. 2025 Mar 28. pii: 2025.03.17.643721. [Epub ahead of print]
    Representing Mitochondrial Dynamics with Abstract Algebra.
    Raphael Mostov, Greyson R Lewis, Gabriel Sturm, Wallace F Marshall.
      This paper addresses the increasing need for comprehensive mathematical descriptions of cell organization by examining the algebraic structure of mitochondrial network dynamics. Mitochondria are cellular structures involved in metabolism that take the form of a network of membrane-based tubes that undergo continuous re-arrangement by a set of morphological processes, including fission and fusion, carried out by protein-based machinery. Because of their network structure, mitochondria can be represented as graphs, and the morphological operations that take place in the cell, referred to as mitochondrial dynamics, can be represented by changes to the graphs. Prior studies have classified mitochondrial graphs based on graph-theoretic features, but an alternative approach is to focus not on the graphs themselves but on the set of morphological operations inducing mitochondrial dynamics, since this may provide a simpler representation. Moreover, the operations are what determine the graphs that will be generated in a biological system. Here we show that mitochondrial dynamics on a single connected mitochondrion constitute a groupoid that includes the automorphism group of each mitochondria graph. For multi-component mitochondria we define a graph structure that encapsulates the structure of mitochondrial dynamics. Using these formalisms we define a distance metric for similarity between mitochondrial structures based on an edit distance. In the course of defining these structures we provide a mathematical motivation for new experimental questions regarding mitochondrial fusion and the impacts of cell division on mitochondrial morphology. This work points to a general strategy for formulating a cell structure state-space, based not on the shapes of cellular structures, but on relations between the dynamic operations that produce them.
    DOI:  https://doi.org/10.1101/2025.03.17.643721
  20. Free Radic Biol Med. 2025 Apr 01. pii: S0891-5849(25)00195-9. [Epub ahead of print]
    Targeting LKB1-AMPK-SIRT1-induced autophagy and mitophagy pathways improves cerebrovascular homeostasis in APP/PS1 mice.
    Yawen Li, Tongxing Wang, Hongrong Li, Yuning Jiang, Xiaogang Shen, Ning Kang, Zhifang Guo, Runtao Zhang, Xuan Lu, Tianyu Kang, Mengnan Li, Yunlong Hou, Yiling Wu.
       BACKGROUND: Alzheimer's disease (AD) is the most common and severe degenerative disorder of the central nervous system in the elderly, profoundly impacting patients' quality of life. However, effective therapeutic agents for AD are still lacking. Bazi Bushen (BZBS) is a traditional Chinese herbal compound with potential neuroprotective effects, yet its underlying mechanisms remain poorly understood.
    METHODS: In this study, we utilized APP/PS1 transgenic mice to assess the therapeutic efficacy of BZBS. Initially, we evaluated the spatial learning and memory of the mice using the Barnes maze. The brain microcirculation was assessed through a small-animal ultrasound system, two-photon in vivo imaging, and micro-computed tomography angiography. Molecular, biochemical, and pathological analyses were conducted on brain tissues. Through network pharmacology, we identified potential intervention pathways and targets for BZBS in the treatment of AD, which we subsequently validated both in vivo and in vitro. Additionally, we employed molecular virtual docking screening and bio-layer interferometry to elucidate the direct interactions of ginsenoside Rg5 and ginsenoside Ro in BZBS with AMPK and LKB1 proteins.
    RESULTS: The BZBS intervention significantly enhanced spatial learning and memory in APP/PS1 mice while decreasing Aβ deposition. Furthermore, BZBS protected cerebrovascular homeostasis and mitigated neuroinflammation, as evidenced by decreased blood-brain barrier permeability, increased expression of tight-junction proteins, and restored cerebral blood flow. Mechanistically, ginsenosides Rg5 and Ro in BZBS directly bind to AMPK and LKB1 proteins, activating the LKB1-AMPK-SIRT1 signaling pathway, promoting autophagy and mitochondrial autophagy, and alleviating oxidative stress damage in endothelial cells.
    CONCLUSIONS: BZBS enhances autophagy-related activity, decreases Aβ deposition, and improves endothelial cell homeostasis through the activation of the LKB1-AMPK-SIRT1 signaling pathway, ultimately leading to improved cognitive function in mice with AD. This study highlights the importance of enhancing autophagic activity and maintaining cerebrovascular homeostasis in mitigating cognitive decline in AD, providing evidence and new insights into the application of compound medicines for treating age-related neurological disorders.
    Keywords:  Alzheimer’s disease; Bazi Bushen; blood–brain barrier; ginsenosides; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.045
  21. ACS Infect Dis. 2025 Apr 01.
    SIRT1 and SIRT3 Impact Host Mitochondrial Function and Host Salmonella pH Balance during Infection.
    Dipasree Hajra, Vikas Yadav, Amit Singh, Dipshikha Chakravortty.
      Mitochondria are important organelles that regulate energy homeostasis. Mitochondrial health and dynamics are crucial determinants of the outcome of several bacterial infections. SIRT3, a major mitochondrial sirtuin, along with SIRT1 regulates key mitochondrial functions. This led to considerable interest in understanding the role of SIRT1 and SIRT3 in governing mitochondrial functions during Salmonella infection. Here, we show that loss of SIRT1 and SIRT3 function either by shRNA-mediated knockdown or by inhibitor treatment led to increased mitochondrial dysfunction with alteration in mitochondrial bioenergetics alongside increased mitochondrial superoxide generation in Salmonella-infected macrophages. Consistent with dysfunctional mitochondria, mitophagy was induced along with altered mitochondrial fusion-fission dynamics in S. typhimurium-infected macrophages. Additionally, the mitochondrial bioenergetic alteration promotes acidification of the infected macrophage cytosolic pH. This host cytosolic pH imbalance skewed the intraphagosomal and intrabacterial pH in the absence of SIRT1 and SIRT3, resulting in decreased SPI-2 gene expression. Our results suggest a novel role for SIRT1 and SIRT3 in maintaining the intracellular Salmonella niche by modulating the mitochondrial bioenergetics and dynamics in the infected macrophages.
    Keywords:  SPI-2 secretion; Salmonella; fusion-fission dynamics; macrophage-bacterial pH regulation; mitochondrial bioenergetics; mitophagy
    DOI:  https://doi.org/10.1021/acsinfecdis.4c00751
  22. bioRxiv. 2025 Mar 15. pii: 2025.03.15.643451. [Epub ahead of print]
    HTLV-1 Tax induces PINK1-Parkin-dependent mitophagy to mitigate activation of the cGAS-STING pathway.
    Suchitra Mohanty, Sujit Suklabaidya, Nelli Mnatsakanyan, Steven Jacobson, Edward W Harhaj.
      Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax regulatory protein plays a critical role in HTLV-1 persistence and pathogenesis; however, the underlying mechanisms are poorly understood. Here we show that Tax dynamically regulates mitochondrial reactive oxygen species (ROS) and membrane potential to trigger mitochondrial dysfunction. Tax is recruited to damaged mitochondria through its interaction with the IKK regulatory subunit NEMO and directly engages the ubiquitin-dependent PINK1-Parkin pathway to induce mitophagy. Tax also recruits autophagy receptors NDP52 and p62/SQSTM1 to damaged mitochondria to induce mitophagy. Furthermore, Tax requires Parkin to limit the extent of cGAS-STING activation and suppress type I interferon (IFN). HTLV-1-transformed T cell lines and PBMCs from HAM/TSP patients exhibit hallmarks of chronic mitophagy which may contribute to immune evasion and pathogenesis. Collectively, our findings suggest that Tax manipulation of the PINK1-Parkin mitophagy pathway represents a new HTLV-1 immune evasion strategy.
    Keywords:  HTLV-1; NDP52; NEMO; Parkin; STING; Tax; cGAS; mitochondria; mitophagy
    DOI:  https://doi.org/10.1101/2025.03.15.643451
  23. Drug Des Devel Ther. 2025 ;19 2173-2188
    MK-4 Ameliorates Diabetic Osteoporosis in Angiogenesis-Dependent Bone Formation by Promoting Mitophagy in Endothelial Cells.
    Fan Ding, Weidong Zhang, Ting Liu, Xing Rong, Yajun Cui, Lingxiao Meng, Luxu Wang, Bo Liu, Minqi Li.
       Purpose: Diabetic osteoporosis (DOP), one of the usual complications in diabetic patients, poses a significant threat to bone health. Type H vessels in metaphysis and medial cortical bone are associated with osteogenesis. As a form of Vitamin K2, menaquinone-4 (MK-4) is a potential treatment for osteoporosis. We aimed to investigate whether MK-4 ameliorates DOP by promoting bone formation through protecting type H vessels and its associated mechanisms.
    Methods: High fat diet (HDF) feeding and streptozotocin (STZ) injection were applied to establish a mouse model of type 2 diabetic osteoporosis (T2DOP). Micro-CT, Masson staining, HE staining and IHC staining were applied to observe bone mass and the osteoblastic ability of osteoblasts. Tissue immunofluorescence (IF) staining and flow cytometry were employed to assess alteration of type H blood vessels. In vitro, to evaluate the functional level and mitophagy of ECs under high glucose conditions, wound healing assay, tube formation assay, EdU assay and IF were employed. Osteogenic differentiation ability in vitro was evaluated by ALP staining, AR staining, Western blot and RT-qPCR.
