Intracellular chloride channels regulate endothelial metabolic reprogramming in pulmonary arterial hypertension
File(s)
Accepted version
Supporting information
Author(s)
Type
Journal Article
Abstract
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 towards 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 pre-clinical PAH. This study is 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.
Date Issued
2023-01-01
Date Acceptance
2022-09-13
Citation
American Journal of Respiratory Cell and Molecular Biology, 2023, 63 (1), pp.103-115
ISSN
1044-1549
Publisher
American Thoracic Society
Start Page
103
End Page
115
Journal / Book Title
American Journal of Respiratory Cell and Molecular Biology
Volume
63
Issue
1
Copyright Statement
©2023 American Thoracic Society, All Rights Reserved.
Publication Status
Published
Date Publish Online
2022-10-20