CELL PROLIFERATION
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2021
·Vol. 54
·期 6
·e13048
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IF 6.831
Wei Feng,Jian Wang,Xin Yan,Qianqian Zhang,Limin Chai,Qingting Wang,Wenhua Shi,Yuqian Chen,Jin Liu,Zhan Qu,Shaojun Li,Xinming Xie,Manxiang Li
Objectives High-mobility group box-1 (HMGB1) and aberrant mitochondrial fission mediated by excessive activation of GTPase dynamin-related protein 1 (Drp1) have been found to be elevated in patients with pulmonary arterial hypertension (PAH) and critically implicated in PAH pathogenesis. However, it remains unknown whether Drp1-mediated mitochondrial fission and which downstream targets of mitochondrial fission mediate HMGB1-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration leading to vascular remodelling in PAH. This study aims to address these issues. Methods Primary cultured PASMCs were obtained from male Sprague-Dawley (SD) rats. We detected RNA levels by qRT-PCR, protein levels by Western blotting, cell proliferation by Cell Counting Kit-8 (CCK-8) and EdU incorporation assays, migration by wound healing and transwell assays. SD rats were injected with monocrotaline (MCT) to establish PAH. Hemodynamic parameters were measured by closed-chest right heart catheterization. Results HMGB1 increased Drp1 phosphorylation and Drp1-dependent mitochondrial fragmentation through extracellular signal-regulated kinases 1/2 (ERK1/2) signalling activation, and subsequently triggered autophagy activation, which further led to bone morphogenetic protein receptor 2 (BMPR2) lysosomal degradation and inhibitor of DNA binding 1 (Id1) downregulation, and eventually promoted PASMCs proliferation/migration. Inhibition of ERK1/2 cascade, knockdown of Drp1 or suppression of autophagy restored HMGB1-induced reductions of BMPR2 and Id1, and diminished HMGB1-induced PASMCs proliferation/migration. In addition, pharmacological inhibition of HMGB1 by glycyrrhizin, suppression of mitochondrial fission by Mdivi-1 or blockage of autophagy by chloroquine prevented PAH development in MCT-induced rats PAH model. Conclusions HMGB1 promotes PASMCs proliferation/migration and pulmonary vascular remodelling by activating ERK1/2/Drp1/Autophagy/BMPR2/Id1 axis, suggesting that this cascade might be a potential novel target for management of PAH.
研究领域:
心血管疾病
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细胞生物学
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分子生物学
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药理学
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JOURNAL OF VIROLOGY
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2026
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IF 4.1
Huan Wang,Yang Hu,Lei Liu,Jiong Chen
Environmental pollutants are increasingly recognized as disease modifiers, reshaping host homeostasis and shifting host-pathogen dynamics toward higher infection risk in aquatic ecosystems. Here, we show that the widely used strobilurin fungicide trifloxystrobin (TFS) persistently erodes antiviral competence in fish and increases susceptibility to spring viremia of carp virus (SVCV) by driving dynamin-related protein 1 (Drp1)-mediated excessive mitophagy and sustained mitochondrial dysfunction. Using epithelioma papulosum cyprini (EPC) cells and zebrafish as complementary models, we find that environmentally plausible TFS exposures (2.5–25 μg/L) elevate SVCV permissiveness; notably, this phenotype resolves incompletely after chemical withdrawal. Transcriptomics revealed a dose-concordant shift toward stress/innate immune signaling and mitophagy programs, alongside broad repression of proliferative and DNA-repair pathways. Consistently, TFS induces persistent mitochondrial membrane depolarization, promotes fragmentation and ultrastructural deterioration, and increases mitochondria–lysosome coupling. Mechanistically, TFS elevates Drp1 abundance and Ser616 phosphorylation, promotes Drp1 recruitment to mitochondria, and sustains microtubule-associated protein 1 light chain 3B (LC3B)/lysosomal-associated membrane protein 2 (LAMP2) engagement, accompanied by persistent induction of core autophagy regulators (gabarap, atg5, wipi1, and ambra1) across extended recovery windows. In vivo, prolonged TFS exposure similarly yields durable enhancement of SVCV susceptibility even after long recovery periods, indicating incomplete restoration of host resistance. Together, these findings link a major agricultural fungicide to persistent Drp1-driven mitophagy overactivation and identify long-term antiviral resistance as an ecologically relevant endpoint for pesticide risk assessment and aquatic disease forecasting.