    Results: MK-4 alleviated type H vessel injury and angiogenesis-dependent osteogenesis in DOP mice, thereby maintaining the bone mass. The vitro results showed that MK-4 could mitigate the dysfunction of ECs subjected to HG treatment, and further facilitate the osteogenic differentiation of MC3T3-E1 cells. Moreover, mechanism exploration found that PINK1/Parkin-mediated mitophagy was required for the impact of MK-4 on ECs. Meanwhile, ERK signal pathway is necessary for the improvement of MK-4 in PINK1/Parkin-mediated mitophagy.
    Conclusion: MK-4 is capable of alleviating the PINK1/Parkin-mediated mitophagy of ECs via the ERK pathway, thereby facilitating angiogenesis-dependent bone formation and further ameliorating DOP.
    Keywords:  Menaquinone-4; PINK1/Parkin-dependent mitophagy; angiogenesis-dependent osteogenesis; diabetic osteoporosis; type H vessels
    DOI:  https://doi.org/10.2147/DDDT.S503930
  24. BMC Med. 2025 Mar 31. 23(1): 189
    Enhancing anti-CD3 mAb-mediated diabetes remission in autoimmune diabetes through regulation of dynamin-related protein 1(Drp1)-mediated mitochondrial dynamics in exhausted CD8+T-cell subpopulations.
    Ruiling Zhao, Zhangyao Su, Junjie Gu, Hang Zhao, Lingling Bian, Yin Jiang, Yun Cai, Tao Yang, Yong Gu, Xinyu Xu.
       BACKGROUND: Antigen-specific immunotherapy shows potential for inducing long-term immune tolerance in type 1 diabetes (T1D), yet its clinical application is hampered by uncertainty regarding dominant epitopes. Conversely, non-antigen-specific treatments such as anti-CD3 monoclonal antibodies (mAbs) present a more straightforward approach but struggle to maintain tolerance after treatment. Addressing these issues is critical for advancing T1D therapies.
    METHODS: The phenotypic and metabolic properties of two subsets of exhausted CD8+ T cells were analyzed in both humans and NOD mice. T-cell receptor (TCR) diversity and Bulk RNA sequencing provided insights into the transcriptomic profiles and TCR reactivity of these cells. Mechanistic studies were conducted using the HEK-293 T cell line and primary cells. Single-cell RNA sequencing (scRNA-seq) was applied to evaluate the characteristics of different CD8+ T cell subsets following two types of immunotherapies. In NY8.3 mice, the effect of mitochondrial fission inhibitors on immunotherapy results was evaluated. Final validation was carried out with peripheral blood mononuclear cells (PBMCs) from T1D patients.
    RESULTS: Our study reveals the diversity of two distinct exhausted CD8+ T cell subsets in T1D through flow cytometry, highlighting unique clinical features, phenotypes, and functions. Notable differences in TCR reactivity and metabolic pathways between these subsets were identified through TCR sequencing and transcriptomic analyses in NOD mice. Both antigen-specific and non-antigen-specific stimuli produced unique exhausted CD8+ T cell subsets. Our research identified leucine-rich repeat kinase 2 (Lrrk2) as a key regulator of mitochondrial fission, influencing the interconversion of exhausted CD8+ T cell subsets by phosphorylating dynamin-related protein 1 (DRP1) at serine 637 (Ser637) and serine 616 (Ser616). scRNA-seq confirmed that antigen-specific immunotherapy effectively suppresses T cell signaling, induces exhaustion, and promotes the development of terminally exhausted T (TEX) cells. Mitochondrial division inhibitor 1 (Mdivi-1) enhanced the therapeutic effect of anti-CD3 mAb treatment by promoting the development of more TEX cells.
    CONCLUSIONS: Our results point to a new immunotherapeutic approach that targets exhausted CD8+ T cells' energy metabolism, offering valuable insights for advancing clinical strategies in T1D therapy.
    Keywords:  Autoimmunity; CD3 mAb; Exhausted T cell; Immune tolerance; Immunotherapy
    DOI:  https://doi.org/10.1186/s12916-025-04001-5
  25. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Nov 28. pii: 1672-7347(2024)11-1769-08. [Epub ahead of print]49(11): 1769-1776
    Regulation of pyroptosis and ferroptosis by mitophagy in chronic kidney disease.
    Yue Huang, Lina Yang.
      Chronic kidney disease (CKD) is a chronic progressive disease characterized by kidney injury or declining renal function. With its insidious onset and significant harm, CKD has become a major global public health concern. Abnormal cell death can directly or indirectly contribute to kidney injury, among which excessive pyroptosis and ferroptosis are central events in CKD pathogenesis. These two forms of cell death may interact through mechanisms such as reactive oxygen species release, further aggravating renal damage. Mitophagy, a selective autophagic process that removes damaged mitochondria, plays an important role in maintaining cellular homeostasis. In CKD, mitophagy is impaired; however, enhancing mitophagy signaling pathways can alleviate inflammation, reduce iron accumulation and lipid peroxidation in renal cells. This suggests that mitophagy may be a key regulator of pyroptosis and ferroptosis in kidney cells and holds potential as a novel target for the prevention, diagnosis, and treatment of CKD.
    Keywords:  cell death; chronic kidney disease; ferroptosis; mitophagy; pyroptosis
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2024.240458
  26. Cell Rep Med. 2025 Mar 19. pii: S2666-3791(25)00112-0. [Epub ahead of print] 102039
    Screening of patient-derived organoids identifies mitophagy as a cell-intrinsic vulnerability in colorectal cancer during statin treatment.
    Zhi-Hang Tao, Ji-Xuan Han, Jia Xu, Enhao Zhao, Ming Wang, Zheng Wang, Xiao-Lin Lin, Xiu-Ying Xiao, Jie Hong, Haoyan Chen, Ying-Xuan Chen, Hui-Min Chen, Jing-Yuan Fang.
      Statins, commonly used to lower cholesterol, are associated with improved prognosis in colorectal cancer (CRC), though their effectiveness varies. This study investigates the anti-cancer effects of atorvastatin in CRC using patient-derived organoids (PDOs) and PDO-derived xenograft (PDOX) models. Our findings reveal that atorvastatin induces mitochondrial dysfunction, leading to apoptosis in cancer cells. In response, cancer cells induce mitophagy to clear damaged mitochondria, enhancing survival and reducing statin efficacy. Analysis of a clinical cohort confirms mitophagy's role in diminishing statin effectiveness. Importantly, inhibiting mitophagy significantly enhances the anti-cancer effects of atorvastatin in CRC PDOs, xenograft models, and azoxymethane (AOM)-dextran sulfate sodium (DSS) mouse models. These findings identify mitophagy as a critical pro-survival mechanism in CRC during statin treatment, providing insights into the variable responses observed in epidemiological studies. Targeting this vulnerability through combination therapy can elicit potent therapeutic responses.
    Keywords:  colorectal cancer; mitophagy; patient-derived organoids; statin
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102039
  27. Neuropharmacology. 2025 Mar 31. pii: S0028-3908(25)00145-5. [Epub ahead of print] 110439
    Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson's Disease therapy.
    Wenjun Wang, Elizabeth Rosalind Thomas, Ruyue Xiao, Tianshun Chen, Shiting Xia, Qulian Guo, Kezhi Liu, You Yang, Xiang Li.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantial nigra. Mitochondrial dysfunction and mitochondrial oxidative stress are central to the pathogenesis of PD, with recent evidence highlighting the role of ferroptosis - a type of regulated cell death dependent on iron metabolism and lipid peroxidation. Mitochondria, the central organelles for cellular energy metabolism, play a pivotal role in PD pathogenesis through the production of Reactive oxygen species (ROS) and the disruption of iron homeostasis. This review explores the intricate interplay between mitochondrial dysfunction and ferroptosis in PD, focusing on key processes such as impaired electron transport chain function, tricarboxylic acid (TCA) cycle dysregulation, disruption of iron metabolism, and altered lipid peroxidation. We discuss key pathways, including the role of glutathione (GSH), mitochondrial ferritin, and the regulation of the mitochondrial labile iron pool (mLIP), which collectively influence the susceptibility of neurons to ferroptosis. Furthermore, this review emphasizes the importance of mitochondrial quality control mechanisms, such as mitophagy and mitochondrial biogenesis, in mitigating ferroptosis-induced neuronal death. Understanding these mechanisms linking the interplay between mitochondrial dysfunction and ferroptosis may pave the way for novel therapeutic approaches aimed at preserving mitochondrial integrity and preventing neuronal loss in PD.
    Keywords:  Ferroptosis; Mitochondria; Parkinson's disease; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110439
  28. Biochim Biophys Acta Mol Cell Res. 2025 Mar 27. pii: S0167-4889(25)00045-X. [Epub ahead of print] 119940
    A dynamin-like protein in Plasmodium falciparum plays an essential role in parasite growth, mitochondrial development and homeostasis during asexual blood stages.
    Vandana Thakur, Md Muzahidul Islam, Shweta Singh, Sumit Rathore, Azhar Muneer, Gaurav Dutta, Mudassir M Banday, Priya Arora, Mohammad E Hossain, Shaifali Jain, Shakir Ali, Asif Mohmmed.
      Malaria parasites harbour a single mitochondrion, and its proper segregation during parasite multiplication is crucial for the propagation of the parasite within the host. Mitochondrial division machinery consists of several proteins that associate with the mitochondrial membrane during segregation. Here, we have identified a dynamin-like protein in P. falciparum, PfDyn2, and deciphered its role in mitochondrial growth and homeostasis. A GFP targeting approach combined with high-resolution microscopy studies showed that the PfDyn2 associates with the mitochondrial membrane at specific sites during mitochondrial division. The C-terminal degradation tag mediated inducible knock-down (iKD) of PfDyn2 significantly inhibited parasite growth. PfDyn2-iKD hindered mitochondrial development and functioning, decreased mtDNA replication, and induced mitochondrial oxidative stress, ultimately causing parasite death. Regulated overexpression of a phosphorylation mutant of PfDyn2 (Ser-612-Ala) did not affect the recruitment of PfDyn2 on the mitochondria; normal mitochondrial division and parasite growth showed that phosphorylation/dephosphorylation of this conserved serine residue (Ser612) may not be responsible for regulating recruitment of PfDyn2 to the mitochondrion. Overall, we show the essential role of PfDyn2 in mitochondrial development and maintaining its homeostasis during the asexual cycle of the parasite.
