bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–06–22
forty-two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Role of mitochondria in physiological activities, diseases, and therapy.
  2. Mitochondrial dynamics dysfunction and neurodevelopmental disorders: From pathological mechanisms to clinical translation.
  3. N6-methyladenosine reader IGF2BP2 regulates NIPSNAP1-mediated mitophagy and mitochondrial dynamics to alleviate hepatic ischemia-reperfusion injury.
  4. Inhibition of Dynamin-Related Protein 1-Dependent Mitochondrial Fission Ameliorates Apical Periodontitis by Attenuating NLRP3 Inflammasome-Mediated M1 Macrophage Polarisation.
  5. Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
  6. Ginsenoside Compound K Mitigates Mitochondrial Fission Through Bile Acid Receptors/YAP Signaling to Counteract Podocyte Injury in Lupus Nephritis.
  7. Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
  8. Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis.
  9. Emodin Inhibits NLRP3 Inflammasome Activation and Protects Against Sepsis via Promoting FUNDC1-Mediated Mitophagy.
  10. Fumarate hits the brakes on mitophagy.
  11. PINK1 Deficiency Facilitates Palmitic Acid-Induced Inflammation by Disrupting Mitochondrial Function to Activate mtDNA-cGAS-STING Signaling.
  12. Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Skeletal Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.
  13. Ginsenoside Rh1 Alleviates Allergic Rhinitis by Mediating Mitochondrial Autophagy via Activation of the AMPK/ULK1/FUNDC1 Pathway.
  14. Taurine alleviates postovulatory oocyte aging via TBK1 associated mitophagy in pigs and mice.
  15. Ciliatoside A attenuates neuroinflammation in Alzheimer's disease by activating mitophagy and inhibiting NLRP3 inflammasome activation.
  16. Targeting Wnt/beta-catenin signaling to attenuate short-chain chlorinated paraffins-triggered hepatocyte mitochondrial fission and subsequent pyroptosis.
  17. BPQDs@Lipo-YSA Nanoplatform Triggers Mitophagy via PRKN/AKT1 to Drive Immunogenic Cell Death in Lung Adenocarcinoma.
  18. Corrigendum: Danqi soft caspule alleviates myocardial ischemia-reperfusion injury induced cardiomyocyte apoptosis by attenuating mitochondrial fission.
  19. Corrigendum to "Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis" [Europ. J. Med. Chem. 283 (2025) 17155].
  20. Echinococcus granulosus induces mitophagy and mitochondrial dysfunction in AML12 hepatocytes.
  21. Medication targeting to subcellular organelles: Emphasizing mitochondria as a therapeutic marvel-Current situation and future prospects.
  22. Triclosan inhibits testosterone synthesis in male offspring by activating mitophagy.
  23. Protective effect of Dan Ze mixture against lipotoxic cardiomyopathy through activating B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3/mitophagy signaling pathway.
  24. NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
  25. A Molecular Chemical Perspective: Mitochondrial Dynamics Is Not a Bystander of Cartilage Diseases.
  26. Oleanolic acid activates the JNK-Sp1-DJ-1 axis to promote mitophagy-mediated neuroprotection in dopaminergic neurons for Parkinson's disease treatment.
  27. Impact of environmental microplastic exposure on HepG2 cells: unraveling proliferation, mitochondrial dynamics and autophagy activation.
  28. Metformin Alleviates Liver Metabolic Dysfunction in Polycystic Ovary Syndrome by Activating the Ethe1/Keap1/PINK1 Pathway.
  29. PGC-1α Expands Neural Precursor Pool and Facilitates Cognitive Recovery Within AD Hippocampus Through the Regulation of Mitochondrial Dynamics.
  30. NIR-II Type I Photosensitizer for Efficient Cancer Therapy Through Synergistic Ferroptosis/Pyroptosis Induction and Mitophagy Inhibition.
  31. The purinergic receptor P2rx7 mediated ATP sensing is required to prevent bone aging by directing mitochondrial fitness of MSCs.
  32. Dental pulp stem cell secretome inhibits mitophagy-induced hippocampal neural injury during hypoxia.
  33. Targeting Drp1 inhibits ESCC progression via the ROS-PGC1-α-Nrf1/2 pathway.
  34. A novel mitochondrial autophagy and aging-related gene signature for predicting ovarian cancer.
  35. Zhen-wu-tang alleviates nephrotic syndrome by upregulating 5-HTR1B to activate AMPK/PGC-1α-mediated mitochondrial biogenesis.
  36. Estradiol inhibits endometrial injury by promoting the stability of the KLF15 protein and the recovery of mitochondrial function.
  37. Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
  38. Restoration of mitochondrial homeostasis by Wnt3a/β-catenin/c-Myc alleviates cadmium-induced neural stem cell senescence and cognitive impairment in mouse hippocampus.
  39. Propionate ameliorates neural degeneration by modulating mitochondrial fission and fusion in nerve cells.
  40. The low-density lipoprotein receptor-related protein-1 (LRP1) in Schwann cells controls mitochondria homeostasis in peripheral nerves.
  41. Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney.
  42. Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
  1. Mol Biomed. 2025 Jun 19. 6(1): 42
    Role of mitochondria in physiological activities, diseases, and therapy.
    Lilin Wang, Xiaoting Zhou, Tianqi Lu.
      Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of damaged mitochondria, maintaining quality control. Mitochondrial transport and communication further enhance their role in cellular processes. In addition, mitochondria are susceptible to damage, resulting in dysfunction and disruption of intracellular homeostasis, which is closely associated with the development of numerous diseases. These include mitochondrial diseases, neurodegenerative diseases, cardiovascular diseases (CVDs) and stroke, metabolic disorders such as diabetes mellitus, cancer, infectious diseases, and the aging process. Given the central role of mitochondria in disease pathology, there is a growing need to understand their mechanisms and develop targeted therapies. This review aims to provide a comprehensive overview of mitochondrial structure and functions, with a particular focus on their roles in disease development and the current therapeutic strategies targeting mitochondria. These strategies include mitochondrial-targeted antioxidants, modulation of mitochondrial dynamics and quality control, mitochondrial genome editing and genetic therapy, and mitochondrial transplantation. We also discuss the challenges currently facing mitochondrial research and highlight potential future directions for development. By summarizing the latest advancements and addressing gaps in knowledge, this review seeks to guide future research and clinical efforts in the field of mitochondrial medicine.
    Keywords:  Cancer; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Therapy
    DOI:  https://doi.org/10.1186/s43556-025-00284-5
  2. Neural Regen Res. 2025 Jun 19.
    Mitochondrial dynamics dysfunction and neurodevelopmental disorders: From pathological mechanisms to clinical translation.
    Ziqi Yang, Yiran Luo, Zaiqi Yang, Zheng Liu, Meihua Li, Xiao Wu, Like Chen, Wenqiang Xin.
       ABSTRACT: Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.
    Keywords:  autism spectrum disorders; autophagic clearance; cellular homeostasis; fusion and fission; mitochondrial dynamics; mitophagy; neural regeneration; neurodevelopmental disorders; neuronal energy metabolism; oxidative stress
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01422
  3. World J Gastroenterol. 2025 Jun 14. 31(22): 105157
    N6-methyladenosine reader IGF2BP2 regulates NIPSNAP1-mediated mitophagy and mitochondrial dynamics to alleviate hepatic ischemia-reperfusion injury.
    Shan-Shan Guo, Yan Zhao, Yan Hu, Xin-Ying Wang, Xu-Zi Zhao, Pei-Yan Zhong, Qin-Rong Luan, Zhe-Cheng Wang, Ji-Hong Yao.
       BACKGROUND: Hepatic ischemia-reperfusion (I/R) injury related to liver transplantation and hepatic resection remains a challenge in clinical practice. Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury. The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.
    AIM: To clarify the protective mechanism of NIPSNAP1 against hepatic I/R, with a focus on mitophagy and mitochondrial dynamics, as well as the potential mechanism by which n6-methyladenosine (m6A) modification regulates NIPSNAP1.
    METHODS: Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R. HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.
    RESULTS: We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) expression in vivo and in vitro. NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics; in contrast, NIPSNAP1 overexpression resulted in the opposite effects. Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1, thereby regulating its mRNA stability.
    CONCLUSION: NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis, serving as a novel target of the m6A reader IGF2BP2. Therefore, targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.
    Keywords:  4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1; Hepatic ischemia-reperfusion; Interacted with insulin-like growing factor 2; Mitochondrial dynamics; Mitophagy; mRNA stability; mRNA-binding protein 2
    DOI:  https://doi.org/10.3748/wjg.v31.i22.105157
  4. Int Dent J. 2025 Jun 14. pii: S0020-6539(25)00142-X. [Epub ahead of print]75(4): 100853
    Inhibition of Dynamin-Related Protein 1-Dependent Mitochondrial Fission Ameliorates Apical Periodontitis by Attenuating NLRP3 Inflammasome-Mediated M1 Macrophage Polarisation.
    Yao Yang, Min Li, Lifei Pan, Yifei Tang, Yuting Wang, Xiaoyue Guan, Tiezhou Hou, Siyu Hou.
       INTRODUCTION AND AIMS: The aim of this study was to determine if Dynamin-related protein 1‌ (Drp1) -dependent mitochondrial fission is involved in the pathological process of apical periodontitis and elucidate the underlying mechanisms.
    METHODS: Immunohistochemistry, immunofluorescence, and western blotting assessed CD86 expression, NLRP3/Caspase1/IL-1β activation, and mitochondrial dynamics-related proteins in human periapical macrophages. In vitro apical periodontitis (AP) models used macrophages stimulated with P. gingivalis LPS (Pg-LPS), pretreated with/without Drp1 inhibitor Mdivi-1 or NLRP3 inhibitor MCC950. CD86, NLRP3/Caspase1/IL-1β, mitochondrial dynamics proteins, TNF, and IL-6 were quantified via western blot, RT-qPCR, or immunofluorescence. ROS (DCFH-DA), ATP (commercial kit), mitochondrial membrane potential (JC-1), and morphology (TEM, MitoTracker/immunofluorescence) were analysed. Multimodal approaches explored Drp1-mediated mitochondrial fission and NLRP3 inflammasome-dependent M1 polarisation. Mdivi-1-treated AP models were established to dissect Drp1's role in pathogenesis.
