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Pharmacological inhibition of the mitochondrial Ca(2+) uniporter: Relevance for pathophysiology and human therapy

Abstract : Mitochondrial Ca(2+) uptake has long been considered crucial for meeting the fluctuating energy demands of cells in the heart and other tissues. Increases in mitochondrial matrix [Ca(2+)] drive mitochondrial ATP production via stimulation of Ca(2+)-sensitive dehydrogenases. Mitochondria-targeted sensors have revealed mitochondrial matrix [Ca(2+)] rises that closely follow the cytoplasmic [Ca(2+)] signals in many paradigms. Mitochondrial Ca(2+) uptake is mediated by the Ca(2+) uniporter (mtCU). Pharmacological manipulation of the mtCU is potentially key to understanding its physiological significance, but no specific, cell-permeable inhibitors were identified. In the past decade, as the molecular identity of the mtCU was brought to light, efforts have focused on genetic targeting. However, in the cells/animals that are able to survive impaired mtCU function, robust compensatory changes were found in the mtCU as well as other mechanisms. Thus, the discovery, through chemical library screens on normal and mtCU-deficient cells, of new small-molecule inhibitors with improved cell permeability and specificity might offer a better chance to test the relevance of mitochondrial Ca(2+) uptake. Success with the development of small molecule mtCU inhibitors is also expected to have clinical impact, considering the growing evidence for the role of mitochondrial Ca(2+) uptake in a variety of diseases, including heart attack, stroke and various neurodegenerative disorders. Here, we review the progress in pharmacological targeting of mtCU and illustrate the challenges in this field using data obtained with MCU-i11, a new small molecule inhibitor.
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Submitted on : Tuesday, June 15, 2021 - 2:56:59 PM
Last modification on : Tuesday, August 3, 2021 - 9:56:01 AM
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K. Márta, P. Hasan, M. Rodríguez-Prados, M. Paillard, G. Hajnóczky. Pharmacological inhibition of the mitochondrial Ca(2+) uniporter: Relevance for pathophysiology and human therapy. Journal of Molecular and Cellular Cardiology, Elsevier, 2021, 151, pp.135-144. ⟨10.1016/j.yjmcc.2020.09.014⟩. ⟨inserm-03261172⟩



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