    Keywords:  Dynamin; Dynamin-like protein (DLPs); Malaria; Mitochondrial development; Mitochondrial homeostasis; Plasmodium
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119940
  29. Cell Rep. 2025 Apr 03. pii: S2211-1247(25)00276-1. [Epub ahead of print]44(4): 115505
    Mitochondrial fission regulates midgut muscle assembly and tick feeding capacity.
    Zhengwei Zhong, Kun Wang, Ting Zhong, Jingwen Wang.
      Ticks ingest over 100 times their body weight in blood. As the primary tissue for blood storage and digestion, the tick midgut's regulation in response to this substantial blood volume remains unclear. Here, we show that blood intake triggers stem cell proliferation and mitochondrial fission in the midgut of Haemaphysalis longicornis. While inhibiting stem cell proliferation does not impact feeding behavior, disruption of mitochondrial fission impairs tick feeding capacity. Mitochondrial fission mediated by dynamin 2 (DNM2) regulates ATP generation, which in turn influences the expression of the tropomyosin-anchoring subunit troponin T (TNT). Knockdown of TNT disrupts muscle fiber assembly, hindering midgut enlargement and contraction, thereby preventing blood ingestion. These findings underscore the indispensable role of musculature in facilitating midgut expansion during feeding in ticks.
    Keywords:  CP: Cell biology; Haemaphysalis longicornis; dynamin 2; feeding capacity; mitochondrial fission; muscle assembly
    DOI:  https://doi.org/10.1016/j.celrep.2025.115505
  30. Phytother Res. 2025 Mar 30.
    Esculetin and Phloretin Combination Mitigates Acute Kidney Injury-Diabetes Comorbidity via Regulating Mitophagy and Inflammation: A Dual-Pronged Approach.
    Neha Dagar, Tahib Habshi, Vishwadeep Shelke, Hemant R Jadhav, Anil Bhanudas Gaikwad.
      Induction of PINK1/Parkin-mediated mitophagy and reducing inflammation via targeting the TLR4/NF-κB axis simultaneously could be a promising therapy for the complex pathophysiology of AKI-diabetes comorbidity. Earlier, esculetin by mitophagy activation and phloretin by inhibiting inflammation have shown promising renoprotection. Therefore, we aimed to evaluate the synergistic renoprotective ability of esculetin and phloretin combination against AKI-diabetes comorbidity. AKI-diabetes comorbidity was mimicked in vivo by bilateral ischemia/reperfusion injury (IRI) in diabetic rats and in vitro by sodium azide-induced hypoxia/reperfusion injury (HRI) under hyperglycemic conditions. The cells were pretreated with esculetin (50 μM) and phloretin (50 μM) for 24 h. Similarly, the diabetic AKI rats received esculetin (50 mg/kg/day, p.o.) and phloretin (50 mg/kg/day, p.o.) pretreatment for 4 days and 1 h before surgery. Further, the obtained samples were utilized for different experiments. Esculetin and phloretin in diabetic AKI rats preserved kidney function and prevented kidney injury, indicated by reduced plasma creatinine, blood urea nitrogen, and kidney injury molecule 1. Esculetin improved mitophagy, indicated by increased mitophagosome formation, increased PINK1, Parkin, LC3B, and decreased p62 expression. Similarly, phloretin suppressed the diabetic AKI-related increased expression of inflammatory mediators including NF-κB, TLR4, TNF-α, and MCP-1. Moreover, combination therapy showed a more pronounced effect via synergistically improving mitophagy, maintaining ΔΨm, preventing mitochondrial dysfunction, reducing inflammation, and apoptosis. Esculetin and phloretin combination ameliorated AKI-diabetes comorbidity more effectively than their monotherapies. Esculetin upregulated the PINK1/Parkin-mediated mitophagy, and phloretin reduced inflammation by inhibiting the TLR4/NF-κB axis, thereby synergistically preventing kidney dysfunction.
    Keywords:  acute kidney injury; diabetes; esculetin; inflammation; mitophagy; phloretin
    DOI:  https://doi.org/10.1002/ptr.8489
  31. Autophagy. 2025 Apr 03.
    Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.
    Minghong Leng, Fenghe Yang, Junhui Zhao, Yufei Xiong, Yiqing Zhou, Mingyang Zhao, Shi Jia, Limei Liu, Qiaoxia Zheng, Lebin Gan, Jingjing Ye, Ming Zheng.
      Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases.
    Keywords:  Endurance exercise; mitochondrial biogenesis; mitophagy; skeletal muscle; sphingosine-1-phosphate
    DOI:  https://doi.org/10.1080/15548627.2025.2488563
  32. Biochem Biophys Res Commun. 2025 Mar 24. pii: S0006-291X(25)00412-7. [Epub ahead of print]759 151698
    Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells.
    Rakesh Kumar Sharma, Rohit Sahai, Nishakumari Chentunarayan Singh, Mayank Maheshwari, Nisha Yadav, Jayanta Sarkar, Kalyan Mitra.
      Ormeloxifene (ORM) is a nonsteroidal selective estrogen receptor modulator (SERM), developed by the CSIR-Central Drug Research Institute that is approved as an oral contraceptive. However, it has also shown promising anti-cancer activity, especially in breast cancer. Here, we have investigated the anti-cancer effect of ORM on colon cancer cells and show that its antiproliferative activity is mediated through mitochondrial fission and autophagy-associated cell death. We observed that ORM treatment led to an elevation in autophagy markers like LC3II, Beclin1, and Atg7. Autophagy induction and LC3II turnover were monitored by immunofluorescence staining and confocal microscopy. Transmission electron microscopy results confirmed the formation of autophagosomes and autophagolysosomes. Autophagic flux was confirmed by the increased expression of LC3II in cells co-treated with BafilomycinA1(autophagy inhibitor) and ORM. This was further corroborated using tandem mRFP-GFP-LC3 (tfLC3) transfection in DLD-1 cells. Interestingly, we observed that inhibition of autophagy reduced the apoptotic cell population, suggesting pro-death autophagy. ORM treatment caused notable ultrastructural alterations indicative of cellular stress. Notably, ORM triggered the generation of mitochondrial ROS, associated with increased levels of mitochondrial fission and a decrease in mitochondrial fusion proteins. Changes in mitochondrial dynamics were observed under the TEM, which included reduced mitochondrial size and increased mitochondrial number. Inhibition of mitochondrial fission resulted in enhanced cell survival and a concomitant decrease in the autophagic markers, implying that ORM-induced autophagy depends on mitochondrial fission. Taken together, our findings bring to light a novel mechanism where Ormeloxifene targets mitochondrial dynamics to promote autophagy-associated cell death in colon cancer cells.
    Keywords:  Autophagy; Cancer; Cell death; Mitochondrial fission; Ormeloxifene
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151698
  33. Neurology. 2025 Apr 22. 104(8): e213532
    What Is the Role of Inner Membrane Metalloproteases in Mitochondrial Quality Control and Disease?
    Eduardo Benarroch.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000213532
  34. Med Sci Sports Exerc. 2025 Mar 26.
    Voluntary Exercise Attenuates Tumor Growth in a Preclinical Model of Castration-Resistant Prostate Cancer.
    Nicolas Berger, Benjamin Kugler, Dong Han, Muqing Li, Paul Nguyen, Meaghan Anderson, Susan Patalano-Salsman, Songqi Zhang, Jill Macoska, Changmeng Cai, Kai Zou.
       PURPOSE: To examine the effects of voluntary wheel running on tumor growth and explore potential intratumoral molecular pathways responsible for the beneficial effects of voluntary wheel running on tumor formation and progression in a mouse model of Castration-Resistant Prostate Cancer (CRPC).
    METHODS: Male immunodeficient mice (SCID) were castrated and subcutaneously inoculated with human CWR-22RV1 cancer cells to construct CRPC xenograft model before assigned to either voluntary wheel running (VWR) or sedentary (SED) group (n = 6/group). Tumor size was measured and calculated throughout the study. After three weeks, tumor tissues were collected. mRNA expression of markers of DNA replication, Androgen Receptor (AR) signaling, and mitochondrial dynamics was determined by RT-PCR. Protein expression of mitochondrial dynamics was determined by western blotting. Finally, transcriptomics analysis was performed using the tumor tissues.
    RESULTS: Voluntary wheel running resulted in smaller tumor volume at the initial stage and attenuated tumor progression throughout the time course (P < 0.05). The reduction of tumor volume in the VWR group coincided with lower mRNA expression of DNA replication markers (MCM2, MCM6, and MCM7), AR signaling (ELOVL5 and FKBP5) and regulatory proteins of mitochondrial fission (Drp1 and Fis1) and fusion (MFN1 and OPA1) when compared to the SED group (P < 0.05). RNA sequencing data further revealed that pathways related to angiogenesis, extracellular matrix formation and endothelial cell proliferation were downregulated.
    CONCLUSIONS: Three weeks of voluntary wheel running was effective in delaying tumor formation and progression, which coincided with reduced transcription of DNA replication, AR signaling targets and mitochondrial dynamics. We further identified a downregulation in molecular pathways related to angiogenesis that may be responsible for the delayed tumor formation and progression by voluntary wheel running.
