Center of Translational Science, Florida International University, Port St Lucie, Florida, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, Florida, USA.
Department of Medicine, University of Arizona Health Sciences, Tucson, Arizona, USA.
J Biol Chem. 2023 Apr;299(4):103067. doi: 10.1016/j.jbc.2023.103067. Epub 2023 Feb 24.
Mitochondrial fission and a Warburg phenotype of increased cellular glycolysis are involved in the pathogenesis of pulmonary hypertension (PH). The purpose of this study was to determine whether increases in mitochondrial fission are involved in a glycolytic switch in pulmonary arterial endothelial cells (PAECs). Mitochondrial fission is increased in PAEC isolated from a sheep model of PH induced by pulmonary overcirculation (Shunt PAEC). In Shunt PAEC we identified increases in the S phosphorylation responsible for dynamin-related protein 1 (Drp1) activation, the mitochondrial redistribution of Drp1, and increased cellular glycolysis. Reducing mitochondrial fission attenuated cellular glycolysis in Shunt PAEC. In addition, we observed nitration-mediated activation of the small GTPase RhoA in Shunt PAEC, and utilizing a nitration-shielding peptide, NipR1 attenuated RhoA nitration and reversed the Warburg phenotype. Thus, our data identify a novel link between RhoA, mitochondrial fission, and cellular glycolysis and suggest that targeting RhoA nitration could have therapeutic benefits for treating PH.
线粒体裂变和细胞糖酵解增加的瓦博格表型与肺动脉高压 (PH) 的发病机制有关。本研究旨在确定线粒体裂变的增加是否与肺血管内皮细胞 (PAEC) 的糖酵解转换有关。在由肺过度循环 (分流 PAEC) 诱导的绵羊 PH 模型中分离的 PAEC 中，线粒体裂变增加。在分流 PAEC 中，我们发现与 dynamin-related protein 1 (Drp1) 激活相关的 S 磷酸化、Drp1 的线粒体重新分布以及细胞糖酵解增加。减少线粒体裂变可减弱分流 PAEC 中的细胞糖酵解。此外，我们观察到分流 PAEC 中 RhoA 的硝化介导激活，并且利用硝化屏蔽肽 NipR1 减弱了 RhoA 的硝化并逆转了瓦博格表型。因此，我们的数据确定了 RhoA、线粒体裂变和细胞糖酵解之间的新联系，并表明靶向 RhoA 硝化可能对治疗 PH 具有治疗益处。
Antioxid Redox Signal. 2013-3-14
Antioxidants (Basel). 2025-2-12
Zotero 插件