Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension

Alzaydi, Mai M, Abdul-Salam, Vahitha B, Whitwell, Harry J, Russomanno, Giusy ORCID: 0000-0002-3378-5524, Glynos, Angelos, Capece, Daria, Szabadkai, Gyorgy, Wilkins, Martin R and Wojciak-Stothard, Beata (2023) Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 68 (1). pp. 103-115.

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Official URL: http://dx.doi.org/10.1165/rcmb.2022-0111oc

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 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.

Item Type:	Article
Uncontrolled Keywords:	mitochondria, metabolism, endothelial, pulmonary hypertension, chloride channels
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	18 May 2023 15:57
Last Modified:	18 May 2023 15:57
DOI:	10.1165/rcmb.2022-0111OC
Open Access URL:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC98179...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3170518