    DOI:  https://doi.org/10.1249/MSS.0000000000003712
  35. Int J Biol Macromol. 2025 Mar 29. pii: S0141-8130(25)03049-1. [Epub ahead of print] 142497
    Cardioprotective effects of Dendrobium officinale polysaccharides on thiacloprid-induced cardiac injury via modulating mitochondrial dynamics.
    Biqi Han, Jiawen Tian, Jiayi Li, Yuyang Chen, Ning Liu, Yitong Ma, Caihan Wang, Xinyu Guo, Yunfeng Liu, Zhigang Zhang.
      Thiacloprid (THI), a widely used neonicotinoid pesticide, has been shown to induce cardiac injury, though the underlying mechanisms remain poorly understood. Dendrobium officinale polysaccharides (DOP), a bioactive compound with potent antioxidant properties, may offer protection against such toxicity. This study investigated the cardioprotective effects of DOP in THI-induced cardiac injury in quails, with a particular focus on the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Network pharmacology analysis identified key targets of DOP, linking them to oxidative stress, mitochondrial dysfunction, and inflammatory pathways. Experimental results demonstrated that DOP significantly reversed THI-induced hematological and biochemical abnormalities, including the restoration of cardiac biomarkers and mitigation of myocardial structural damage. DOP treatment notably activated the Nrf2 pathway, leading to the upregulation of antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), which countered THI-induced oxidative stress. Additionally, DOP restored mitochondrial dynamics by balancing mitochondrial fission and fusion proteins. These findings highlight the central role of Nrf2 activation in the cardioprotective effects of DOP, suggesting that DOP may serve as a promising therapeutic agent for mitigating pesticide-induced cardiovascular toxicity.
    Keywords:  Cardiac injury; Cardioprotection; Dendrobium officinale polysaccharides; Mitochondrial dynamics; Thiacloprid
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142497
  36. Mol Cell Endocrinol. 2025 Mar 27. pii: S0303-7207(25)00084-X. [Epub ahead of print]602 112533
    Obesity prevention by different exercise protocols (HIIT or MICT) involves beige adipocyte recruitment and improved mitochondrial dynamics in high-fat-fed mice.
    Daiana Araujo Santana-Oliveira, Henrique Souza-Tavares, Aline Fernandes-da-Silva, Thatiany Souza Marinho, Flavia Maria Silva-Veiga, Julio Beltrame Daleprane, Vanessa Souza-Mello.
       AIM: This study evaluated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on UCP1-dependent and UCP1-independent thermogenic and mitochondrial dynamics markers in the inguinal sWAT of high-fat-fed mice.
    METHODS: Sixty male C57BL/6 mice (3 months old) were divided into six experimental groups: control diet (C), C + HIIT (C-HIIT), C + MICT (C-MICT), high-fat diet (HF), HF + HIIT (HF-HIIT) and HF + MICT (HF-MICT). The diet and exercise protocols started simultaneously and lasted ten weeks.
    RESULTS: HIIT and MICT prevented body mass gain and fat pad expansion, improved insulin sensitivity, and induced browning in C-fed and HF-fed animals. Chronic intake of a HF diet caused adipocyte hypertrophy with a proinflammatory adipokine profile and impaired the expression of thermogenic and mitochondrial dynamics markers. However, both exercise intensities increased anti-inflammatory adipokine concentrations and improved gene markers of mitochondrial dynamics, resulting in sustained UCP1-dependent and UCP1-independent thermogenic markers and maintenance of the beige phenotype in inguinal sWAT. The principal component analysis placed all trained groups opposite the HF group and near the C group, ensuring the effectiveness of HIIT and MICT to prevent metabolic alterations.
    CONCLUSIONS: This study provides reliable evidence that, regardless of intensity, exercise is a strategy to prevent obesity by reducing body fat accumulation and inducing browning. The anti-inflammatory adipokine profile and the increased expression of UCP1-dependent and UCP1-independent thermogenic markers sustained active beige adipocytes and mitochondrial enhancement to halt metabolic disturbances due to HF-feeding in exercised mice.
    Keywords:  Beige adipocyte; Browning; Exercise; HIIT; High-fat diet; Mitochondrial dynamics; Principal component analysis
    DOI:  https://doi.org/10.1016/j.mce.2025.112533
  37. Mol Biotechnol. 2025 Apr 01.
    SIRT5 Inhibits Mitophagy and Inflammation of Hypoxia-Induced Pulmonary Hypertension by Regulating the Desuccinylation of PDK1.
    Lin Guo, Kangkang Ji, Yi Yin.
      Hypoxia-induced pulmonary hypertension (HPH), a consequence of lung pathologies, is linked to changes in immune responses and inflammation. SIRT5 is recognized as the only enzyme capable of removing succinyl groups. The focus of this research was to explore the involvement of SIRT5 in HPH and to elucidate the associated mechanisms. Models simulating HPH were created in both living organisms and controlled laboratory settings under conditions of low oxygen. To investigate autophagy, transmission electron microscopy (TEM) was employed for ultrastructural analysis, while reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to measure the expression of autophagy-related genes. Cell viability was determined using the cell counting kit-8 (CCK-8) assay. The concentrations of inflammatory cytokines were quantified using ELISA, and flow cytometry was applied to evaluate reactive oxygen species (ROS) levels. To explore the interaction between PDK1 and SIRT5, co-immunoprecipitation (Co-IP) followed by Western blot analysis was conducted. Findings revealed that low oxygen conditions prompted mitophagy and elevated levels of both mRNA and proteins associated with this process in experiments conducted in organisms as well as in cellular models. Under conditions of low oxygen, the expression of SIRT5 was found to be reduced. Hypoxia enhanced cell viability, ROS level, angiogenesis-related protein levels, and inflammatory cytokine levels in pulmonary microvascular endothelial cells (PMVECs), effects that were reversed upon SIRT5 overexpression. Mechanistically, SIRT5 interacted with PDK1, desuccinylating PDK1 and thereby inhibiting mitophagy and inflammation associated with HPH. In conclusion, SIRT5 inhibited mitophagy and inflammation in HPH by regulating the desuccinylation of PDK1, potentially offering effective therapeutic strategies for treating HPH.
    Keywords:  Desuccinylation; Hypoxia-induced pulmonary hypertension; Inflammation; Mitophagy; PDK1; SIRT5
    DOI:  https://doi.org/10.1007/s12033-025-01430-8
  38. J Inflamm Res. 2025 ;18 4367-4379
    Analysis and Validation of Mitophagy-Related Genes in Diabetic Foot Ulcers.
    Shaoyihan Fang, Huijuan Zhang, Wenjian Liu, Shuangyan Li, Zhenzhen Chen, Jingjie Min, Chengyu Dai, Jingwen An, Hongxiao Zhang, Dewu Liu.
       Purpose: This study aimed to identify hub genes associated with mitophagy involved in the pathogenesis and progression of diabetic foot ulcer (DFU), and to characterize their immune cell infiltration features and single-cell expression profiles.
    Methods: DFU-related datasets (GSE80178, GSE68183) were retrieved from the GEO database. Subsequently, differentially expressed genes (DEGs) were identified via limma analysis, followed by gene set enrichment analysis (GSEA) to assess gene function enrichment. Identified DEGs were intersected with mitophagy-related genes. Machine learning (ML) algorithms were further employed to identify hub genes. Additionally, immune cell infiltration was examined via the CIBERSORT algorithm, and the correlation between the identified genes and immune infiltration was investigated. Finally, hub genes identified were validated via the single-cell RNA sequencing dataset GSE165816, and further validated using RT-PCR and Western blot (WB) assays.
    Results: Two hub genes, ANO6 and ALDH2, were identified and found to be significantly downregulated in the skin tissues of patients with DFU. Receiver operating characteristic (ROC) analysis demonstrated robust diagnostic potential (ANO6, AUC = 0.833, ALDH2, AUC = 0.806). Immune cell infiltration analysis demonstrated notable differences between the DFU and normal groups in naïve B cells, monocytes, resting mast cells, γδT cells, and regulatory T cells (Tregs). The findings were further validated through single-cell RNA sequencing (scRNA-seq) analysis and experimental studies, which confirmed the downregulation of ANO6 and ALDH2 in DFU tissues.
    Conclusion: Two mitophagy-related hub genes, ANO6 and ALDH2, were identified and validated as being significantly downregulated in DFU. Both genes demonstrated diagnostic potential and showed an association with immune cell infiltration. These findings suggest that mitophagy dysfunction may contribute to the pathophysiology of DFU, potentially through the dysregulation of inflammatory pathways and immune responses. While the results provide valuable insights into DFU and its management, further studies with larger cohorts and deeper exploration of mechanistic links to inflammation are necessary to translate these findings into therapeutic strategies.
    Keywords:  DFU; bioinformatics analysis; mitophagy; single-cell RNA-seq
    DOI:  https://doi.org/10.2147/JIR.S504001
  39. Trends Biochem Sci. 2025 Mar 27. pii: S0968-0004(25)00050-7. [Epub ahead of print]
    Understanding mitochondrial protein import: a revised model of the presequence translocase.
    Naintara Jain, Agnieszka Chacinska, Peter Rehling.