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BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY
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2025
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IF 2.7
Bin Xu,Yifei Zheng,Yi Wang,Jie Sun,Dehai Lang,Qiyang Xu
Aquaporin 9 (AQP9) expression is significantly elevated in vulnerable carotid plaque (VCP). Hence, we probed the mechanism of AQP9 in VCP formation. The VCP model was established in ApoE −/− C57BL/6 mice. Dataset GSE163154 was analyzed by R software. Human aortic endothelial cells (HAECs) were incubated with 50 µg/mL oxidized low-density lipoprotein (ox-LDL) and 20 mM l -(+)-lactic acid for 24 h. Mice (AQP9 overexpression plasmid) and HAECs (AQP9 overexpression/dynamin-related protein 1 [DRP1] silencing plasmids) were infected by lentivirus. Mouse plasma lipid level was estimated. The histopathological condition of model mice was observed by oil red lipid staining, hematoxylin–eosin (H&E) staining, and Masson staining. Levels of AQP9 and DRP1 in model mice and HAECs were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Levels of AQP9, DRP1, and mitochondrial fission-/endothelium–mesenchymal transition (EndMT)-related factors in model mice and HAECs were assayed by western blot. Lactate level in model mice was detected. Promoter histone lactylation level of DRP1 was measured by chromatin immunoprecipitation (ChIP). Behaviors of HAECs were tested by cell counting kit-8 (CCK-8), colony formation test, and scratch test. AQP9 was highly expressed in intraplaque hemorrhage patients. AQP9 overexpression promoted levels of DRP1, lactate, histone lactylation, mitochondrial fission factor, vimentin, and N -cadherin, while inhibiting vascular endothelial (VE)-cadherin level and plaque stability in model mice and facilitating viability, proliferation, and migration of HAECs. DRP1 silencing reversed the impacts of AQP9 overexpression on cell viability, proliferation, migration, and levels of mitochondrial fission-/EndMT-related factors in HAECs. AQP9 enhances DRP1-mediated mitochondrial fission by lactate and thus promotes EndMT to exacerbate the VCP formation.
研究领域:
医学
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分子生物学
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心血管研究
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Nature Communications
·
2025
·
IF 15.7
Fang Zhou,Robert J Ju,Chenlu Kang,Jiayi Li,Ao Yang,Alexandre Libert,Yujie Sun,Ling Liang,Youwei Ai,Xiaoqing Hu,Samantha J Stehbens,Congying Wu
Cells in highly crowded environments are exposed to fluctuating mechanical forces. While cells can activate the cortical migration machinery to escape from undesirable compressive stress, the consequence to less motile cells and of prolonged extensive confinement is yet to be uncovered. Here, we demonstrate that nuclear deformation generated by axial confinement triggers a specific form of regulated cell death – ferroptosis. We show that axial confinement is sensed by the nucleus and results in Drp1-dependent mitochondrial fragmentation and mitochondrial ROS accumulation. Meanwhile, we detect cPLA2 translocation to mitochondria. These mitochondrial ROS accumulation and arachidonic acid production concertedly lead to lipid peroxidation and evoke ferroptosis. Interestingly, we find in osteoarthritis, a disease intimately associated with mechanical overloading and inflammation, characteristics of confinement-induced ferroptosis including mitochondrial localization of cPLA2 and high ROS. Together, our findings unveil a pivotal role of cell nucleus and mitochondria in linking mechanical confinement with cell death, highlighting the orchestration of Drp1 and cPLA2 in confinement-induced ferroptosis. A groundbreaking study reveals how physical confinement triggers ferroptosis. It finds the nucleus acts as a mechanosensor, orchestrating Drp1 and cPLA2 that leads to mitochondrial dysfunction and ultimately, cell death.
