Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension.
Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension.
复制标题
细胞内氯离子通道调节肺动脉高压的内皮代谢重编程。
DOI：
10.1165/rcmb.2022-0111oc
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发表时间：
2023
影响因子：
6.4
通讯作者：
Alzaydi MM
中科院分区：
文献类型：
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作者：
Alzaydi MM
线粒体分裂和从氧化磷酸化到糖酵解的代谢转换是肺动脉高压（PAH）血管病理学的关键特征，并与旺盛的内皮细胞增殖和凋亡相关。其基本机制尚不清楚。我们描述了两种细胞内氯离子通道蛋白CLIC 1和CLIC 4对PAH内皮细胞线粒体功能障碍和能量代谢的贡献，CLIC 1和CLIC 4在PAH和癌症中均高度表达。CLIC蛋白的病理性过表达诱导人肺动脉内皮细胞中线粒体片段化，抑制线粒体嵴形成，并诱导代谢向糖酵解转变，这与在患者来源的细胞中观察到的变化一致。CLIC蛋白与线粒体内膜的结构组分的相互作用提供了机制见解。内皮细胞CLIC 4切除和mitofusin 2补充在人PAH细胞和临床前PAH中具有保护作用。本研究首次证明了内皮细胞内氯离子通道在调节PAH表型表达中的线粒体结构、生物发生和代谢重编程中的关键作用。
Mitochondrial fission and a metabolic switch from oxidative phosphorylation to glycolysis are key features of vascular pathology in pulmonary arterial hypertension (PAH) and are associated with exuberant endothelial proliferation and apoptosis. The underlying mechanisms are poorly understood. We describe the contribution of two intracellular chloride channel proteins, CLIC1 and CLIC4, both highly expressed in PAH and cancer, to mitochondrial dysfunction and energy metabolism in PAH endothelium. Pathological overexpression of CLIC proteins induces mitochondrial fragmentation, inhibits mitochondrial cristae formation, and induces metabolic shift toward glycolysis in human pulmonary artery endothelial cells, consistent with changes observed in patient-derived cells. Interactions of CLIC proteins with structural components of the inner mitochondrial membrane offer mechanistic insights. Endothelial CLIC4 excision and mitofusin 2 supplementation have protective effects in human PAH cells and preclinical PAH. This study is the first to demonstrate the key role of endothelial intracellular chloride channels in the regulation of mitochondrial structure, biogenesis, and metabolic reprogramming in expression of the PAH phenotype.