    RESULTS: Our findings indicate that the Drp1-mediated excessive mitochondrial fission is present in human periapical lesions. Moreover, there was a positive correlation between the p-Drp1(Ser616) and the elevation of NLRP3, Cleaved-Caspase1, and CD86. In vitro experiments demonstrated that Mdivi-1 effectively inhibited the Pg-LPS induced abnormal mitochondrial fragmentation dependent on p-Drp1(Ser616), rescued mitochondrial dysfunction, and further suppressed the activation of NLRP3/Caspase1/IL1β and the expression of CD86. In vivo experiments showed that Mdivi-1 treatment could significantly alleviate the inflammatory bone erosion at the apex in a murine AP model by inhibiting macrophage polarisation and the NLRP3 inflammatory pathway.
    CONCLUSION: Drp1-mediated excessive mitochondrial fission plays a crucial role in the development of AP by promoting NLRP3 signaling pathway-dependent macrophage M1 polarisation. Targeting Drp1 may serve as a potential therapeutic strategy to prevent AP development, highlighting its clinical translational value.
    CLINICAL RELEVANCE: Mdivi-1 can restore mitochondrial dynamics homeostasis in periapical macrophages, inhibit NLRP3/M1 polarisation, and reduce bone resorption. This suggests that Mdivi-1 might be a promising agent for management of AP in future.
    Keywords:  Apical periodontists; Dynamin-related protein 1; Macrophage; Mdivi-1; Mitochondria dynamics
    DOI:  https://doi.org/10.1016/j.identj.2025.100853
  5. Cancer Res. 2025 Jun 20.
    Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
    Natalia V Oleinik, Firdevs Cansu Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M Szulc, Elizabeth G Hill, Alexander V Alekseyenko, Huseyin Cimen, Jessica H Hartman, Christina Voelkel-Johnson, Michael B Lilly, John J Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.
      Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma (HNSCC), which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. Here, we evaluated the ability of the ceramide analog LCL768 to induce mitophagy and metabolic stress in HNSCC. Mechanistically, LCL768 induced CerS1-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin and thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feed-forward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4042
  6. Phytother Res. 2025 Jun 18.
    Ginsenoside Compound K Mitigates Mitochondrial Fission Through Bile Acid Receptors/YAP Signaling to Counteract Podocyte Injury in Lupus Nephritis.
    Ying Li, Ziyu Song, Sumei Xu, Ke Xu, Wangda Xu, Li Xu, Fengyuan Tian.
      Irreversible renal damage in lupus nephritis (LN) results from critical podocyte injury. Disruption in the actin cytoskeleton initiates mitochondrial fission to exacerbate podocyte injury. While ginsenoside compound K (CK) alleviates podocyte injury in lupus-prone mice, its mechanism in regulating mitochondrial dynamics underlying remains elusive. Based on the open-source single-cell RNA sequencing dataset, this study clarified CK's role in alleviating podocyte injury in MRL/lpr mice by regulating cytoskeleton-mediated mitochondrial fission and elucidated the molecular mechanisms underlying the BA receptor-YAP axis. MRL/lpr mice were administered CK (20 or 40 mg/kg) for 10 weeks. Renal function and pathological changes were evaluated, along with renal metabolite profiles and metabolomics analysis. We analyzed publicly available single-cell RNA sequencing data to specifically profile gene mapping and enrichment analysis during immune-mediated renal injury. Furthermore, podocyte-based in vitro assays were conducted to investigate the impact of the BA receptors-YAP axis on mitochondrial dynamics. CK effectively cleared anti-dsDNA antibodies, attenuated systemic inflammation, and improved renal function through resolving immune complex deposition. Mechanistically, CK restored actin cytoskeleton integrity via Rho GTPase regulation and reshaped BA metabolism to activate TGR5/FXR receptors in podocytes. This dual action suppressed DRP1 s616 phosphorylation, inhibiting excessive mitochondrial fission, regulating while enhancing TFAM-mediated mtDNA replication for mitochondrial homeostasis. Concurrently, CK attenuated podocyte apoptosis through Hippo signaling inhibition and YAP activation. In conclusion, CK ameliorates podocyte injury by preventing excessive mitochondrial fission through the BA receptors-YAP axis, thus providing a potential therapy for LN.
    Keywords:  bile acid receptor; ginsenoside compound K; lupus nephritis; mitochondrial dynamics; podocyte
    DOI:  https://doi.org/10.1002/ptr.8492
  7. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809
    Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
    Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.
      Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.
    Keywords:  CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2025.115809
  8. Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2425015122
    Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis.
    Dawon Jeong, Seo Hyeong Park, Jiwon Kim, Hyeyoon Kim, Yejin Jang, Jaemoon Koh, Yoon Kyung Jeon, Takafumi Tasaki, Yong Tae Kwon, Dohyun Han, Sung-Yup Cho, Min Jae Lee.
      Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD). Public genome databases revealed high UBR4 expression in LUAD patients, associated with a dysregulated cell cycle and impaired mitochondrial homeostasis. UBR4 knockout (ΔUBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the ΔUBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in ΔUBR4 cells, contributing to diverse cellular phenotypes. Additionally, ΔUBR4 cells exhibited substantially slow tumor growth in mouse xenograft models. In LUAD patients, UBR4 levels correlated with tumor stage, mitophagy markers, and poor survival. These findings suggest a tumor-promoting function of UBR4 in LUAD by regulating mitochondrial quality control. Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.
    Keywords:  UBR4; lung adenocarcinoma; mitophagy; oncogene; senescence
    DOI:  https://doi.org/10.1073/pnas.2425015122
  9. Int J Biol Sci. 2025 ;21(8): 3631-3648
    Emodin Inhibits NLRP3 Inflammasome Activation and Protects Against Sepsis via Promoting FUNDC1-Mediated Mitophagy.
    Wei Fu, Shu-Chang Liu, Tong-Xiang Xu, Ying Liu, Teng Zhang, Dong-Jie Liu, Xiao Wang, Jian-Yao Wang, Yu-Xin He, Tao Ma.
      Dysregulated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contributes to the pathogenesis of numerous inflammatory and infectious diseases; however, effective targeted therapies remain elusive. In this study, we identify emodin-a bioactive anthraquinone derived from Rheum palmatum (radix Rhei) and Polygonum cuspidatum (Polygonaceae)-as a potent and selective inhibitor of NLRP3 inflammasome activation. Notably, emodin disrupts the assembly of the NLRP3 complex without impairing inflammasome priming. Transcriptomic profiling via RNA sequencing reveals that emodin reprograms mitochondrial quality control pathways, markedly enhancing mitophagy flux. Mechanistically, emodin suppresses casein kinase II (CK2)-mediated phosphorylation of FUNDC1, a pivotal mitophagy receptor, thereby promoting mitochondrial clearance and preventing mitochondrial reactive oxygen species-induced NLRP3 inflammasome assembly. Both genetic silencing of FUNDC1 and pharmacological inhibition of mitophagy with 3-methyladenine abrogated abrogate the inhibitory effects of emodin, establishing a direct mechanistic link between FUNDC1-dependent mitophagy and NLRP3 regulation. In vivo, emodin confers significant protection in sepsis models, with these protective effects being lost in NLRP3-deficient mice or upon macrophage-specific deletion of FUNDC1. Collectively, our findings uncover a novel CK2-FUNDC1-mitophagy axis through which emodin inhibits NLRP3 inflammasome activation, highlighting its promise as a clinically translatable candidate for the treatment of NLRP3-driven inflammatory diseases.
    Keywords:  Emodin; FUNDC1; Mitochondrial homeostasis; Mitophagy; NLRP3 inflammasome; Sepsis.
    DOI:  https://doi.org/10.7150/ijbs.110904
  10. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00471-X. [Epub ahead of print]85(12): 2261-2263
    Fumarate hits the brakes on mitophagy.
    Ana Paula Magalhães Rebelo, Christian Frezza.
      In this issue of Molecular Cell, Ham et al.1 demonstrate that the metabolite fumarate, when accumulated in cells, can influence mitochondrial quality control by inhibiting Parkin translocation to mitochondria and blocking its E3 ligase activity via the fumarate-dependent post-translational modification called succination.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.032
  11. Cell Biochem Funct. 2025 Jun;43(6): e70092
    PINK1 Deficiency Facilitates Palmitic Acid-Induced Inflammation by Disrupting Mitochondrial Function to Activate mtDNA-cGAS-STING Signaling.
    Bin Ye, Yingting Pei, Henian Li, Yuqi Jiang, Wenying Jin, Yueqiu Gao, Wen Liu, Xin Guan, Yu Qiao, Xu Gao, Yanfen Zhang, Ning Ma, Hao Chang.
      Metabolic cells exhibit low-grade chronic inflsammation characterized by excessive production and secretion of proinflammatory cytokines and chemokines in response to overnutrition and energy excess. Mitochondrial dysfunction is closely associated with metabolic inflammation. PINK1 (phosphatase and tensin homology-induced putative kinase 1) is a crucial pathway controlling mitochondrial autophagy, essential for maintaining mitochondrial quality control and metabolic homeostasis. The aim of this study was to investigate the role of PINK1 in metabolic inflammation. Our findings indicate that in adipocytes, palmitic acid (PA) activates the expression of PINK1. Additionally, knockdown of PINK1 exacerbates PA-induced adipocyte inflammation. Mechanistically, PINK1 deficiency impairs mitochondrial function, leading to the release of mtDNA and further activation of the cGAS-STING pathway. Therefore, targeting mitochondrial autophagy in adipocytes and the cGAS-STING pathway may represent effective approaches to alleviate the chronic inflammation associated with obesity and related metabolic disorders.
    Keywords:  PINK1; cGAS‐STING; inflammation; mitochondria; obesity
    DOI:  https://doi.org/10.1002/cbf.70092
  12. Am J Physiol Cell Physiol. 2025 Jun 16.
    Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Skeletal Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.
    H Grace Rosen, Nicolas J Berger, Shantel N Hodge, Atsutaro Fujishiro, Jared Lourie, Vrusti Kapadia, Tessa Duzz, Melissa A Linden, Eunbin Jee, Jonghan Kim, Yuho Kim, Kai Zou.
      Although current treatments for Duchenne Muscular Dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2-mdx model of DMD (9-10 weeks old) with Mdivi-1, a selective Drp1 inhibitor, every other day (i.p. injection) for 5 weeks. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation and Fis1 in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-HNE, in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated expression of markers of fibrosis (Col1a1, MMP2 and MMP9) and inflammation (IL-6, MCP1, and CXCL12). In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation.
