| Autor: |
Alzaydi MM; National Heart and Lung Institute.; National Center for Biotechnology, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia., Abdul-Salam VB; National Heart and Lung Institute.; Centre for Cardiovascular Medicine and Device Innovation, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom., Whitwell HJ; National Phenome Centre and Imperial Clinical Phenotyping Centre, and.; Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion, and Reproduction, and., Russomanno G; National Heart and Lung Institute.; Medical Research Council (MRC) Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom., Glynos A; Mitochondrial Biology Unit, Medical Research Council, University of Cambridge, Cambridge, United Kingdom; and., Capece D; Centre for Cell Signalling and Inflammation, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom., Szabadkai G; Cell and Developmental Biology, University College London, London, United Kingdom., Wilkins MR; National Heart and Lung Institute., Wojciak-Stothard B; National Heart and Lung Institute. |
| Abstrakt: |
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. |