      Mitochondrial function relies on the precise targeting and import of cytosolic proteins into mitochondrial subcompartments. Most matrix-targeted proteins follow the presequence pathway, which directs precursor proteins across the outer mitochondrial membrane (OMM) via the Translocase of the Outer Membrane (TOM) complex and into the matrix or inner mitochondrial membrane (IMM) via the Translocase of the Inner Membrane 23 (TIM23) complex. While classical biochemical studies provided detailed mechanistic insights into the composition and mechanism of the TIM23 complex, recent cryogenic-electron microscopy (cryo-EM) data challenge these established models and propose a revised model of translocation in which the TIM17 subunit acts as a 'slide' for precursor proteins, with Tim23 acting as a structural element. In this review, we summarize existing models, highlighting the questions and data needed to reconcile these perspectives, and enhance our understanding of TIM23 complex function.
    Keywords:  inner mitochondrial membrane (IMM); mitochondria; presequence pathway; protein sorting; protein translocation; translocase of the inner membrane 23 (TIM23)
    DOI:  https://doi.org/10.1016/j.tibs.2025.03.001
  40. J Lipid Res. 2025 Apr 01. pii: S0022-2275(25)00050-1. [Epub ahead of print] 100790
    Diet-induced obesity dampens the temporal oscillation of hepatic mitochondrial lipids.
    Rashi Jain, Rajprabu Rajendran, Sona Rajakumari.
      Mitochondria play a pivotal role in energy homeostasis and regulate several metabolic pathways. The inner and outer membrane of mitochondria comprises unique lipid composition and proteins that are essential to form electron transport chain complexes, orchestrate oxidative phosphorylation, β-oxidation, ATP synthesis, etc. As known diet-induced obesity affects mitochondrial function, dynamics, and mitophagy, which are governed by circadian clock machinery. Though DIO impairs the interplay between circadian oscillation and lipid metabolism, the impact of DIO on mitochondrial membrane lipid composition and their temporal oscillation is unknown. Thus, we investigated the diurnal oscillation of liver mitochondrial lipidome at various Zeitgeber times using quantitative lipidomics. Our data suggested that obesity disrupted lipid accumulation profiles and diminished the oscillating lipid species in the hepatic mitochondria. Strikingly, HFD manifested a more homogenous temporal oscillation pattern in phospholipids regardless of possessing different fatty acyl-chain lengths and degrees of unsaturation. In particular, DIO impaired the circadian rhythmicity of phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine and ether-linked phosphatidyl ethanolamine. Also, DIO altered the rhythmic profile of PE/PC, ePE/PC, PS/PC ratio and key proteins related to mitochondrial function, dynamics, and quality control. Since HFD dampened lipid oscillation, we examined whether the diurnal oscillation of mitochondrial lipids synchronized with mitochondrial function. Also, our data emphasized that acrophase of mitochondrial lipids synchronized with increased oxygen consumption rate and Parkin levels at ZT16 in chow-fed mice. Our study revealed that obesity altered the mitochondrial lipid composition and hampered the rhythmicity of mitochondrial lipids, oxygen consumption rate and Parkin levels in the liver.
    Keywords:  Circadian rhythm; Diet-induced obesity; High-fat diet; MASLD; Membrane lipids; Mitochondrial lipidome; OXPHOS; Temporal oscillation
    DOI:  https://doi.org/10.1016/j.jlr.2025.100790
  41. Int Immunopharmacol. 2025 Mar 28. pii: S1567-5769(25)00541-7. [Epub ahead of print]154 114551
    Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.
    Saurabh Losarwar, Bhaskaranand Pancholi, Raja Babu, Debapriya Garabadu.
      Mitochondria, known as the powerhouse of cells, play a crucial role in host innate immunity during flavivirus infections such as Dengue, Zika, West Nile, and Japanese Encephalitis Virus. Mitochondrial antiviral signaling protein (MAVS) resides on the outer mitochondrial membrane which is triggered by viral RNA recognition by RIG-I-like receptors (RLRs). This activation induces IRF3 and NF-κB signaling, resulting in type I interferon (IFN) production and antiviral responses. Upon flavivirus infection, mitochondrial stress and dysfunction may lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which serves as a damage-associated molecular pattern (DAMP). Cytosolic mtDNA is sensed by cGAS (cyclic GMP-AMP synthase), leading to the activation of the STING (Stimulator of Interferon Genes) pathway to increase IFN production and expand inflammation. Flaviviral proteins control mitochondrial morphology by controlling mitochondrial fission (MF) and fusion (MFu), disrupting mitochondrial dynamics (MD) to inhibit MAVS signaling and immune evasion. Flaviviral proteins also cause oxidative stress, resulting in the overproduction of reactive oxygen species (ROS), which triggers NLRP3 inflammasome activation and amplifies inflammation. Additionally, flaviviruses drive metabolic reprogramming by shifting host cell metabolism from oxidative phosphorylation (OxPhos) to glycolysis and fatty acid synthesis, creating a pro-replicative environment that supports viral replication and persistence. Thus, the present review explores the complex interaction between MAVS, mtDNA, and the cGAS-STING pathway, which is key to the innate immune response against flavivirus infections. Understanding these mechanisms opens new avenues in therapeutic interventions in targeting mitochondrial pathways to enhance antiviral immunity and mitigate viral infection.
    Keywords:  Flavivirus; Innate immunity; Mitochondria; Mitochondrial antiviral signaling protein (MAVS); Mitochondrial dynamics (MD); RIG-I-like receptors (RLRs)
    DOI:  https://doi.org/10.1016/j.intimp.2025.114551
  42. Int J Nanomedicine. 2025 ;20 3843-3844
    Gold Nanoparticles Enhance TRAIL Sensitivity Through Drp1-Mediated Apoptotic and Autophagic Mitochondrial Fission in NSCLC Cells [Retraction].
      [This retracts the article DOI: 10.2147/IJN.S129274.].
    DOI:  https://doi.org/10.2147/IJN.S530388
  43. Cell Death Dis. 2025 Apr 02. 16(1): 239
    HELLS controls mitochondrial dynamics and genome stability in liver cancer by collusion with MIEF1.
    Sung Kyung Choi, Jihye Park, Sang Yun Ha, Myoung Jun Kim, Seor I Ahn, Jeongah Kim, Woong Sun, Yeong Min Park, Suk Woo Nam, Jeung-Whan Han, Keunsoo Kang, Jueng Soo You.
      Dysregulated chromatin remodelers have emerged as critical disease targets. However, owing to the pleiotropic functions of chromatin remodelers, the underlying mechanisms of their effects on cancer have been difficult to elucidate. Here, we investigated the helicase lymphoid-specific (HELLS) oncogenic mechanism by identifying a new direct transcriptional target. Using loss or gain experiments, we identified Mitochondrial elongation factor 1 (MIEF1) as a critical target of the HELLS molecular network in liver cancer. Liver cancer patients with a poor prognosis exhibited upregulated expression of MIEF1, and MIEF1 knockdown led to the loss of tumor capabilities, indicating MIEF1 as an oncogene in liver cancer. Suppressing the HELLS-MIEF1 axis caused mitochondrial hyperfusion, energy deprivation, and further resulting senescence. HELLS knockdown globally increased histone 3 lysine 9 trimethylation (H3K9me3), especially in genomic hotspots with upregulation of SUV39H1 and further augmented DNA methylation. This stabilized genome and hyperfused mitochondria led to reduced levels of reactive oxygen species (ROS) and DNA damage. Finally, tumor cells became famished and calm. We further validated the functions of the HELLS-MIEF1 axis by MIEF1 overexpression and mitochondrial fusion drug. Our study has important implications for medical science by highlighting the crosstalk between epigenetics and metabolism through nuclear chromatin remodeler HELLS and mitochondrial protein MIEF1.
    DOI:  https://doi.org/10.1038/s41419-025-07589-x
  44. Nat Struct Mol Biol. 2025 Apr 02.
    Author Correction: DELE1 oligomerization promotes integrated stress response activation.
    Jie Yang, Kelsey R Baron, Daniel E Pride, Anette Schneemann, Xiaoyan Guo, Wenqian Chen, Albert S Song, Giovanni Aviles, Martin Kampmann, R Luke Wiseman, Gabriel C Lander.
      
    DOI:  https://doi.org/10.1038/s41594-025-01547-z
  45. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Mar 20. pii: 1673-4254(2025)03-0614-08. [Epub ahead of print]45(3): 614-621
    [Protein C activator derived from snake venom protects human umbilical vein endothelial cells against hypoxia-reoxygenation injury by suppressing ROS via upregulating HIF-1α and BNIP3].
    Ming Liao, Wenhua Zhong, Ran Zhang, Juan Liang, Wentaorui Xu, Wenjun Wan, Chao Li Shu Wu, 曙 李.
       OBJECTIVES: To investigate the antioxidative mechanism of snake venom-derived protein C activator (PCA) in mitigating vascular endothelial cell injury.
    METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in DMEM containing 1.0 g/L D-glucose and exposed to hypoxia (1% O2) for 6 h followed by reoxygenation for 2 h to establish a cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The cell model was treated with 2 μg/mL PCA alone or in combination with 2-ME2 (a HIF-1α inhibitor) or DMOG (a HIF-1α stabilizer), and intracellular production of reactive oxygen species (ROS) and protein expression levels of HIF-1α, BNIP3, and Beclin-1 were detected using DCFH-DA fluorescence probe, flow cytometry, and Western blotting. The OGD/R cell model was transfected with a BNIP3-specific siRNA or a scrambled control sequence prior to PCA treatment, and the changes in protein expressions of HIF-1α, BNIP3 and Beclin-1 and intracellular ROS production were examined.