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Frontiers in Pharmacology
·
2021
·
IF 5.811
Song Nanshan,Zhu Hong,Xu Rong,Liu Jiaqi,Fang Yinquan,Zhang Jing,Ding Jianhua,Hu Gang,Lu Ming
Glia-mediated inflammatory processes are crucial in the pathogenesis of Parkinson’s disease (PD). As the most abundant cells of the brain and active participants in neuroinflammatory responses, astrocytes largely propagate inflammatory signals and amplify neuronal loss. Hence, intensive control of astrocytic activation is necessary to prevent neurodegeneration. In this study, we report that the astrocytic kir6.2, as a abnormal response after inflammatory stimuli, promotes the reactivity of A1 neurotoxic astrocytes. Using kir6.2 knockout (KO) mice, we find reversal effects of kir6.2 deficiency on A1-like astrocyte activation and death of dopaminergic neurons in lipopolysaccharide (LPS)-induced mouse models for PD. Further in vitro experiments show that aberrant kir6.2 expression induced by inflammatory irritants in astrocytes mediates the dynamin-related protein 1 (Drp1)-dependent excessive mitochondrial fragmentation and results in mitochondrial malfunctions. By deleting kir6.2, astrocytic activation is reduced and astrocytes-derived neuronal injury is prevented. We therefore conclude that astrocytic kir6.2 can potentially elucidate the pathology of PD and promote the development of therapeutic strategies for PD.
研究领域:
神经科学
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神经炎症
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神经退行性疾病
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FASEB JOURNAL
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2026
·Vol. 40
·期 19
·e72301
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IF 4.3
Xiaodie Chen,Huiqun Huang,Yutong Yang,Xiangyu Chen,Nan Xiao,Chenghui Li,Yanbin Pan,Yongan Deng,Xiaodong Duan,Shuting Zeng,Simin Yang,Chengkai Chen,Yixuan Huang,Yuliang Zhou,Yubin Yang,Zunpeng Shu,Li Zhang
Cardiac aging is a major risk factor for cardiovascular diseases, with an imbalance in mitochondrial dynamics homeostasis being a pivotal aspect. Although Astragaloside IV (AS-IV) has been shown to delay aging, its specific effects on cardiac aging and the link to mitochondrial dynamics remain unclear. This study aimed to elucidate the role and regulatory mechanism of AS-IV in delaying cardiac aging by using naturally aged mouse models and D-galactose (D-gal)-induced H9c2 cell senescence models. The results demonstrated that AS-IV reduced the expression of senescence markers (p16 INK4a , p21, and p53), β-galactosidase (SA-β-gal), and senescence-associated secretory phenotype (SASP) factors ( Il6 , Il1b , and Tnfa ) while also significantly ameliorating aging-induced cardiac dysfunction and myocardial fibrosis. Furthermore, AS-IV significantly enhanced mitochondrial morphology and function in cardiomyocytes. This improvement was demonstrated by increased mitochondrial membrane potential, elevated ATP production, and reduced ROS levels. Mechanistically, AS-IV upregulated SIRT3 and promoted its interaction with DRP1, leading to the inhibition of DRP1 acetylation. This action suppressed excessive mitochondrial fission and thereby improved mitochondrial dynamics. Transfection with SIRT3-siRNA attenuated the beneficial effects of AS-IV. In conclusion, this study demonstrates that AS-IV mitigates cardiac aging by activating SIRT3 to mediate DRP1 deacetylation, which in turn improves mitochondrial dynamics. These findings provide a strong theoretical and experimental foundation for the potential application of AS-IV in preventing and treating age-related cardiovascular diseases. Graphical This study demonstrates that AS-IV upregulates and activates the deacetylase SIRT3, thereby prompting the deacetylation of DRP1, a key mitochondrial fission protein. This modification inhibits the excessive activation and mitochondrial localization of DRP1, thereby correcting aging-associated mitochondrial hyper-fission and restoring dynamic balance. The reestablished mitochondrial homeostasis effectively improves mitochondrial structure and function, ultimately conferring protective effects against cardiac aging.