    Keywords:  Drp1; Mitochondrial Dynamics; Muscular Dystrophy; lipid peroxidation; mitochondria dynamics; muscle; muscular dystrophy
    DOI:  https://doi.org/10.1152/ajpcell.01009.2024
  13. Food Sci Nutr. 2025 Jun;13(6): e70464
    Ginsenoside Rh1 Alleviates Allergic Rhinitis by Mediating Mitochondrial Autophagy via Activation of the AMPK/ULK1/FUNDC1 Pathway.
    Jiangang Wang, Yalin Zhang, Jingmei Chai, Jianing Yang, Longzhu Dai, Yi Yang, Yulian Zhang, Yongde Jin, Chongyang Wang, Guanghai Yan.
      Ginsenoside Rh1, a bioactive compound derived from ginseng, exhibits notable anti-inflammatory and antioxidant effects and has shown promising therapeutic potential in the treatment of allergic diseases. However, its exact role in allergic rhinitis (AR) and the underlying molecular mechanisms remain inadequately understood. This study investigates whether Rh1 alleviates AR through AMPK/ULK1/FUNDC1-mediated mitochondrial autophagy. In this study, human nasal epithelial cells (HNEpCs) were stimulated with house dust mite (HDM) and treated with mitochondrial autophagy inhibitors or siRNA transfection techniques to assess the effects of Rh1. Network pharmacology and molecular docking (MD) were used to explore the interactions between Rh1 and AMPK, ULK1, and FUNDC1. To explore the effects of Rh1, enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FC) were employed to measure IgE levels and various inflammatory mediators. Western blot (WB) analysis was conducted to assess protein expression related to mitochondrial autophagy, inflammation, and apoptosis in nasal tissues and HNEpCs. Immunofluorescence (IF) and transmission electron microscopy (TEM) provided further verification. The experimental data reveal that Rh1 effectively alleviates HDM-induced nasal mucosal epithelial thickening and eosinophil infiltration by modulating mitochondrial autophagy via the AMPK/ULK1/FUNDC1 signaling pathway. Additionally, Rh1 inhibits IL-4 secretion in nasal airway lavage fluid (NALF) and helps restore the Th1/Th2 immune balance. It also reduces mtROS production, inhibits NLRP3 inflammasome activation, and prevents apoptosis, thereby mitigating tissue damage associated with AR. Knockdown of AMPK or treatment with 3-Methyladenine (3-MA) further confirmed Rh1's inducing effect on mitophagy. In summary, Rh1 modulates mitophagy through the AMPK/ULK1/FUNDC1 pathway, reducing inflammatory responses and inhibiting apoptosis, thereby offering significant protection against AR.
    Keywords:  AMPK/ULK1/FUNDC1 pathway; Ginsenoside Rh1; allergic rhinitis; apoptosis; mitochondrial autophagy
    DOI:  https://doi.org/10.1002/fsn3.70464
  14. Theriogenology. 2025 Jun 11. pii: S0093-691X(25)00257-2. [Epub ahead of print]246 117531
    Taurine alleviates postovulatory oocyte aging via TBK1 associated mitophagy in pigs and mice.
    Fa-Li Zhang, Chen-Xi Gao, Wen-Wen Li, Ai-Ying Li, Lan Li, Wei Shen.
      Taurine deficiency is a driver of aging, however the mechanisms by which taurine regulates postovulatory oocyte aging (POA) remain an unanswered question. Here, we used differential gene expressions and functional enrichment analysis of transcriptomes to determine transcriptional dynamics in POA. Transcriptional conservation between mouse and pig was determined by comparative analysis of transcriptomes. Candidate key targets were identified by WGCNA analysis combined with comparative analysis of transcriptomes. Expression levels were validated using cell-based immunofluorescence assays. We observed increased fragmentation and apoptosis of oocytes during POA, which was significantly improved after adding taurine. Transcriptome analysis showed that mitochondrial function was disrupted in oocytes. Our mitochondrial immunofluorescence assay showed that mitochondrial distribution in the POA group was abnormal compared with fresh group, and ROS levels were increased. Moreover, comparative analysis highlighted the role of mitophagy, and the immunofluorescence assay highlighted the significant decrease in PINK1. On the note, we combined comparative analysis and WGCNA results to identify TBK1 as a key gene, subsequent protein fluorescence confirmed that TBK1 was downregulated during POA. As expected, the taurine increased the expression level of TBK1 in the aged group. In summary, our evidence demonstrates that taurine can improve oocyte quality during POA via TBK1-associated mitophagy.
    Keywords:  Mitophagy; PINK1; Postovulatory oocyte aging; TBK1; Taurine
    DOI:  https://doi.org/10.1016/j.theriogenology.2025.117531
  15. Phytomedicine. 2025 Jun 07. pii: S0944-7113(25)00566-5. [Epub ahead of print]145 156928
    Ciliatoside A attenuates neuroinflammation in Alzheimer's disease by activating mitophagy and inhibiting NLRP3 inflammasome activation.
    Minsong Guo, Zhengqin Wang, Xiaogang Zhou, Chonglin Yu, Jianming Wu, Lu Yu, Jianing Mi, Fang Ren, Betty Yuen Kwan Law, Hudan Pan, Vincent Kam Wai Wong, Dalian Qin, Anguo Wu.
       BACKGROUND: Alzheimer's disease (AD) is a gradually worsening neurological condition that involves memory loss, brain inflammation, and impaired mitochondrial function. The NLRP3 inflammasome activation in microglia plays a pivotal role in promoting neuroinflammation and worsening disease progression. Mitochondrial dysfunction and impaired mitophagy further create a detrimental feedback loop of oxidative stress and inflammation. Despite extensive research, pharmacological agents capable of simultaneously targeting both NLRP3 inflammasome activation and impaired mitophagy remain scarce.
    METHODS: We explored the therapeutic potential of Ciliatoside A (CA), a novel natural compound isolated from Peristrophe japonica, utilizing comprehensive cellular and animal models. In lipopolysaccharide/nigericin (LPS/Nig)-stimulated BV-2 microglial cells, the impact of CA on inflammasome activation, pyroptosis, mitochondrial health, and oxidative stress was assessed. Mechanistic evaluations were conducted using Western blotting, immunofluorescence, and advanced mitophagy assays. Furthermore, the efficacy of CA was validated in Caenorhabditis elegans (C. elegans) models expressing human amyloid-beta (Aβ) and the well-established 3xTg-AD mouse model.
    RESULTS: Our results demonstrate CA effectively inhibits NLRP3 inflammasome activation, reduces microglial pyroptosis, and mitigates oxidative stress-induced mitochondrial impairment in BV-2 cells. Notably, we identified the AMPK/ULK1 and PINK1/Parkin pathways as novel targets through which CA robustly activates mitophagy. Consistent therapeutic effects were observed in vivo, with CA significantly reducing Aβ-induced paralysis, ROS generation, and enhancing autophagy in worms. In 3xTg-AD mice, CA markedly improved cognitive function, diminished Aβ plaque deposition, alleviated neuroinflammation, and preserved neuronal integrity.
    CONCLUSION: For the first time, this study reveals that CA offers dual neuroprotective benefits by promoting mitophagy while inhibiting NLRP3 inflammasome-mediated neuroinflammation. These novel insights highlight the innovative therapeutic potential of CA, suggesting its promising application in slowing AD progression and mitigating its pathological features.
    Keywords:  Alzheimer's disease; Ciliatoside A; Mitophagy; NLRP3 inflammasome; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.phymed.2025.156928
  16. Int Immunopharmacol. 2025 Jun 17. pii: S1567-5769(25)01092-6. [Epub ahead of print]161 115102
    Targeting Wnt/beta-catenin signaling to attenuate short-chain chlorinated paraffins-triggered hepatocyte mitochondrial fission and subsequent pyroptosis.
    Jing Xiao, Donglei Huang, Fengxu Wang, Liting Gan, Wen Zhang, Fangsicheng Zhang, Jiayi Tang, Zhaoping Shen, Mengna Jiang, JohnPaul Otuomasiri Egbobe, Jianguo Shao, Xiaoke Wang, Ya Zhang, Linling Ju, Xinyuan Zhao.
      Short-chain chlorofluorocarbons (SCCPs), have been found to cause liver toxicity. This investigation probes into the mechanisms of SCCPs-induced mitochondrial dysfunction and cellular pyroptosis. The introduction of SCCPs via gavage instigates inflammasome activation and pyroptosis in mouse liver and HepG2 cells. Also, SCCPs disrupt mitochondrial dynamics in HepG2 cells and impair mitochondrial function. The use of the mitochondrial division inhibitor Mdivi-1, which reduces disturbances in mitochondrial dynamics, improved the mitochondrial dysfunction and cellular pyroptosis caused by SCCPs. Moreover, exposure to SCCPs resulted in the downregulation of the β-catenin signal in mouse liver and HepG2 cells. Restoring β-catenin levels through plasmid transfection and lithium chloride treatment alleviated the disruptions in mitochondrial dynamics and function, as well as cellular pyroptosis induced by SCCPs. These findings confirm that SCCPs disrupt mitochondrial dynamics by downregulating β-catenin signaling, resulting in mitochondrial dysfunction and the activation of the NLRP3 inflammasome and pyroptosis, ultimately causing hepatocyte injury.
    Keywords:  Liver injury; Mitochondrial fission; Pyroptosis; Short-chain chlorinated paraffins; β-Catenin signaling
    DOI:  https://doi.org/10.1016/j.intimp.2025.115102
  17. J Nanobiotechnology. 2025 Jun 16. 23(1): 446
    BPQDs@Lipo-YSA Nanoplatform Triggers Mitophagy via PRKN/AKT1 to Drive Immunogenic Cell Death in Lung Adenocarcinoma.
    Li Ai, Zhijuan Liu, Ran Li, Ying Hu, Yongxia Li.
       BACKGROUND: Lung adenocarcinoma, the most common type of non-small cell lung cancer (NSCLC), is a leading cause of cancer-related deaths globally due to its high incidence and treatment difficulty. Despite recent advancements in treatment methods, the prognosis for patients with advanced disease remains poor. Studies have shown that targeting mitophagy, the selective clearance of damaged mitochondria, can influence the sensitivity of cancer cells to treatment.