    RESULTS: In the OGD/R cell model, PCA treatment significantly upregulated HIF-1α, BNIP3 and Beclin-1 expressions and reduced ROS production. The effects of PCA were obviously attenuated by co-treatment with 2-ME2 but augmented by treatment with DMOG (a HIF-1α stabilizer). In the cell model with BNIP3 knockdown, PCA treatment increased BNIP3 expression and decreased ROS production without causing significant changes in HIF-1α expression. Compared with HUVECs with PCA treatment only, the cells with BNIP3 knockdown prior to PCA treatment showed significantly lower Beclin-1 expression and higher ROS levels.
    CONCLUSIONS: Snake venom PCA alleviates OGD/R-induced endothelial cell injury by upregulating HIF-1α/BNIP3 signaling to suppress ROS generation, suggesting its potential as a therapeutic agent against oxidative stress in vascular pathologies.
    Keywords:  hypoxia-inducible factor-1α; mitochondrial autophagy; oxygen-glucose deprivation/reoxygenation; protein C activator
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.03.19
  46. bioRxiv. 2025 Mar 10. pii: 2025.03.09.641258. [Epub ahead of print]
    Environmental NaCl affects C. elegans development and aging.
    Franziska Pohl, Brian M Egan, Daniel L Schneider, Matthew C Mosley, Micklaus A Garcia, Sydney Hou, Chen-Hao Chiu, Kerry Kornfeld.
      Sodium is an essential nutrient, but is toxic in excess. In humans, excessive dietary sodium can cause high blood pressure, which contributes to age-related diseases including stroke and heart disease. We used C. elegans to elucidate how sodium levels influence animal aging. Most experiments on this animal are conducted in standard culture conditions: Nematode Growth Medium (NGM) agar with a lawn of E. coli . Here, we report that the supplemental NaCl in standard NGM, 50 mM, accelerates aging and decreases lifespan. For comparison, we prepared NGM with reduced NaCl or excess NaCl. Considering reduced NaCl as a baseline, wild-type worms on standard NGM displayed normal development and fertility but reduced lifespan and health span, indicating toxicity in old animals. The long-lived mutants daf- 2, age-1 , and nuo-6, cultured on standard NGM, also displayed reduced lifespan. Thus, NaCl in standard NGM accelerates aging in multiple genetic backgrounds. Wild-type worms on excess NaCl displayed delayed development and reduced fertility, and reduced lifespan and health span, indicating toxicity in both young and old animals. These results suggest that young animals are relatively resistant to NaCl toxicity, but that aging causes progressive sensitivity, such that old animals display toxicity to both standard and excess NaCl. We investigated pathways that respond to NaCl. Young animals cultured with excess NaCl activated gpdh-1, a specific response to NaCl stress. Old animals cultured with excess NaCl activated gpdh-1 and hsp-6 , a reporter for the mitochondrial unfolded protein response. Thus, excess NaCl activates multiple stress response pathways in older animals.
    DOI:  https://doi.org/10.1101/2025.03.09.641258
  47. bioRxiv. 2025 Mar 18. pii: 2025.03.18.643991. [Epub ahead of print]
    Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms including sleep.
    Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Sabrina Diano, Jonathan Cedernaes, Joseph T Bass, Tamas L Horvath.
      Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark cycle. Here, we show that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide (VIP)-expressing neurons show circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons cause disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons leading to desynchronization of entrainment to the light/dark cycle in Mfn2 deficient mice that resulted in advanced phase angle of their locomotor activity onset, alterations in core body temperature and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
    DOI:  https://doi.org/10.1101/2025.03.18.643991
  48. Int Heart J. 2025 ;66(2): 302-312
    Upstream Stimulatory Factor 2 Protects Cardiomyocytes by Regulating Mitochondrial Homeostasis.
    Wenbin Wu, Kexin Zhao, Kejuan Li, Ziwei Zhu, Yongnan Li, Jianshu Chen, Hong Ding, Xiaowei Zhang.
      Myocardial ischemia and hypoxia are the main causes of heart failure, and cardiomyocyte apoptosis induced by mitochondrial injury is the basis of adverse heart remodeling and heart failure. Upstream stimulatory factor 2 (USF2), a transcription factor involved in multiple cellular processes, was recently shown to play an active role in mitochondrial function and energy homeostasis. However, its involvement in cardiovascular disease has not been previously reported. In this study, we demonstrated that under hypoxic conditions, USF2 protein expression can be degraded via the ubiquitin-proteasome pathway in cardiomyocytes. The deletion of USF2 results in mitochondrial dysfunction and exacerbates mitochondrial damage, ultimately promoting apoptosis. Mechanistically, we demonstrated that USF2 deficiency induces apoptosis in cells by modulating the AMPK/mTOR signaling pathway. In conclusion, this study provides new insights into the protective role of USF2 in hypoxic cardiomyocyte injury and indicates that USF2 could be a potential therapeutic target for myocardial hypoxia.
    Keywords:  Heart failure; Reactive oxygen species; mTOR signaling pathway
    DOI:  https://doi.org/10.1536/ihj.23-619
  49. Int J Biochem Cell Biol. 2025 Mar 28. pii: S1357-2725(25)00041-X. [Epub ahead of print]182-183 106774
    Mitochondrial and peroxisomal fission in cortical neurogenesis.
    Gabriella L Robertson, Caroline Bodnya, Vivian Gama.
      The human brain is unique in its cellular diversity, intricate cytoarchitecture, function, and complex metabolic and bioenergetic demands, for which mitochondria and peroxisomes are essential. Mitochondria are multifunctional organelles that coordinate various signaling pathways central to neurogenesis. The dynamic morphological changes of the mitochondrial network have been linked to the regulation of bioenergetic and metabolic states. Specific protein machinery is dedicated to mitochondrial fission and fusion, allowing organelle distribution during cell division, organelle repair, and adaptation to environmental stimuli (excellent reviews have been published on these topics [Kondadi and Reichert, 2024; Giacomello et al., 2020; Tilokani et al., 2018; Kraus et al., 2021; Navaratnarajah et al., 2021]). In parallel, peroxisomes contain over 50 different enzymes which regulate metabolic functions that are critical for neurogenesis (Berger et al., 2016; Hulshagen et al., 2008). Peroxisomes share many of the components of their fission machinery with the mitochondria and undergo fission to help meet metabolic demands in response to environmental stimuli (Schrader et al., 2016). This review focuses primarily on the machinery involved in mitochondrial and peroxisomal fission. Mitochondrial fission has been identified as a critical determinant of cell fate decisions (Iwata et al., 2023, 2020; Khacho et al., 2016; King et al., 2021; Prigione and Adjaye, 2010; Vantaggiato et al., 2019; Kraus et al., 2021). The connection between alterations in peroxisomal fission and metabolic changes associated with cellular differentiation remains less clear. Here, we provide an overview of the functional and regulatory aspects of the mitochondrial and peroxisomal fission machinery and provide insight into the current mechanistic understanding by which mitochondrial and peroxisomal fission influence neurogenesis.
    Keywords:  Brain; DRP1; Metabolism; Mitochondria; Neurons; Peroxisomes
    DOI:  https://doi.org/10.1016/j.biocel.2025.106774
  50. PLoS One. 2025 ;20(4): e0313803
    PM2.5 from automobile exhaust induces apoptosis in male rat germ cells via the ROS-UPRmt signaling pathway.
    Cao Wang, Yingchi Zhao, Bin Liu, Zhen Luo, Guangxu Zhou, Kaiyi Mao.
       OBJECTIVE: To explore the underlying mechanism behind the fine particulate matter's (PM2.5)-mediated regulation of reproductive function in male rats, and to determine the role of vitamins in this process.
    METHODS: In all, 32 male SD rats were randomized to a control cohort (normal saline), a Vit cohort (vitamin C at 100 mg/kg +  vitamin E at 50 mg/kg), a PM2.5 cohort (PM2.5 10 mg/kg), and a PM2.5 + Vit cohort (PM2.5 exposure +  vitamin C at 100 mg/kg +  vitamin E at 50 mg/kg), with eight rats in each cohort. After four weeks of exposure, mating experiments were carried out. Thereafter, rats were euthanized, and the testis and epididymis tissues were excised for hematoxylin-eosin (HE) staining and sperm quality analysis. Apoptosis of testis tissues was quantified via a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the testicular oxidative stress (OS)-, apoptosis- and mitochondrial unfolded protein response (UPRmt)-related essential protein expressions were measured via western blotting (WB).
    RESULTS: After PM2.5 exposure, the sperm count and motility decreased, while sperm abnormality and the apoptosis index increased. HE staining showed that the number of spermatogenic cells decreased. WB showed that the PM2.5 group had decreased expressions of superoxide dismutase (SOD), nuclear factor E2-related factor 2 (Nrf2), and B-cell lymphoma-2 (Bcl-2) (p <  0.05), increased expressions of malondialdehyde (MDA), Bcl-2 associated X protein (Bax), and Caspase3 (p <  0.05), and downregulated expressions of C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and activating transcription factor 5 (ATF5) (p <  0.05). These were all reversed by vitamin intervention.
    CONCLUSION: PM2.5 from automobile exhaust disrupts male reproductive function. A combination of vitamins may protect reproductive function via the reactive oxygen species (ROS)-UPRmt signaling pathway.
    DOI:  https://doi.org/10.1371/journal.pone.0313803
  51. J Pharm Anal. 2025 Mar;15(3): 101039
    Coral calcium hydride promotes peripheral mitochondrial division and reduces AT-II cells damage in ARDS via activation of the Trx2/Myo19/Drp1 pathway.
    Qian Li, Yang Ang, Qing-Qing Zhou, Min Shi, Wei Chen, Yujie Wang, Pan Yu, Bing Wan, Wanyou Yu, Liping Jiang, Yadan Shi, Zhao Lin, Shaozheng Song, Manlin Duan, Yun Long, Qi Wang, Wentao Liu, Hongguang Bao.
      Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2 (Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation.
    Keywords:  ARDS; Coral calcium hydrogenation; Mitochondria; Peripheral division; Trx2
    DOI:  https://doi.org/10.1016/j.jpha.2024.101039
  52. BMC Cardiovasc Disord. 2025 Mar 29. 25(1): 232
    Cardioprotective role of SIRT1 activation on mitochondrial function in insulin-resistant H9c2 cells.
    Buğrahan Sancak, Deniz İnönü, Gülsüm Alp, Faruk Tuna Sağlam, Leila Aryan, Suatnur Şık, Fırat Akat, Erkan Tuncay.
       BACKGROUND: Insulin-resistance in cardiomyocytes is often associated with metabolic disorders like obesity, and type2 diabetes. Studies demonstrated that sirtuin1 (SIRT1) plays a protective role in cells resistant to insulin by enhancing insulin sensitivity and improving glucose metabolism. Based on these protective functions observed in SIRT1, this study aims to investigate the roles of SIRT1 in palmitate (PA)-induced insulin-resistant H9C2 cells.
    METHODS: Insulin-resistance was induced in H9c2 cells via incubation with palmitic acid (50µM;24 h). Control and Insulin-resistant cells were incubated with SIRT1 inhibitor (EX527;10µM) and SIRT1 activator (SRT1720;2µM) for 24 h, respectively. Mitochondrial membrane potential (MMP), reactive oxygen/nitrogen species (ROS/RNS), total ATP production, intracellular free zinc and calcium levels ([Ca2+]i and [Zn2+]i) were monitored with fluorescence techniques. Protein levels were determined by using western-blot analysis.
    RESULTS: K-acetylation level was increased in PA-induced Insulin-resistant cells and SIRT1 inhibited control cells. ROS/RNS production, [Ca2+]i, and [Zn2+]i levels were elevated, MMP was depolarized and ATP production was decreased in PA and EX527 treated cells compared to control cells. Mfn1 and Fis1 levels were remained unchanged, however Mfn2 protein level was elevated in cells treated with PA and SIRT1 inhibitor. Nevertheless, anti- and pro-apoptotic protein level was reduced and augmented respectively in insulin-resistant and SIRT1 inhibited cells. Activation of SIRT1 in PA-treated cells restored mitochondrial function and intracellular ionic homeostasis, reduced K-acetylation, and mitigated apoptosis.
    CONCLUSION: Therefore, it can be proposed that the activation of SIRT1, acting as a novel regulator, may offer direct cardioprotection by restoring mitochondrial function in the insulin-resistant heart.
    Keywords:  Calcium; Cardiomyocytes; Insulin-resistant; Mitochondria; SIRT1; Zinc
    DOI:  https://doi.org/10.1186/s12872-024-04397-7
  53. Br J Pharmacol. 2025 Mar 31.
    Rhynchophylline as an agonist of sirtuin 3 ameliorates endothelial dysfunction via antagonizing mitochondrial damage of endothelial progenitor cells.
    Lin Lin, Bowen Sun, Yuanlong Hu, Wenqing Yang, Jie Li, Danyang Wang, Lei Zhang, Mengkai Lu, Yuan Li, Yunlun Li, Dan Zhang, Chao Li.
       BACKGROUND AND PURPOSE: Mitochondrial dysregulation of endothelial progenitor cells (EPCs) has been implicated in endothelial destruction and hypertension. Regulation of silent information regulator 3 (sirtuin 3; SIRT3) in mitochondrial damage of EPCs and the underlying molecular mechanisms remain unclear, and evidence of selective SIRT3 agonists for the treatment of hypertension also is lacking.
    EXPERIMENTAL APPROACH: Here, we discovered a potent SIRT3 agonist, rhynchophylline (Rhy), and explored its underlying action on mitochondrial damage of EPCs and endothelial dysfunction.
    KEY RESULTS: In spontaneously hypertensive rats, Rhy reduced blood pressure and ameliorated vasomotion, paralleling improved EPC function in the peripheral circulation. Moreover, Rhy alleviated mitochondrial damage and inhibited apoptosis via the mitochondrial apoptotic pathway. SIRT3 knockdown interrupted the regulation of mitochondrial homeostasis induced by Rhy, thus abolishing its antagonizing effect on EPC dysfunction and endothelial damage, suggesting that Rhy protection of EPC mitochondria is mediated via the activation of SIRT3. Rhy restrained the production of mitochondrial ROS and improved the activity of superoxide dismutase 2 (SOD2) in a SIRT3-dependent manner, whereas silencing SOD2 eliminated the inhibition by Rhy of oxidative stress and apoptosis, reflecting that SOD2 was indispensable for the regulation of Rhy on mitochondrial dysfunction and the mitochondrial-mediated apoptosis pathway.
    CONCLUSION AND IMPLICATIONS: SIRT3-dependent mitochondrial homeostasis contributes to attenuating hypertension-related EPC dysfunction and endothelial injury, and Rhy itself is a potent and targeted SIRT3 agonist that prevented mitochondrial dysfunction by regulating the SIRT3/SOD2 pathway, which may provide new clues for drug candidates for hypertension therapeutics.
    Keywords:  SIRT3; endothelial progenitor cells; hypertension; mitochondria; rhynchophylline
    DOI:  https://doi.org/10.1111/bph.70032
  54. Rev Cardiovasc Med. 2025 Mar;26(3): 28195
    Roles of Autophagy, Mitophagy, and Mitochondria in Left Ventricular Remodeling after Myocardial Infarction.
    Xin Zhang, Shuai Shao, Qiuting Li, Yi Wang, Mowei Kong, Chunxiang Zhang.
      This review examines the mechanisms of left ventricular dysfunction, focusing on the interplay between ventricular remodeling, autophagy, and mitochondrial dysfunction following myocardial infarction. Left ventricular dysfunction directly affects the heart's pumping efficiency and can lead to severe clinical outcomes, including heart failure. After myocardial infarction, the left ventricle may suffer from weakened contractility, diastolic dysfunction, and cardiac remodeling, progressing to heart failure. Thus, this article discusses the pathophysiological processes involved in ventricular remodeling, including the injury and repair of infarcted and non-infarcted myocardia, adaptive changes, and specific changes in left ventricular systolic and diastolic functions. Furthermore, the role of autophagy in maintaining cellular energy homeostasis, clearing dysfunctional mitochondria, and the key role of mitochondrial dysfunction in heart failure is addressed. Finally, this article discusses therapeutic strategies targeting mitochondrial dysfunction and enhancing mitophagy, providing clinicians and researchers with the latest insights and future research directions.
    Keywords:  autophagy; heart failure; left ventricular dysfunction; myocardial infarction; therapeutic strategies; ventricular remodeling
    DOI:  https://doi.org/10.31083/RCM28195
  55. Discov Oncol. 2025 Apr 04. 16(1): 461
    Identification of necroptosis & mitophagy-related key genes and their prognostic value in colorectal cancer.
    Xiuling Zhang, Li Meng, Tingjian Zu, Qian Zhou.
       BACKGROUND: Our study aimed to elucidate the potential necroptotic&mitophagy-related key genes in colorectal cancer (COAD) by bioinformatics analysis and identify their prognostic value in COAD.
    METHODS: Firstly, we integrated the cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets to identify necroptosis & mitophagy-related differentially expressed genes (N&MRDEGs) in COAD using "TCGAbiolinks" and "GEOquery" packages. Secondly, the obtained data were used for differential expression analysis using the "limma" package, and further functional enrichment analysis using the "clusterProfiler" package. Then, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were utilized to explore pathway associations of the N&MRDEGs. Thirdly, the predictive model was developed utilizing LASSO (Least absolute shrinkage and selection regression) regression implemented through the "glmnet" package and validated via Kaplan-Meier analysis. Finally, we validated the function of the key genes by receiver operating characteristic (ROC) curve analysis, multivariate cox proportional hazards model and COAD cell lines.
    RESULTS: There is a strong association between the 4 key genes (UCHL1, HSPA1A, MAPK8, and PLEC) of COAD and the necroptotic&mitophagy, which were found to be lowly mRNA level in COAD cell lines. Among them, PLEC exhibited a pronounced contribution to the utility of the model in the TCGA database and UCHL1 has excellent diagnostic potential with an area under the curve (AUC) greater than 0.9.
    CONCLUSIONS: The perspective of bioinformatics analysis provides robust evidence suggested that UCHL1, HSPA1A, MAPK8, and PLEC genes are the prognostic biomarkers of COAD, the predictive model established herein provides a novel tool for risk stratification in clinical practice and serves as a foundation for further investigation into its underlying molecular mechanisms.
    Keywords:  Colorectal cancer; HSPA1A; MAPK8; Mitophagy; Necroptosis; PLEC; UCHL1
    DOI:  https://doi.org/10.1007/s12672-025-02221-y
  56. ACS Nano. 2025 Apr 04.
    Engineered Extracellular Vesicles Derived from Juvenile Mice Enhance Mitochondrial Function in the Aging Bone Microenvironment and Achieve Rejuvenation.
    Jiaqian Zheng, Yipeng Ren, Junhua Ke, Guanglin Zhu, Zhen Wang, Xuetao Shi, Yingjun Wang.