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DRUG DEVELOPMENT RESEARCH
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2026
·Vol. 87
·期 1
·e70224
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IF 4.2
Sitao Liang,Yonghua Zhu,Jiahao Su,Chuangcai Luo,Chunhong Yang
Mitochondrial dynamics play a crucial role in glioma progression by regulating cellular metabolism, proliferation, and survival. This study investigated the effects of desmopressin (dDAVP), a synthetic vasopressin analog, on mitochondrial function in human U87 MG glioma cells. Our results demonstrate that dDAVP treatment induces dose-dependent cytotoxicity while upregulating vasopressin type 2 receptor expression. The compound significantly increased oxidative stress markers and impaired mitochondrial function, as evidenced by reduced ATP production, compromised respiratory chain activity, and decreased oxygen consumption. Furthermore, dDAVP promoted mitochondrial fragmentation through Drp1 activation, enhancing its phosphorylation at Ser616 and subsequent mitochondrial translocation. Mechanistically, dDAVP was found to activate CaMKII signaling, which mediated the observed changes in Drp1 phosphorylation and mitochondrial dynamics. The CaMKII inhibitor KN-93 effectively reversed dDAVP-induced mitochondrial fragmentation, Drp1 phosphorylation, and energy metabolism impairment. The AVPR2 antagonist tolvaptan blocked dDAVP effects, confirming receptor specificity. These findings reveal that dDAVP disrupts mitochondrial homeostasis in glioma cells through AVPR2-mediated CaMKII-dependent regulation of Drp1 activity, leading to mitochondrial dysfunction and cell damage. The study provides new insights into the molecular mechanisms underlying dDAVP's effects on glioma cells and suggests potential therapeutic applications targeting the CaMKII-Drp1 axis in glioma treatment.
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International Journal of Biological Sciences
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2026
·Vol. 22
·期 13
·7427
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IF 11.7
Hong Xu,Hongyu Chen,Fengling He,Xinlan Li,Wanxin Li,Qingqing Yang,Tingting Zhang,Jin Liu,Xiaoke Shi,Shilin Chen,Defang Li,Jun Lu
Aberrant activation of macrophages and their amplification of inflammatory responses constitute the core pathological basis driving the progression of acute lung injury (ALI). Celastrol (CE), despite its potent anti-inflammatory activity, suffers from poor aqueous solubility and substantial systemic toxicity, which severely limit its clinical translation. Capitalizing on the metabolic signature of pro-inflammatory M1 macrophages, specifically their high expression of glucose transporter 1 (GLUT1), we designed a glucose-modified CE prodrug that self-assembled into carrier-free nanoparticles CG NPs. With markedly improved solubility and systemic stability, CG NPs rapidly and persistently accumulated in the inflammatory lungs of LPS-induced ALI mice facilitated by GLUT1-mediated targeting and uptake by M1 macrophages. Compared with free CE, CG NPs exhibited enhanced overall therapeutic efficacy while significantly reducing hepatorenal toxicity. Mechanistic studies revealed that by targeting Drp1, CG NPs disrupt Drp1-MiD51 interaction, thus inhibiting excessive mitochondrial fission and ROS accumulation, which blocks NF-κB-mediated inflammatory signaling and M1-driven cytokine release. Molecular docking suggested that glucose conjugation may confer CG with a superior ability to regulate mitochondrial homeostasis over CE, potentially driven by its unique U-shaped conformation that inserts into Drp1 and forms a denser hydrogen-bond network, which could contribute to enhanced binding affinity. In summary, this study proposes a nanoprodrug strategy that combines precise targeting with mitochondrial protection, offering a promising therapeutic avenue for inflammatory diseases such as ALI.