    METHODS: In this study, we designed and synthesized BPQDs@Lipo-YSA, a novel nanomaterial, aimed at specifically inducing mitophagy in lung adenocarcinoma cells. The nanomaterial was characterized using techniques such as transmission electron microscopy (TEM) and dynamic light scattering (DLS). The ability of BPQDs@Lipo-YSA to induce mitophagy was evaluated using Western blot, immunofluorescence, and flow cytometry. Additionally, in vitro and in vivo experiments were conducted to investigate the impact of BPQDs@Lipo-YSA on lung adenocarcinoma cells through the induction of immunogenic cell death (ICD).
    RESULTS: Experimental results showed that BPQDs@Lipo-YSA effectively induced mitophagy in lung adenocarcinoma cells by activating the PRKN/AKT1 pathway. More importantly, this induction of mitophagy significantly enhanced the cytotoxic effect on lung adenocarcinoma cells. In animal models, BPQDs@Lipo-YSA, by inducing ICD, markedly inhibited tumor growth and extended survival.
    CONCLUSIONS: This study reveals the potential value of BPQDs@Lipo-YSA in lung adenocarcinoma treatment through the induction of mitophagy and ICD. This finding provides theoretical and technical support for the development of new therapeutic strategies for lung adenocarcinoma.
    Keywords:  BPQDs@Lipo-YSA; Immunogenic cell death (ICD); Lung adenocarcinoma; Mitophagy; PRKN/AKT1 pathway
    DOI:  https://doi.org/10.1186/s12951-025-03496-7
  18. Front Pharmacol. 2025 ;16 1625578
    Corrigendum: Danqi soft caspule alleviates myocardial ischemia-reperfusion injury induced cardiomyocyte apoptosis by attenuating mitochondrial fission.
    Ye Yang, Cuiting Lin, Yan Wang, Yu Liu, Qiuxiong Chen, Shiyu Ma, Jin Ma.
      [This corrects the article DOI: 10.3389/fphar.2025.1526253.].
    Keywords:  Chinese botanical drug; cell apoptosis; mitochondrial dynamics; myocardial ischemia-reperfusion injury; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2025.1625578
  19. Eur J Med Chem. 2025 Jun 19. pii: S0223-5234(25)00646-4. [Epub ahead of print] 117881
    Corrigendum to "Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis" [Europ. J. Med. Chem. 283 (2025) 17155].
    Fangjie Wang, Lairong Song, Qianqian Xu, Ang Jia, Xiangwei Meng, Hongfei Jiang, Renshuai Zhang.
      
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117881
  20. Diagn Microbiol Infect Dis. 2025 Jun 16. pii: S0732-8893(25)00275-5. [Epub ahead of print]113(2): 116952
    Echinococcus granulosus induces mitophagy and mitochondrial dysfunction in AML12 hepatocytes.
    Xiaoyu Mu, Chongyu Zhao, Li Li, Haomin Sun, Yanni Wang, Deguang Li.
      The pathogenesis of Cystic echinococcosis (CE) remains incompletely understood. This study aimed to explore the effects of Echinococcus granulosus protoscoleces (E. granulosus PSCs)on mitochondrial function and mitophagy pathways in AML12 hepatocytes, providing insights into the pathogenesis of CE. AML12 hepatocytes were co-cultured with 50, 100, and 200 E. granulosus PSCs for 48 hours. The following methods were employed: isolation of E. granulosus PSCs , MTT assay for cell viability assessment, LDH release assay for cytotoxicity evaluation, measurement of oxidative stress markers (MDA levels, SOD activity, and GSH levels), Rh123 staining for mitochondrial membrane potential (MMP) determination, intracellular ATP measurement, mitochondrial respiratory rate detection, Real-time PCR for gene expression analysis, and Western blotting. E. granulosus PSCs infection significantly reduced cell viability and increased LDH release in a dose-dependent manner. Oxidative stress was evident, with elevated MDA levels, decreased SOD activity, and reduced GSH levels. Mitochondrial dysfunction was demonstrated by decreased MMP and ATP levels, as well as reduced mitochondrial respiration rates. Furthermore, E. granulosus PSCs infection upregulated the expression of mitophagy markers (p62 and LC3 Ⅱ/Ⅰ) and mitophagy signaling proteins (PINK1 and Parkin). Notably, silencing PINK1 mitigated the E. granulosus PSCs induced mitophagy activation in AML12 hepatocytes. E. granulosus PSCs infection induces mitophagy and mitochondrial dysfunction in AML12 hepatocytes.
    Keywords:  Echinococcus granulosus; Hepatic cystic echinococcosis; Mitochondrial dysfunction; Mitophagy; PINK1
    DOI:  https://doi.org/10.1016/j.diagmicrobio.2025.116952
  21. Exp Cell Res. 2025 Jun 13. pii: S0014-4827(25)00247-2. [Epub ahead of print]450(2): 114647
    Medication targeting to subcellular organelles: Emphasizing mitochondria as a therapeutic marvel-Current situation and future prospects.
    Riyad F Alzhrani, Adel Ali Alhowyan, Ehab I Taha, Sabry M Attia, Samir A Salama, Gamaleldin I Harisa.
      Subcellular disorders are linked with several diseases, specifically mitochondrial dysfunction linked to age, metabolic disorders, cancer, cardiovascular disease, and other mitochondrial diseases (MDs). Intracellular medication delivery is a promising option for effective therapy. This study aims to highlight subcellular delivery with focus on mitochondrial pharmacology, gene therapy, transplantation, and drug targeting. PubMed, Google Scholar, Scopus, and other scholarly sources were leveraged to prepare this narrative review. According to current studies, intermittent fasting, consistent exercise, well-balanced diets, and proper sleep can all help to increase mitochondrial quality. Molecular therapies improve mitochondrial bioenergetics, redox status, biogenesis, dynamics, mitophagy, bioenergetic, and sirtuins. The antioxidant supplementation restores endogenous antioxidants such as alpha-lipoic acid, tocopherols, L-carnitine, and coenzyme Q10 to prevent mitochondrial damage. Mdivi-1, melatonin, resveratrol, PGC-1α agonists, metformin, and Opa1 activators modify the dynamics and biogenesis of mitochondria. Bioactive phytochemicals, including curcumin, berberine, quercetin, and capsaicin, affect OXPHOS and mitochondrial sirtuins. These agents affect gene expression, antioxidant defenses, inflammation, and mitochondrion functions. Therefore, bioactive phytochemicals limit oxidative damage, increase insulin sensitivity, and improve extended cell longevity. Mitochondrial transplantation and gene therapy using mRNA and gene editing technologies are promising treatment options for MDs. Mitoquidone, triphenylphosphine, mitochondrial-targeting peptides, and nanocarriers localize medicines within mitochondrial compartments. In conclusion, a good lifestyle and bioactive materials, alongside mitochondrial medications, gene therapy, transplantation, and drug targeting, could restore overall cellular health.
    Keywords:  Bioactive compounds; Gene therapy; MDT; Mitochondrial biogenesis; Sirtuins; Uncouplers
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114647
  22. Ecotoxicol Environ Saf. 2025 Aug;pii: S0147-6513(25)00861-9. [Epub ahead of print]301 118516
    Triclosan inhibits testosterone synthesis in male offspring by activating mitophagy.
    Huili Lan, Yan Jiang, Lixiang Wu, Shushu Xie, Hui Huang, Dapeng Ji, Bingqi Zhu, Zhishan Ding, Jie Yu, Xiaoqing Ye.
      Triclosan (TCS), a typical endocrine disruptor, has been shown to interfere with testosterone biosynthesis in male animals. However, the effects and mechanisms of environmental TCS levels on testosterone synthesis in male mice offspring remain unclear. In this study, male mice offspring were exposed to TCS (0, 30, 300, and 3000 μg/kg/day) during prenatal and lactation periods, and Leydig (TM3) cells exposed to TCS (0, 30, 300 and 3000 nM) were used to establish an in vitro model. Results indicated that TCS exposure led to reduced testicular weight, organ coefficient, serum testosterone levels and steroidogenic enzyme activity, along with pathological changes in testicular tissue. RNA sequencing and lipid metabolome analysis suggested that TCS exposure may disrupt testicular lipid metabolism and is closely related to mitophagy and the PI3K/AKT/mTOR pathway. For in vitro experiments, TCS activated mitophagy in TM3 cells, characterized by elevated reactive oxygen species, mitochondrial damage, reduced mitochondrial membrane potential, formation of mitochondrial phagosomes and phagolysosomes, and altered expression of mitophagy-related proteins. TCS also decreased PI3K/AKT/mTOR pathway activity and steroidogenic enzyme expression, inhibiting testosterone secretion. In conclusion, environmental TCS levels inhibit testosterone synthesis in male offspring by inducing Leydig cell mitophagy, which may be linked to the suppression of the PI3K/AKT/mTOR pathway.
    Keywords:  Male offspring; Mitophagy; Testosterone; Triclosan
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118516
  23. J Tradit Chin Med. 2025 Jun;45(3): 538-551
    Protective effect of Dan Ze mixture against lipotoxic cardiomyopathy through activating B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3/mitophagy signaling pathway.
    Shi Cheng, Chen Jian, Zhang Yufang, Gao Ya, L I Dantong, Yue Shijun, Zhang Yixin.
       OBJECTIVE: To investigate the mechanism of Dan Ze mixture (, DZM) in the treatment of lipotoxic cardiomyopathy.
    METHODS: Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize the serum migration constituents of DZM. A lipotoxic cardiomyopathy rat model was established through high-fat diet and intervened by different doses of DZM. The cardiac function was assessed using echocardiography, and hematoxylin and eosin, oil red O, and Masson staining were conducted to evaluate morphological changes, lipid accumulation, and fibrosis in myocardial tissue. Serum myocardial enzyme activity, lipid levels, and lipid content of myocardial tissue were measured, while fluorescent staining and colorimetry were used to assess oxidation levels in myocardial tissue. Mitochondrial membrane potential was detected by 5,5', 6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanineio-dide (JC-1). Transmission electron microscopy was employed to observe ultrastructure and mitochondrial structure changes in myocardial tissue. Fluorescence double staining and colocalization were utilized to observe the binding of autophagosomes and mitochondria, while immunohistochemical staining was used to detect the expression of mitophagy-related proteins. Terminal deoxynucleoitidyl transferase mediated nick end labeling staining was employed for the identification of apoptosis in myocardial tissue, while quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were utilized for the detection of apoptosis, B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)/ mitophagy signaling pathway-related genes and proteins. In palmitic acid-induced Rat H9C2 cardiomyocytes (H9c2) cells, various cellular parameters including cell viability, lactate dehydrogenase release, apoptosis rate, oxidative stress level, mitochondrial structure and function, and mitophagy level were assessed after the treatment of DZM drug-containing serum for a duration of 24 h. The cellular expressions of BNIP3/mitophagy signaling pathway relevant genes and proteins were further evaluated using qRT-PCR and Western blot techniques.