      Aging-related bone degeneration and impaired healing capacity remain significant challenges in regenerative medicine, necessitating innovative, efficient, and targeted strategies to restore bone health. Here, we engineered extracellular vesicles (EVs) derived from the serum of pretreated juvenile mice, with the goals of reversing aging, enhancing osteogenic potential, and increasing bioavailability to rejuvenate the aging bone environment. First, we established bone healing models representing different phases of healing to identify the EV type with the highest potential for improving the bone microenvironment in older individuals. Second, we employed DSS6 for bone targeting to enhance the biological effects of the selected EVs in vivo. The engineered EVs effectively targeted bone repair sites and promoted fracture healing more effectively than unmodified EVs in older mice. RNA sequencing revealed that the translocase of outer mitochondrial membrane 7 (Tomm7) is crucial for the underlying mechanism. Silencing Tomm7 significantly diminished the positive regulatory effects of the EVs. Specifically, the engineered EVs may enhance mitochondrial function in aging cells by activating the Tomm7-mediated Pink1/Parkin mitophagy pathway, promoting stemness recovery in aging bone marrow stromal cells (BMSCs) and reversing the adverse conditions of the aging bone microenvironment. Overall, the developed engineered EVs derived from serum from juvenile mice offer an alternative approach for treating aging bones. The identified underlying biological mechanisms provide a valuable reference for precision treatment of aging bones in the future.
    Keywords:  aging tissue rejuvenation; bone-targeting; extracellular vesicles; mitophagy; rejuvenation
    DOI:  https://doi.org/10.1021/acsnano.4c17989
  57. Life Sci Alliance. 2025 Jun;pii: e202402921. [Epub ahead of print]8(6):
    The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.
    Mashiat Zaman, Govinda Sharma, Walaa Almutawa, Tyler Gb Soule, Rasha Sabouny, Matt Joel, Armaan Mohan, Cole Chute, Jeffrey T Joseph, Gerald Pfeffer, Timothy E Shutt.
      Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause a variety of additional pathologies including myopathy. Here, we identified an uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Supporting the hypothesis that this variant contributes to the patient's pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that colocalized with early endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Re-expressing the Q367H variant in MFN2 KO cells also induced mtDNA release, demonstrating this phenotype is a direct result of the variant. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signalling can explain the patient's myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.
    DOI:  https://doi.org/10.26508/lsa.202402921
  58. ACS Cent Sci. 2025 Mar 26. 11(3): 393-403
    Cellular Discrepancy of Platinum Complexes in Interfering with Mitochondrial DNA.
    Suxing Jin, Yafeng He, Chenyao Feng, Jian Yuan, Yan Guo, Zijian Guo, Xiaoyong Wang.
      Mitochondria are associated with cellular energy metabolism, proliferation, and mode of death. Damage to mitochondrial DNA (mtDNA) greatly affects mitochondrial function by interfering with energy production and the signaling pathway. Monofunctional trinuclear platinum complex MTPC demonstrates different actions on the mtDNA of cancerous and normal cells. It severely impairs the integrity and function of mitochondria in the human lung cancer A549 cells, such as dissipating mitochondrial membrane potential, decreasing the copy number of mtDNA, interfering in nucleoid proteins and polymerase gamma gene, reducing adenosine triphosphate (ATP), and inducing mitophagy, whereas it barely affects the mtDNA of the human kidney 2 (HK-2) cells. Moreover, MTPC promotes the release of mtDNA into the cytosol and stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, thus showing the potential to trigger antitumor immunity. MTPC displays significant cytotoxicity against A549 cells, while it exhibits weak toxicity toward HK-2 cells, therefore displaying great advantage to overcome the lingering nephrotoxicity of platinum anticancer drugs. Discrepant effects of a metal complex on mitochondria of different cells mean that targeting mitochondria has special significance in cancer therapy.
    DOI:  https://doi.org/10.1021/acscentsci.4c01941
  59. Oncol Rep. 2025 May;pii: 57. [Epub ahead of print]53(5):
    Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway.
    Jie Zhang, Shanshan Qi, Yanyan Du, Honghong Dai, Ninghua Liu.
      It has been reported that treatment of patients with non‑small cell lung cancer (NSCLC) with gefitinib increases the risk of QT interval prolongation. Therefore, the present study aimed to investigate whether quercetin could delay gefitinib‑induced cardiomyocyte apoptosis and its underlying mechanism. A total of 32 nude mice were divided into the sham, NSCLC, NSCLC + gefitinib and NSCLC + gefitinib + quercetin groups. Cardiac fibrosis in mouse heart tissues was assessed by Masson's trichrome staining. Additionally, immunohistochemical staining was performed to detect the expression levels of Src homology‑2 domain‑containing protein tyrosine phosphatase (SHP2), X‑box binding protein 1 (XBP‑1), phosphorylated (p)‑stimulator of interferon genes (STING) and Nod‑like receptor protein 3. Bioinformatics analysis was carried auto to predict the association between quercetin and the SHP2/reactive oxygen species (ROS) axis. Furthermore, the effects of adenosine triphosphate (ATP) + gefitinib, SHP2 silencing and H2O2 on ROS levels, as well as on the p‑AMP‑activated protein kinase (AMPK)/XBP‑1/Parkinsonism associated deglycase (DJ‑1) axis, mitochondrial autophagy and apoptosis were assessed via detecting the expression levels of the corresponding proteins in cardiomyocytes by western blot analysis. JC‑1 immunofluorescence was performed to evaluate mitochondrial membrane damage. The results showed that NSCLC could not significantly affect cardiac function. In addition, compared with NSCLC alone, ventricular fibrosis was exacerbated in the NSCLC + gefitinib group. However, treatment with quercetin inhibited gefitinib‑induced ventricular fibrosis, activated the gefitinib‑suppressed SHP2 protein expression and downregulated the gefitinib‑induced XBP‑1 and p‑STING expression. Furthermore, the bioinformatics analysis results predicted that quercetin could interact with SHP2/ROS. The in vitro experiments demonstrated that the expression levels of the ROS‑related proteins, namely NADPH oxidase 4 and XBP‑1/DJ‑1, and those of the mitochondrial autophagy‑ and apoptosis‑related proteins were enhanced, while those of p‑AMPK, were reduced in cardiomyocytes of the NSCLC + ATP + gefitinib group. However, cell treatment with quercetin inhibited ROS production and the expression levels of XBP‑1/DJ‑1 and apoptosis‑related proteins activated by NSCLC + ATP + gefitinib. By contrast, quercetin activated the expression levels of mitochondrial autophagy‑related proteins and those of p‑AMPK. Furthermore, SHP2 silencing and cell treatment with H2O2 could separately inhibit the NSCLC + ATP + gefitinib‑induced expression of mitochondrial autophagy‑related proteins and p‑AMPK, while they could promote ROS production and upregulate XBP‑1/DJ‑1 and apoptosis‑related proteins. In summary, the results of the current study revealed a promising therapeutic approach for addressing cardiac issues caused by gefitinib treatment in patients with NSCLC. Therefore, quercetin could inhibit the gefitinib‑induced NSCLC‑mediated cardiomyocyte apoptosis via regulating the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway through mitochondrial autophagy.
    Keywords:  SHP2/ROS/AMPK/XBP‑1/JD‑1 signaling pathway; gefitinib; mitochondrial autophagy; non‑small cell lung cancer; pyroptosis
    DOI:  https://doi.org/10.3892/or.2025.8890
  60. Mol Biol Rep. 2025 Apr 01. 52(1): 356
    DNMT1 targets SRD5A2 to induce mitochondrial homeostasis and EMT in urothelial cells of hypospadias.
    Yifu Chen, Jianjun Hu, Liucheng Peng, Yaowang Zhao.
       BACKGROUND: Hypospadias, a common congenital malformation of the urinary system, significantly impacts neonatal development. The enzyme Steroid 5 Alpha-Reductase 2 (SRD5A2), essential for androgen metabolism, is regulated epigenetically through methylation by DNA Methyltransferase 1 (DNMT1). This modification plays a critical role in cell differentiation and development. This study aims to reveal the molecular mechanisms by which DNMT1-mediated methylation of SRD5A2 affects the pathophysiology of hypospadias.
    METHODS AND RESULTS: Western blot was utilized to quantify DNMT1 and SRD5A2 expression in primary urethral epithelial cells derived from rats afflicted with hypospadias. The regulation of SRD5A2 expression by DNMT1 methylation was confirmed through Chromatin Immunoprecipitation (ChIP) assays. Additionally, the influence of SRD5A2 on epithelial-mesenchymal transition (EMT), mitochondrial homeostasis, and energy metabolism was elucidated by further in vitro experiments, highlighting its potential biological impacts on hypospadias. DNMT1 methylation significantly upregulates SRD5A2 expression in urethral epithelial cells from hypospadias rats. Knockdown of DNMT1 and SRD5A2 elevated the levels of proteins associated with the cell cycle and mitochondrial function, and genes related to energy metabolism. Concurrently, these alterations inhibited EMT, promoted cellular proliferation and migration, arrested the cell cycle in the G1/S phase, and reduced apoptosis.
    CONCLUSIONS: DNMT1 and SRD5A2 exhibit elevated expression in hypospadias, with DNMT1 enhancing the expression of key proteins involved in the cell cycle, mitochondrial function, and energy metabolism through the methylation of SRD5A2. This inhibition of EMT and modulation of cellular functions suggest that SRD5A2 is a viable therapeutic target for hypospadias.
    TRIAL REGISTRATION: Not applicable.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  DNMT1; EMT; Hypospadias; Mitochondrial homeostasis; SRD5A2
    DOI:  https://doi.org/10.1007/s11033-025-10453-y
  61. Sci Adv. 2025 Apr 04. 11(14): eadr6415
    Retromer promotes the lysosomal turnover of mtDNA.
    Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.
      Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.
    DOI:  https://doi.org/10.1126/sciadv.adr6415
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