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POULTRY SCIENCE
·
2025
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IF 4.2
Yi Li,Fan Yang,Chenghong Xing,Penghui Liu,Yike Zhang,Caiying Zhang,Jirong Chen,Huabin Cao,Xueyan Dai
Di(2-ethylhexyl) phthalate (DEHP) has been used commonly in industrial production and has endocrine disrupting ability. DEHP has potential adverse effects on the development of fetal programming, but the toxic effects and mechanism study in neural crest cells is not enough understood. To investigate DEHP's effects on neural tube closure injury, the chicken embryos and primary cranial neural crest (CNC) cells model of DEHP-treatment was established. Here, we show that the development of neural tube is disrupted by DEHP, which causes an observed decrease in levels of HNK1 and Pax7 and increase in levels of adhesion molecules and extracellular matrix. This led to inhibit the migration and epithelial-mesenchymal transition (EMT) mechanism in neural crest cells, which cause dysraphism in chicken embryos. Furthermore, DEHP exposure also disrupts mitochondrial function accompanied by the elevation of Drp1 and FIS1 level, and the decrease of MFN1, MFN2, and OPA1 level, causing excessive mitochondrial fragmentation, mitophagy and apoptosis, eventually decreasing the MMP levels and ATP concentration in chicken embryos. Conversely, the addition of Drp1 inhibitor dramatically alleviate the mitochondrial fragmentation and mitophagy induced by DEHP in primary CNC cells. Our results reveal the mechanism of DEHP-induced mitophagy in neural crest cells was regulated by excessive activation of Drp1-mediated mitochondrial fission. These findings deepen the research of reproductive toxicology of DEHP and guide its application in different areas, especially in the agricultural field.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
·
IF 3.4
Simiao Qiao,Fanshu Li,Jia Huang,Xiaoqian Wu,Xiaoying Cao,Xifeng Zhang,Zhifeng Wei
This study was designed to clarify the reason for PM 2.5 to induce the ferroptosis of bronchial epithelial cells and worsen asthma in detail, advancing the development of relevant drugs. Results displayed that PM 2.5 mainly induced ferroptosis but not apoptosis of bronchial epithelial cells, indicating by the changes of lipid reactive oxygen species (ROS), iron, malondialdehyde, lactic dehydrogenase, nuclear receptor coactivator 4, glutathione and glutathione peroxidase 4 levels, and further confirmed by using in combination with the ferroptosis and apoptosis inhibitors. It also caused the mitochondrial disturbance, reduced the level of mitochondrial membrane potential, up-regulated the level of mitochondrial ROS, and mechanisms were subsequently ascribed to dynamin-related protein 1 (DRP1)-related mitochondrial fission. Furthermore, the up-regulation on ubiquitination of pyruvate kinase M2 (PKM2) but not macrophage stimulating 1 or interferon regulatory factor 1, the transcriptional regulators locating at the upstream of DRP1, was showed by PM 2.5 via controlling “aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90)” axis. In addition, isoliquiritigenin (ISL), the main active ingredients in licorice, was demonstrated to prevent the PM 2.5 -induced activation of AHR-PKM2-ferroptosis in asthma. In conclusion, PM 2.5 activated “AHR-HSP90” axis to disturb DRP1-related mitochondrial fission, induced ferroptosis of bronchial epithelial cells, and worsened asthma. Conversely, ISL restored the above-mentioned signals, ferroptosis and asthma mediated by PM 2.5 , and was suggested as a potential compound to combat the exacerbation of asthma.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
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IF 4.8
Yongping Chen,Haotian Yang,Xueyuan Hu,Tianyuan Yang,Yuan Zhao,Huanqi Liu,Honggang Fan