    RESULTS: A total of 295 prototypes (e.g., phenolic acids, quinones, terpenoids) were identified in serum of rats after oral administration of DZM. In vivo, DZM therapy has been shown to effectively enhance cardiac function, mitigate high-fat diet-induced myocardial structural damage and lipid accumulation. Furthermore, DZM has demonstrated the ability to reduce lipid levels, attenuate cell apoptosis, combat oxidative stress, enhance mitochondrial structure and function, and activate the BNIP3/mitophagy signaling pathway. Furthermore, the silencing of BNIP3 has been shown to exacerbate palmitic acid-induced damages in H9c2 cells, while inhibiting the BNIP3/mitophagy signaling pathway can mitigate the inhibitory effects of DZM on palmitic acid-induced apoptosis, lipid deposition and oxidative stress.
    CONCLUSION: This study presents preliminary evidence for the therapeutic efficacy of DZM on lipotoxic cardiomyopathy through the activating BNIP3/mitophagy signaling pathway.
    Keywords:  Bcl2/adenovirus E1B gene 19 kDa protein-interacting protein 3; Dan Ze mixture; lipotoxic cardiomyopathy; mitochondrial autophagy; mitophagy; signal transduction
    DOI:  https://doi.org/10.19852/j.cnki.jtcm.2025.03.010
  24. Metabolism. 2025 Jun 13. pii: S0026-0495(25)00193-3. [Epub ahead of print]170 156324
    NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
    Jian Lv, Junmei Wang, Qin Chen, Qianhua Zhong, Hongchao Zhan, Qiuxiao Guo, Jiajie Li, Ningning Guo, Yu Fang, Jingjing Tong, Zhihua Wang.
      Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a Nipsnap1/2 double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of Nipsnap1/2 impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, Nipsnap1/2 depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.
    Keywords:  Aging; Cardiac aging; Metabolic disorder; Mitochondrial dysfunction; NIPSNAP1/2
    DOI:  https://doi.org/10.1016/j.metabol.2025.156324
  25. ACS Pharmacol Transl Sci. 2025 Jun 13. 8(6): 1473-1497
    A Molecular Chemical Perspective: Mitochondrial Dynamics Is Not a Bystander of Cartilage Diseases.
    Jianing Wu, Xin Zhou, Xin Xu, Jing Xie.
      Cartilage-related osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are typical degenerative diseases that cause a heavy socioeconomic burden for lack of disease-modifying treatments. Due to the avascular and hypoxic microenvironment of cartilage, chondrocytes primarily achieve energy supply through cytoplasmic anaerobic glycolysis; thus, mitochondria, energy producers through aerobic phosphorylation, have received little attention until recently. Mitochondria carry out a crucial role in the regulation of cellular bioenergetics, metabolism, and signaling while also serving as a central platform where diverse biological processes converge, thereby contributing significantly to cellular homeostasis and cartilage physiology. Mitochondrial functionality is intertwined with mitochondrial morphology, which is determined by a dynamic balance between mitochondrial fusion and fission. Disruption of the equilibrium leads to mitochondrial dysfunction and the onset of diseases. Although the potential role of mitochondria in the pathogenesis of cartilage-related diseases has been proposed and sporadic studies have begun to focus on the underlying molecular mechanisms of mitochondrial fusion/fission, the importance of the physiological and pathological functions of mitochondrial fusion-fission dynamics in cartilage biological processes is little discussed. This review aims to bridge the gap by characterizing its interplay with mitochondrial quality control, energy metabolism, redox homeostasis regulation, cellular senescence, and apoptosis, which are all closely associated with cartilage physiology and pathology. Moreover, its role in cartilage-related diseases, especially OA and IVDD, is further discussed. This review emphasizes the emerging field of mitochondrial fusion-fission dynamics in skeletal systems and possibly provides new cues for disease control and clinical intervention.
    Keywords:  Cartilage; Chondrocytes; Intervertebral disc degeneration; Mitochondrial fission; Mitochondrial fusion; Osteoarthritis
    DOI:  https://doi.org/10.1021/acsptsci.4c00706
  26. Arch Pharm Res. 2025 Jun 19.
    Oleanolic acid activates the JNK-Sp1-DJ-1 axis to promote mitophagy-mediated neuroprotection in dopaminergic neurons for Parkinson's disease treatment.
    Han-Bin Yang, Chien-Hsing Lee, Nguyen Thao Nhung, Shih-Ya Hung.
      Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by mitochondrial dysfunction and oxidative stress. Although levodopa remains the gold standard for managing PD motor symptoms, it lacks neuroprotective and disease-modifying effects, highlighting the need for new neuroprotective therapies. Mitophagy, the selective mitochondrial degradation by autophagy, is critical for neuronal health. Oleanolic acid, a natural hepatoprotective compound, shows uncertain efficacy in PD treatment. This study investigated the neuroprotective effects and underlying mechanisms of oleanolic acid using the 1-methyl-4-phenylpyridinium (MPP⁺)-induced cellular model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In vitro, oleanolic acid demonstrated dopaminergic neuroprotection by reducing mitochondrial dysfunction and reactive oxygen species accumulation in PD cells. It upregulated the mitophagic protein DJ-1, enhancing the sequestration of damaged mitochondria into autophagosomes by mitophagy. DJ-1 knockdown attenuated oleanolic acid's neuroprotection, confirming DJ-1's role in oleanolic acid's action. In vivo, pre-treatment with oleanolic acid in MPTP-induced PD mice prevented PD-like motor symptoms, reduced neuronal death in the substantia nigra, and mitigated striatal neurodegeneration. Post-treatment with oleanolic acid not only reduced these effects but also increased Bcl-2 and DJ-1 levels in the substantia nigra and striatum. In vitro, oleanolic acid activated JNK for Sp1 upregulation and nuclear translocation, which induced DJ-1 expression. Computational modeling predicted that oleanolic acid likely interacts with JNK, suggesting this binding might be necessary for JNK-Sp1-DJ-1 axis activation for mitophagy-driven neuroprotection. These results highlight oleanolic acid's potential as a therapeutic agent in PD prevention and treatment via the JNK-Sp1-DJ-1 pathway. Further studies are required to validate its efficacy.
    Keywords:  DJ-1; JNK-Sp1 pathway; Mitophagy; Neuroprotection; Oleanolic acid; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12272-025-01550-4
  27. Part Fibre Toxicol. 2025 Jun 17. 22(1): 17
    Impact of environmental microplastic exposure on HepG2 cells: unraveling proliferation, mitochondrial dynamics and autophagy activation.
    Hana Najahi, Nicola Alessio, Massimo Venditti, Ida Lettiero, Domenico Aprile, Gea Oliveri Conti, Tiziana Cappello, Giovanni Di Bernardo, Umberto Galderisi, Sergio Minucci, Margherita Ferrante, Mohamed Banni.
      The rise of microplastic (MPs) pollution presents a pressing environmental issue, raising concerns about its potential health impacts on human populations. Given the critical role of the liver in detoxification and metabolism, understanding the effects of MPs on the human hepatoma cell line HepG2 cells is essential for comprehensively assessing the dangers associated with MPs pollution to human health. Until now, the assessment of the harmful impact of polyethylene (PE) and polyethylene terephthalate (PET) on HepG2 has been incomplete and lacks certain essential data points. In this particular setting, we examined parameters such as cell viability, oxidative stress, mtDNA integrity, mitochondrial membrane potential, and autophagy in HepG2 cells exposed for 72 h to PET and PE at a concentration of 10 µg/mL. Our data revealed that exposure of HepG2 to MPs causes an increase in cell viability accompanied by a heightened ROS and altered mitochondrial function, as revealed by decreased mtDNA integrity and membrane potential. In addition, results demonstrated that exposure to PET and PE activated autophagic events, as suggested by the increased levels of the specific markers LC3 and p62. This last point was further confirmed using bafilomycin, a specific blocker that hinders the merging of autophagosomes and lysosomes, thereby blocking autophagic degradation processes. Given the increasing evidence of food chain MPs contamination and its possible harmful effects, our data should be carefully considered.
    Keywords:  Bafilomycin A1; Hepatocellular carcinoma cell line; Macroautophagy; Mitophagy; PE; PET
    DOI:  https://doi.org/10.1186/s12989-025-00632-x
  28. Int J Biol Sci. 2025 ;21(8): 3505-3526
    Metformin Alleviates Liver Metabolic Dysfunction in Polycystic Ovary Syndrome by Activating the Ethe1/Keap1/PINK1 Pathway.
    Yuan Xie, Ying Tian, Junting Huang, Wanying Deng, Xiaohui Li, Yujia Liu, Hao Liu, Lei Gao, Qiu Xie, Qi Yu.
      Background: Polycystic ovary syndrome (PCOS) is a reproductive endocrine disease characterized by metabolic abnormalities, with 34-70% of patients with PCOS also presenting non-alcoholic fatty liver disease (NAFLD). Metformin is a first-line treatment for relieving insulin resistance in PCOS; however, the potential therapeutic application of metformin for preventing NAFLD/metabolic dysfunction-associated fatty liver disease (MAFLD) in PCOS remains under-explored. Here, we investigated the potential protective effects and the underlying mechanisms of metformin against hepatic lipid metabolic disorders in prenatal anti-Müllerian hormone (PAMH)-induced PCOS mice. Methods: First, we developed a prenatal AMH-induced PCOS-like model using pregnant C57BL/6N mice. Female offspring of mice were then subjected to the glucose tolerance test and insulin tolerance test pre- and post-treatment with metformin. H&E staining, serum hormone, and biochemical analyses were performed to determine the effects of metformin on metabolic abnormalities and liver damage in the PCOS-like model. To verify the specific mechanism of action of metformin, dehydroepiandrosterone (DHEA) and free fatty acids (FFAs; palmitic acid and oleic acid) induced alpha mouse liver 12 (AML-12) cells were used to establish a mouse liver cell model of adipose-like degeneration and lipid deposition. Results: Metformin effectively alleviated hepatic lipid accumulation in the PCOS mice. Furthermore, mitochondrial dysfunction and loss of redox homeostasis in the liver of PCOS mice were rescued upon metformin administration. Mechanistic insights reveal that metformin regulates mitochondrial autophagy in PCOS liver tissue via the activation of the Ethe1/Keap1/Nrf2/PINK1/Parkin pathway, thereby improving liver recovery in PCOS mice. Conclusions: Our findings highlight the role and mechanism of metformin in ameliorating abnormal mitophagy and lipid metabolic disorders in the PCOS mice livers and the potential of metformin for addressing NAFLD in PCOS mice.
