Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension

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.

Correspondence and requests for reprints should be addressed to Beata Wojciak-Stothard, M.Sc., Ph.D., National Heart and Lung Institute, ICTEM Building, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, UK. E-mail:
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*These authors contributed equally to this work.

Supported by Saudi Arabia Cultural Bureau in London PhD studentship, British Heart Foundation grants PG/15/69/31719 (V.B.A.-S.) and RE/18/4/34215, National Institute for Health Research infrastructure grant (H.J.W.), and Clinical Research Facility and Biomedical Research Centre infrastructure support.

Author Contributions: M.M.A. and V.B.A.-S. performed experiments, analyzed data, and contributed to manuscript writing. G.R., A.G., and D.C. performed experiments and analyzed data. H.J.W. performed proteomic analysis. G.S. and M.R.W. contributed to discussions and critically evaluated the manuscript. B.W.-S. conceived the study, performed experiments, analyzed data, and wrote the manuscript.

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Originally Published in Press as DOI: 10.1165/rcmb.2022-0111OC on October 20, 2022

Author disclosures are available with the text of this article at www.atsjournals.org.

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