National Heart and Lung Institute.
National Center for Biotechnology, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia.
Am J Respir Cell Mol Biol. 2023 Jan;68(1):103-115. doi: 10.1165/rcmb.2022-0111OC.
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.
线粒体裂变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，与旺盛的内皮细胞增殖和凋亡有关。其潜在机制尚不清楚。我们描述了两种细胞内氯离子通道蛋白 CLIC1 和 CLIC4 的贡献，这两种蛋白在 PAH 和癌症中均高度表达，对 PAH 内皮细胞中线粒体功能障碍和能量代谢有影响。CLIC 蛋白的病理性过表达诱导线粒体碎片化，抑制线粒体嵴形成，并诱导人肺动脉内皮细胞向糖酵解代谢转变，与在患者来源的细胞中观察到的变化一致。CLIC 蛋白与线粒体内膜结构成分的相互作用提供了机制上的见解。内皮细胞 CLIC4 切除和线粒体融合蛋白 2 的补充对人 PAH 细胞和临床前 PAH 具有保护作用。这项研究首次证明了内皮细胞细胞内氯离子通道在调节线粒体结构、生物发生和代谢重编程中的关键作用，表达了 PAH 表型。