    Keywords:  Ethe1; Metabolic Dysfunction-associated Fatty Liver Disease; Metformin; Mitochondrial Dysfunction; Mitophagy; Polycystic Ovary Syndrome
    DOI:  https://doi.org/10.7150/ijbs.104778
  29. Mol Neurobiol. 2025 Jun 20.
    PGC-1α Expands Neural Precursor Pool and Facilitates Cognitive Recovery Within AD Hippocampus Through the Regulation of Mitochondrial Dynamics.
    Yu-Xin Wang, Yi-Jie Wang, Wen Pan, Long-Fei Xu, Jia-Qing Wang, Hua Wang, Xin Qian, Cheng-Zhi Zou, Xu Zhu, Jia Wang.
      The dysfunction in learning and memory observed in Alzheimer's disease (AD) is strongly associated with impaired neurogenesis in the hippocampal region. As research on adult neurogenesis advances, it becomes increasingly crucial to identify potential targets for interventions aimed at enhancing endogenous neurogenesis and promoting functional recovery in AD patients. Our previous studies have demonstrated the potential of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in mitigating the pathological abnormalities associated with AD. Serving as a ubiquitous metabolic regulator, PGC-1α is highly expressed in energy-demanding tissues, such as the hippocampus. However, the precise role and underlying mechanisms by which PGC-1α regulates neurogenesis within the AD-affected hippocampus remain to be fully elucidated. In this study, we induced PGC-1α overexpression by microinfusing AAV-Pgc-1α into the dentate gyrus (DG) of the hippocampus in APP/PS1 mice. Our findings indicate that PGC-1α effectively alleviates AD-related pathological abnormalities and behavioral dysfunction, including deficits in short-term habituation and spatial reference memory impairment. PGC-1α induces the activation of quiescent radial-glia like neural stem cells (NSCs) in the hippocampal DG region, giving rise to intermediate progenitor cells and neuroblasts that ultimately differentiate into mature neurons. By regulating mitochondrial dynamics-specifically promoting fusion while inhibiting fission-PGC-1α facilitates the expansion of precursor cell populations. Collectively, these findings highlight the significance of PGC-1α in maintaining NSC self-renewal, promoting neuronal lineage progression, and contributing to endogenous neurogenesis in AD. Elevating PGC-1α levels, either pharmacologically or through alternative approaches, may represent a promising therapeutic strategy for treating AD.
    Keywords:  Alzheimer’s disease; Mitochondrial dynamics; Neural stem cell; PGC-1α; Proliferation
    DOI:  https://doi.org/10.1007/s12035-025-05146-3
  30. Adv Healthc Mater. 2025 Jun 17. e2501346
    NIR-II Type I Photosensitizer for Efficient Cancer Therapy Through Synergistic Ferroptosis/Pyroptosis Induction and Mitophagy Inhibition.
    Jiabao Zhuang, Shaoyang Song, Lijin Yang, Quan Pan, Yun He, Lantian Huo, Nan Li, Na Zhao.
      The advancement of tumor-targeted phototheranostics requires photosensitizers (PSs) exhibiting multimodal intervention capacities, such as mitophagy regulation and programmed cell death activation. However, the rational design of such PSs remains a significant challenge in precision oncology. In this study, a mitochondria-targeted near-infrared II (NIR-II) emissive PS (MTC) is reported, which synergistically induces ferroptosis and pyroptosis while inhibiting mitophagy for precise tumor ablation. Through strategic π-conjugation extension, MTC achieves NIR-I absorption and NIR-II emission properties. Its optimized radiative and non-radiative decay facilitates type I reactive oxygen species (ROS) generation and high photothermal conversion. The lipocationic nature of MTC ensures its selective accumulation in the mitochondria of cancer cells. Upon laser irradiation, MTC-mediated phototherapy triggers lipid peroxidation and mitochondrial membrane disruption, inducing synergistic ferroptosis and pyroptosis. Meanwhile, mitochondrial damage initiates mitophagy but subsequently blocks mitophagic flux at the autophagosome stage, amplifying ferroptosis and pyroptosis. These collaborative actions elicit immunogenic cell death, stimulating a robust immune response. MTC nanoparticles (NPs) enable high-resolution NIR-II fluorescence imaging of murine vasculature and dynamic respiratory tracking. Notably, MTC NPs demonstrate precise tumor-specific accumulation, enabling highly effective antitumor phototherapy. This mitochondria-targeted theranostic paradigm advances precision oncology by interlinking photodamage with programmed cell death networks and mitophagy regulation.
    Keywords:  ferroptosis; mitophagy inhibition; near‐infrared II emission; pyroptosis; type I photosensitizer
    DOI:  https://doi.org/10.1002/adhm.202501346
  31. J Adv Res. 2025 Jun 13. pii: S2090-1232(25)00435-7. [Epub ahead of print]
    The purinergic receptor P2rx7 mediated ATP sensing is required to prevent bone aging by directing mitochondrial fitness of MSCs.
    Zimeng Zhuang, Chunshan Han, Meilian Cai, Mingzhao Li, Shuai Lin, Liujing Chen, Zilu Zhu, Han Zhang, Chenyang Xing, Bing Han, Ruili Yang.
       BACKGROUND: Bone aging, displays osteoporosis and impaired bone formation, intricately linked to the metabolic alteration of mesenchymal stem cells (MSCs). However, the precise mechanisms underlying this relationship remain unclear.
    OBJECTIVES: To determine how P2rx7 modulates mitochondrial dynamics during bone aging and osteogenic differentiation of MSCs.
    METHODS: We established P2rx7-/- mice, to verify the role of P2rx7 in bone metabolism and aging. The bone phenotype was evaluated by micro-CT and histological analyses. The differentiations of MSCs were analyzed by Alizarin red staining and alkaline phosphatase staining. Mitochondrial function was assessed by Seahorse assay, ATP content and membrane potential. Mitochondrial morphology was analyzed by transmission electron microscopy and confocal microscopy.
    RESULTS: A decreased expression of P2rx7 concurrent with abnormal mitochondrial dynamics was observed in aged bone tissue. To confirm the role of P2rx7 in bone metabolism and aging, we deleted P2rx7 by using P2rx7-/- mice and the mice demonstrated premature and exacerbated bone aging. Mechanically, deletion of P2rx7 attenuated the sensitivity of ERK pathway to stimulus, which in turn weakened mitochondrial fusion and resulted in a sparsely connected mitochondrial network via Mitofusion 1. Consistently, P2rx7 deficiency impaired the mitochondrial fitness and bone formation of MSCs. The activation of P2rx7 in MSCs by Benzoylbenzoyl-ATP enhanced the sensitivity of ERK signaling, thereby enhancing mitochondrial fusion and promoting the osteogenic differentiation of MSCs and bone regeneration. Furthermore, restoring mitochondrial fitness in MSCs by Dichloroacetate could rescue the impaired bone regeneration and bone aging observed in P2rx7-/- mice.
    CONCLUSION: Taken together, our results highlight a role for P2rx7 in regulating mitochondrial dynamics coordinates with ERK pathway, thereby highlighting P2rx7 as a promising target to rejuvenate the tissue aging.
    Keywords:  Bone aging; ERK pathway; Mesenchymal stem cells; Mitochondrial dynamics; P2X7 receptor
    DOI:  https://doi.org/10.1016/j.jare.2025.06.026
  32. Free Radic Biol Med. 2025 Jun 18. pii: S0891-5849(25)00770-1. [Epub ahead of print]
    Dental pulp stem cell secretome inhibits mitophagy-induced hippocampal neural injury during hypoxia.
    Kyung-Joo Seong, Sehoon Park, Se Hwan Jang, Zee-Yong Park, Ji-Yeon Jung, Won-Jae Kim.
      Hypoxic stress induces neuronal damage by increasing mitochondrial reactive oxygen species (mtROS), triggering mitophagy-associated cell death, and promoting neuroinflammation. However, the neuroprotective potential of human dental pulp stem cell (hDPSC) secretome in this process remains unclear. Here, we show that the hDPSC secretome mitigates hypoxic stress-induced neuronal injury by modulating mitophagy and inflammatory pathways. Proteomic analysis revealed key therapeutic proteins in the hDPSC secretome, which appear to reduce mtROS levels and suppress mitophagy markers, including PHB2, BCL2L13, BNIP3, and LC3-II. CoCl2-induced activation of the TLR4-NF-κB pathway increased pro-inflammatory cytokines, promoting cell death, but the hDPSC secretome inhibited this activation while enhancing anti-apoptotic proteins to support neuronal survival. Furthermore, the hDPSC secretome restored neuronal and synaptic markers, including neurofilament heavy chain, synaptophysin, and PSD95, contributing to neuronal recovery and synaptic integrity. This study provides evidence that the hDPSC secretome alleviates hypoxic stress-induced neuronal damage through a multifaceted neuroprotective mechanism. These findings indicate its potential as a therapeutic strategy for neurodegenerative conditions.
    Keywords:  HT22 cells; Human dental pulp stem cell; Hypoxia; Mass spectrometry; Mitochondrial ROS; Secretome
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.021
  33. J Transl Med. 2025 Jun 17. 23(1): 674
    Targeting Drp1 inhibits ESCC progression via the ROS-PGC1-α-Nrf1/2 pathway.
    Zhixiong Jiang, Yating Yang, Jinchi Zhou, Xin Li, Qingqing Meng, Xiangyi Yu, Yaxin Xue, Mengyu Li, Yichen Cai, Pengchun Han, Mingjun Jiang, Huizhen Wang, Congrong Liu, Jing Zhao, Lixin Wan, Dengke Bao.