Increasing evidence has demonstrated that coenzyme Q10 (CoQ10) exhibits a range of biological properties. Herein, we explored the protective effect and potential molecular mechanism of CoQ10 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We found that medium (10 mg/kg) and high (50 mg/kg) doses of CoQ10 ameliorated LPS (50 µg/µL)-induced ALI to varying degrees, as demonstrated by reduced lung coefficient, lower wet/dry weight lung tissue ratio, decreased bronchoalveolar lavage fluid protein concentration, less anatomical and histopathological damage to the lung, and increased expression of proteins related to lung epithelial barrier structure. CoQ10 also alleviated LPS-induced oxidative stress and inflammation mediated by NOD-like receptor protein 3 (NLRP3) by reducing the reactive oxygen species (ROS), malondialdehyde, and mitochondrial ROS concentrations, increasing superoxide dismutase, glutathione, and catalase activity, and decreasing NLRP3 expression at the protein and mRNA levels. Moreover, CoQ10 alleviated structural and functional damage to the mitochondria, inhibited mitochondrial fission, and promoted mitochondrial fusion, mainly by inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and Ser637. Correlation analysis revealed that mitochondrial fission (especially Drp1) was positively correlated with oxidative stress, NLRP3-mediated inflammation, and structural damage to the lung epithelial barrier. Molecular docking analysis showed that CoQ10 binds stably to Drp1, with a binding energy of −5.9 kcal/mol. Furthermore, the use of schaftoside (a Drp1 inhibitor) has further elucidated the mechanism of action of CoQ10. Together, these results suggest that CoQ10 alleviates LPS-induced ALI by regulating mitochondrial dynamics, attenuating oxidative stress, and decreasing NLRP3-medated inflammation, thereby promoting lung epithelial barrier structural remodeling.
研究领域:
药理学
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免疫学
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呼吸医学
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分子生物学
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Translational Cancer Research
·
2026
·Vol. 15
·期 2
·97
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IF 2.1
Xiang Lei,Shi Jinjie,Huang Xueqing,Zhou Shi
Background Donafenib (DON) has been found to be effective in prolonging progression-free survival for advanced hepatocellular carcinoma (HCC), although it remains limited in improving long-term survival outcomes. Quercetin (QUE) has also been demonstrated to exhibit anticancer effects in various malignant tumors. The most recent research has shown that the combination therapy of QUE and conventional chemotherapy drugs can enhance its anti-cancer activity. Therefore, this study aimed to investigate whether QUE and DON in combination could synergistically suppress tumor growth in HepG2 cells. Methods In this study, the effects of QUE alone and in combination with DON were assessed on HCC HepG2 cells. Both in vitro and in vivo (subcutaneous xenograft models in nude mice) experiments were conducted. The expression of cyclic AMP-responsive element-binding protein 1 (CREB1), a putative common target, was evaluated, and its role in lipid metabolism was investigated. Results CREB1 was confirmed to be highly expressed in HepG2 cells and serves as a molecular target for both QUE and DON. Suppressing CREB1 expression significantly inhibited lipid metabolism and reduced the biological activity of HepG2 cells. Furthermore, QUE, both alone and in combination with DON, was shown to down-regulate the CREB1/dynamin-related protein 1 (DRP1)/sterol regulatory element-binding protein 1 (SREBP1) signaling axis. This inhibition significantly suppressed lipid metabolism and tumor growth in the nude mouse xenograft models. Conclusions These findings indicate that the combination of QUE and DON exerts its antitumor effects by inhibiting the CREB1/DRP1/SREBP1 axis mediated lipid metabolism pathway in HepG2 cells. This offers a novel potential approach for enhancing the therapeutic efficacy of DON in the treatment of HCC.
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