Intracellular chloride channels regulate endothelial metabolic reprogramming in pulmonary arterial hypertension

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Title: Intracellular chloride channels regulate endothelial metabolic reprogramming in pulmonary arterial hypertension
Authors: Alzaydi, M
Abdul Salam, V
Whitwell, H
Russomanno, G
Glynos, A
Capece, D
Szabadkai, G
Wilkins, M
Wojciak Stothard, B
Wojciak-Stothard, B
Item 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 of Acceptance: 13-Sep-2022
URI: http://hdl.handle.net/10044/1/99808
ISSN: 1044-1549
Publisher: American Thoracic Society
Journal / Book Title: American Journal of Respiratory Cell and Molecular Biology
Copyright Statement: Subject to copyright. All rights reserved.
Sponsor/Funder: King Abdulaziz City for Science and Technology (KACST)
British Heart Foundation
Funder's Grant Number: 120/16281
PG/15/69/31719
Keywords: Respiratory System
1102 Cardiorespiratory Medicine and Haematology
Publication Status: Accepted
Embargo Date: Embargoed for 12 months after publication date
Appears in Collections:National Heart and Lung Institute