       BACKGROUND: Esophageal squamous cell carcinoma (ESCC) ranks among the most prevalent malignancies of the digestive tract. Due to the absence of obvious symptoms in patients with early-stage ESCC, most cases are diagnosed at advanced stages, highlighting the urgent need to investigate the specific mechanisms underlying ESCC progression. Mitochondrial dysfunction plays a pivotal role in tumor progression by regulating multiple biological processes. Dynamin-related protein 1 (Drp1), which is involved in the regulation of mitochondrial fission, is closely associated with tumor progression. However, its role in the metastasis of ESCC remains to be fully elucidated.
    METHODS: This study utilized database analysis and immunohistochemistry to evaluate the expression of Drp1 in ESCC tissues. Functional cell experiments and mouse models were performed to elucidate the mechanisms by which Drp1 influences ESCC cell growth and metastasis. Furthermore, the TargetScan online platform was employed to predict microRNAs that may interact with Drp1 to further explore the specific mechanism of Drp1 on the progression of ESCC.
    RESULTS: We found that high expression of Drp1 was correlated with poor prognosis of ESCC patients. Furthermore, Drp1 overexpression significantly enhanced the growth and metastasis of ESCC cell both in vitro and in vivo. Mechanistically, we showed that Drp1 overexpression activated the PGC1-α-Nrf1/2 signaling and promoted the process of epithelial-mesenchymal transition (EMT) in ESCC cells, thereby facilitating tumor cell metastasis. Additionally, miR-203a-3p targeted and down-regulated Drp1 expression in ESCC cells, effectively inhibiting Drp1-mediated metastasis through the ROS-PGC1-α-Nrf1/2 pathway.
    CONCLUSIONS: These findings uncover that Drp1 overexpression drived the growth and metastasis of ESCC via ROS-PGC1-α-Nrf1/2 signaling pathway, while miR-203a-3p significantly inhibited Drp1 expression and its capacity to mediate the malignant progression of ESCC cells. Our results provide potential novel therapeutic targets for the treatment of ESCC.
    Keywords:  Drp1; Esophageal squamous cell carcinoma; Metastasis; MiR-203a-3p; ROS
    DOI:  https://doi.org/10.1186/s12967-025-06697-8
  34. Front Immunol. 2025 ;16 1594021
    A novel mitochondrial autophagy and aging-related gene signature for predicting ovarian cancer.
    Hongyu Zhang, Qiaoying Jin, Huijuan Cao, Yunyun Wang, Yiling Zhao, Hongwen Zhu, Tiansheng Qin.
      Ovarian cancer (OC) is a highly malignant gynecologic tumor with a poor prognosis. In recent years, mitochondrial autophagy and aging (MiAg) have been recognized as crucial pathophysiological mechanisms leading to tumorigenesis. However, the expression of MiAg-related genes in OC and their correlation with prognosis remain unclear. In this study, we used multiple machine learning methods to identify 52 MiAg genes that were differentially expressed between OC and normal ovarian tissues. Based on these 52 differentially expressed genes (DEGs), 375 OC patients were classified into two subtypes by consensus clustering analysis. Subsequently, we evaluated the prognostic value of MiAg-related genes in relation to survival in 375 OC patients with complete survival information, and developed a MiAg prognostic score model. By applying Cox and LASSO regression methods, a five-gene signature was constructed, and the 375 OC patients in the TCGA cohort were categorized into low-risk and high-risk group based on the median risk score. Meanwhile, we categorized 174 OC patients from the Gene Expression Omnibus (GEO) database into high- and low-risk groups using the median risk score of the TCGA cohort to validate the MiAg scoring model. Furthermore, we analyzed these data with unifactorial and multifactorial analyses, functional enrichment analysis, gene mutation analysis, immune infiltration, drug susceptibility analysis, cell line analysis, and immunohistochemistry data from the HPA database. In conclusion, the MiAgscore predicted patient survival, and lower MiAgscore values were associated with a better survival advantage. A comprehensive assessment of mitochondrial autophagy and cellular senescence alterations in OC could help advance disease target development and provide more effective personalized treatment strategies for OC patients.
    Keywords:  cellular senescence; machine learning; mitochondrial autophagy; ovarian cancer; prognosis
    DOI:  https://doi.org/10.3389/fimmu.2025.1594021
  35. J Ethnopharmacol. 2025 Jun 16. pii: S0378-8741(25)00848-7. [Epub ahead of print]351 120160
    Zhen-wu-tang alleviates nephrotic syndrome by upregulating 5-HTR1B to activate AMPK/PGC-1α-mediated mitochondrial biogenesis.
    Beini Lao, Xiaotong Lin, Xipan Zhao, Yuxian Li, Xiuye Huang, Yiwen Cao, Shengliang Yuan, Jiuyao Zhou.
       ETHNOPHARMACOLOGICAL RELEVANCE: Zhen-wu-tang (ZWT) as a classic herbal formula is widely recognized for its therapeutic efficacy in treating nephropathy. It is commonly used to alleviate edema, improve renal function, and manage symptoms associated with kidney yang deficiency. However, its therapeutic efficacy and mechanism for nephrotic syndrome (NS) is not yet clear.
    AIM OF THE STUDY: To investigate the underlying mechanism of ZWT in regulating mitochondrial biogenesis (MB) to treat NS.
    METHODS: An adriamycin (ADR)-induced NS animal model and a renal tubular epithelial cell injury model were used, followed by intervention with three concentrations of ZWT. The location of 5-HTR1B in kidney cells was observed using immunofluorescence co-localization. Protein levels of the MB-related proteins, including recombinant transcription factor A (TFAM), peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), adenosine 5'-monophosphate-activated protein kinase (AMPK) and p-AMPK, were determined by western blotting after administration of 5-hydroxytryptamine receptor 1B (5-HTR1B) agonist and inhibitor interventions. The bioactive compounds of ZWT-containing serum were determined using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry.
    RESULTS: ZWT treatment ameliorated renal dysfunction and pathological damage in NS rats by attenuating podocyte and tubular cell damage. Additionally, ZWT reduced NS-induced mitochondrial dysfunction and reactive oxygen species levels. Immunofluorescence revealed that 5-HTR1B was predominantly expressed in the collecting ducts and proximal tubule cells. In ADR-induced models, ZWT upregulated the levels of PGC-1α, TFAM, AMPK and p-AMPK proteins involved in MB. In addition, a novel finding was that both gene and protein levels of 5-HTR1B were downregulated in these injury models, whereas ZWT intervention upregulated them. Studies on 5-HTR1B agonists and antagonists indicated that ZWT regulates AMPK/PGC-1α through 5-HTR1B-mediated mechanisms. Furthermore, 24 bioactive compounds were identified in ZWT-containing serum, of which paeoniflorin bound best to 5-HTR1B and acted similarly to 5-HTR1B agonists.
    CONCLUSION: Overall, this study demonstrated that ZWT alleviates NS by upregulating MB via the 5-HTR1B/AMPK/PGC-1α signaling. This novel mechanism enriches the reference of ZWT for NS therapy.
    Keywords:  5-HTR1B; AMPK/PGC-1α pathway; Mitochondrial biogenesis; Nephrotic syndrome; Paeoniflorin; Zhen-wu-tang
    DOI:  https://doi.org/10.1016/j.jep.2025.120160
  36. Exp Cell Res. 2025 Jun 11. pii: S0014-4827(25)00251-4. [Epub ahead of print]450(2): 114651
    Estradiol inhibits endometrial injury by promoting the stability of the KLF15 protein and the recovery of mitochondrial function.
    Jianghong Zhou, Zhenghua Xiong, Xicui Long, Lijuan Yang, Wenjiao Jin, Xuesong Han.
       BACKGROUND: Endometrial injury (EI) is an important factor leading to infertility, which seriously affects women's fertility and reproductive health. Research indicates that estradiol (E2) therapy can promote the repair of EI, but the specific mechanism of E2 action in EI remains unclear.
    METHODS: The research involved creating an EI model for human endometrial epithelial cells (hEECs) using lipopolysaccharide (LPS), and constructing a rat intrauterine adhesion (IUA) model through simulating mechanical injury of human endometrial. Western blot, immunohistochemistry and RT-qPCR were used to detect the expression of key proteins and genes; endometrial damage was detected by HE, TUNEL and Masson staining; mitochondrial function changes were detected by detecting ROS, ATP levels and mitochondrial membrane potential.
    RESULTS: Our research revealed a reduced expression of E2 and Krüppel-like factor 15 (KLF15) in IUA rats. Exogenous E2 treatment inhibited EI by activating the expression of KLF15, inhibited the expression of apoptosis-related proteins Bax and cleaved caspase-3, and promoted the expression of Bcl-2 protein. Additionally, our findings revealed that treatment with E2 decreased mitochondrial ROS (mROS) levels, enhanced mitochondrial membrane potential, and promoted ATP production in EI model cells, whereas KLF15 interference weakens the therapeutic effect of E2, suggesting that E2 treatment alleviates EI by promoting the expression of KLF15 and restoring mitochondrial function. In addition, E2 promotes PGC-1α expression by inhibiting WWP1-mediated ubiquitination degradation of KLF15, thereby restoring mitochondrial function and easing the development of EI.
    CONCLUSION: Our study reveals that E2 alleviates EI progression by stabilizing KLF15 protein and restoring mitochondrial function, providing potential targets for EI treatment.
    Keywords:  Endometrial injury; Estradiol; KLF15; Mitochondrial dynamics; PGC-1α; WWP1
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114651
  37. Cell Signal. 2025 Jun 16. pii: S0898-6568(25)00363-8. [Epub ahead of print] 111948
    Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
    Kai Ma, Haoxuan Sun, Xiaoyun Wu, Jinping Quan, Rong Tang, Weiwei Liu, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Takashi Ikejima.
      Adipocyte hyperplasia refers to the increase in the number of adipocytes, whereas adipocyte hypertrophy pertains to the enlargement of individual adipocytes resulting from the accumulation of lipid droplets. In this study, we found that activation of the STING signalling pathway occurs during adipogenic differentiation of 3 T3-L1 preadipocytes. Interestingly, inhibiting the STING pathway by using STING antagonist H151 or siRNA targeting STING promotes adipocyte differentiation and increases adipocyte numbers, while activation of STING inhibits adipogenic differentiation. Silencing the STING canonical downstream IRF3, or inhibiting the proton channel activity of STING enhances adipogenic differentiation, confirming the negative modulation of adipogenic differentiation by STING. In vivo, intraperitoneal injection of H151 into mice with a high-fat diet further enhances the adipocyte hyperplasia, as shown by the increased volume of adipose tissues, but consistent sizes of adipocytes. During the adipogenic differentiation of 3 T3-L1 cells, DRP1-mediated mitochondrial fission is enhanced, and causes mitochondrial DNA leakage, which in turn activates the STING pathway. However, inhibition of mitochondrial fission represses adipogenic differentiation of 3 T3-L1 cells in spite of the down-regulation of STING pathway. Therefore, our results indicate that adipogenic differentiation is associated with DRP1-induced mitochondrial fission. However, the leakage of mitochondrial DNA caused by DRP1-induced mitochondrial fission activates the STING signalling pathway, which negatively regulates adipogenic differentiation. Tissue specific reduction of DRP1-associated mitochondrial fission or STING enhancement might be new strategies for the therapy of obesity-associated diseases.
    Keywords:  3 T3-L1 cells; Adipocyte differentiation; DRP1; Mitochondria; STING
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111948
  38. J Hazard Mater. 2025 Jun 17. pii: S0304-3894(25)01888-6. [Epub ahead of print]495 138972
    Restoration of mitochondrial homeostasis by Wnt3a/β-catenin/c-Myc alleviates cadmium-induced neural stem cell senescence and cognitive impairment in mouse hippocampus.
    Yuwei Zhang, Qiuyun Gu, Yixi Li, Jiayi Li, Yaxin Han, Longfei Feng, Xutong Qin, Jiming Zhang, Zhijun Zhou, Xiuli Chang.
      Cadmium (Cd), a prevalent environment heavy metal, has been associated with cognitive impairment and an increased risk of neurodegenerative diseases. However, the precise mechanisms underlying Cd-induced cognitive dysfunction remain poorly understood, particularly regarding its effects on hippocampal neural stem cells (NSCs). In this study, we identified NSC senescence as a key contributor to Cd-induced cognitive impairment using both animal and cellular models. We demonstrated that chronic exposure to environmentally relevant doses of Cd led to hippocampal-dependent cognitive deficits and accelerated NSC senescence in the subgranular zone (SGZ) of the hippocampus. Hallmarks of Cd-induced NSC senescence included reduced proliferative capacity, mitochondrial dysfunction, lysosomal hyperactivity, and nuclear morphological abnormalities. Mechanism investigations revealed that Cd disrupted the Wnt3a/β-catenin/c-Myc signaling pathway, leading to impaired mitochondrial homeostasis. Importantly, Wnt3a overexpression effectively mitigated mitochondrial damage and NSC senescence, highlighting its protective role in maintaining NSC function. Furthermore, c-Myc was identified as a key downstream mediator in Wnt3a/β-catenin-driven mitochondrial protection, linking impaired mitochondrial integrity to NSC senescence. These findings elucidate the molecular mechanisms underlying Cd-induced neurotoxicity and identify potential therapeutic targets to mitigating the adverse effects of environmental toxicants on the nervous system.
    Keywords:  Cadmium; Cellular senescence; Mitochondrial homeostasis; Neural stem cell; Wnt3a/β-catenin pathway
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.138972
  39. Neurol Res. 2025 Jun 15. 1-10
    Propionate ameliorates neural degeneration by modulating mitochondrial fission and fusion in nerve cells.
    Song Xi, Tang Lin, Zhang Haiyan, Zeng Shiyue, Qing Qi, Xiong Qiangqiang, Zheng Mingzhi, Luo Liu.
       BACKGROUND: Sporadic global cognitive decline is on the rise, and current drugs exhibit limited efficacy. Propionate, an SCFAs of the human microbiome, exhibits robust neuroprotective effects.
    METHODS: We used CCK8 to evaluate neuronal proliferation, DCFH-DA fluorescence probe to quantify ROS production, ELISA to detect IL-1β and IL-6 release, MitoTracker to assess mitochondrial membrane potential, real-time quantitative PCR, and western blotting to analyze DRP1 and anti-Mfn2 protein expression. We also established an in vitro blood-brain barrier model and AD mouse model.
    RESULTS: Propionate normalized the mitochondrial membrane potential in glutamate-treated HT22 cells, reversed growth suppression, ROS accumulation, and elevated IL-1 and IL-6 release. Propionate also decreases Drp1 expression and elevates Mfn2 expression via GRP41 receptor binding. In vitro blood-brain barrier models illustrated the potential of propionate to ameliorate glutamate-induced blood-brain barrier damage. In vivo, propionate notably improved the learning and memory capabilities of AD mice and mitigated AD-induced mitochondrial defects.
    CONCLUSION: Supplementation with propionate provides neuroprotection against neurodegenerative diseases. Propionate supplementation may provide a novel strategy for early intervention of neurological disorders.
    Keywords:  Drp1; Mfn2; Propionate; blood-brain barrier; neural degeneration
    DOI:  https://doi.org/10.1080/01616412.2025.2520019
  40. Prog Neurobiol. 2025 Jun 18. pii: S0301-0082(25)00087-5. [Epub ahead of print] 102796
    The low-density lipoprotein receptor-related protein-1 (LRP1) in Schwann cells controls mitochondria homeostasis in peripheral nerves.
    Stefano Martellucci, Melissa Heredia, Zixuan Wang, Thomas Whisenant, Dudley K Strickland, Richard Sanchez, Takahito Arai, Morgan Zhang, Haoming Wang, Zhiting Gong, Kesava Asam, Brad E Aouizerat, Gulcin Pekkurnaz, Yi Ye, Wendy M Campana.
      Following peripheral nerve injury, Schwann cell (SC) survival is imperative for successful nerve regeneration. The low-density lipoprotein receptor-related protein-1 (LRP1) has been identified as a pro-survival SC plasma membrane signaling receptor, however, the responsible mechanisms underlying SC homeostasis remain incompletely understood. Herein, we establish that LRP1 largely manages mitochondrial dynamics and bioenergetics in SCs by limiting mitochondria fission, maintaining healthy mitochondria membrane potentials, and reducing lactate production associated with peripheral sensitization. When SC LRP1 is suppressed, inner-mitochondria-linked pathways in peripheral nerve proteome are dramatically altered, and cristae integrity in unmyelinated C-fibers is compromised. SC LRP1 protected sensory neurons from mitochondrial dysfunction and modulated mitochondria-related biological pathways in the DRG transcriptome. Conditional deletion of LRP1 in SCs induces pain-related behaviors in mice without nerve injury. Results point to a significant role for LRP1 in SC mitochondrial homeostasis and advance our understanding of the sensory neuron response to alterations in SC bioenergetics.
    Keywords:  C-fibers; DRGs; LRP1; Schwann cells; bioenergetics; mitochondria; neuropathic pain
    DOI:  https://doi.org/10.1016/j.pneurobio.2025.102796
  41. ACS Pharmacol Transl Sci. 2025 Jun 13. 8(6): 1741-1755
    Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney.
    Paul Victor Santiago Raj, Giri Gnawali, Jaroslav Janda, Natalie E Scholpa, Vishal Kaleeswaran, Ishika Girdhar, Wei Wang, Rick G Schnellmann.
      Serotonin, or 5-hydroxytryptamine (5-HT), is a multifaceted neurotransmitter that plays a vital role in the central nervous system (CNS). Beyond the CNS, 5-HT is intricately involved in modulating hemostasis, immune response, blood pressure, and metabolism in tissues such as skeletal muscle, heart, and kidney. Accumulating evidence highlights the interplay between 5-HT receptors and mitochondrial bioenergetics. Here, we report the discovery of a novel, potent, and selective 5-hydroxytryptamine 2B receptor (5-HT2BR) antagonist, MARY1, which induces mitochondrial biogenesis (MB) in the kidney. MARY1 is a small molecule belonging to the pyridinylpiperazine class that exhibits selectivity and moderate affinity (K i = 764 nM) for the human 5-HT2BR, as well as efficacy (IC50 = 380 nM; E max = 90%) in cellular-based binding and functional assays. Treatment with MARY1 (1 nM) increases mitochondrial respiratory capacity, mitochondrial protein levels, and mitochondrial number in renal proximal tubule cells (RPTCs). Mechanistically, the MB effects of MARY1 in RPTCs are mediated through 5-HT2BR and the activation of dual cell signaling pathways: PI3K/AKT and RAS/MEK/ERK. Moreover, MARY1 administration in mice and rats induces renal cortical MB, and increases levels of mitochondrial and fatty acid oxidation proteins. These findings identify MARY1 as a selective and potent 5-HT2BR antagonist that induces MB and enhances mitochondrial function in the kidney, offering a potential therapeutic strategy for metabolic and mitochondrial dysfunction-associated renal disorders.
    Keywords:  5-HT2B receptor antagonist; mitochondrial biogenesis; mitochondrial dysfunction; piperazine
    DOI:  https://doi.org/10.1021/acsptsci.5c00161
  42. Front Neurosci. 2025 ;19 1602149
    Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
    Luis Armando Valenzuela-Ahumada, Octavio Fabián Mercado-Gómez, Rubi Viveros-Contreras, Rosalinda Guevara-Guzmán, Alberto Camacho-Morales.
      Neurodegenerative diseases affect up to 349.2 million individuals worldwide. Preclinical and clinical advances have documented that altered energy homeostasis and mitochondria dysfunction is a hallmark of neurological disorders. Diet-derived ceramides species might target and disrupt mitochondria function leading to defective energy balance and neurodegeneration. Ceramides as bioactive lipid species affect mitochondria function by several mechanism including changes in membrane chemical composition, inhibition of the respiratory chain, ROS overproduction and oxidative stress, and also by activating mitophagy. Promising avenues of intervention has documented that intermittent fasting (IF) is able to benefit and set proper energy metabolism. IF is an eating protocol that involves alternating periods of fasting with periods of eating which modulate ceramide metabolism and mitochondria function in neurons. This review will address the detrimental effect of ceramides on mitochondria membrane composition, respiratory chain, ROS dynamics and mitophagy in brain contributing to neurodegeneration. We will focus on effect of IF on ceramide metabolism as a potential avenue to improve mitochondria function and prevention of neurodegeneration.
    Keywords:  ceramides; intermittent fasting; microglia; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fnins.2025.1602149
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒24 at 9:56.