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A high throughput screening identifies MICU1 targeting compounds

Di Marco, Giulia and Vallese, Francesca and Jourde, Benjamin and Bergsdorf, Christian and Sturlese, Mattia and De Mario , Agnese and Techer-Etienne, Valerie and Haasen, Dorothea and Oberhauser, Berndt and Schleeger, Simone and Minetti, Giulia and Moro, Stefano and Rizzuto, Rosario and De Stefani, Diego and Fornaro, Mara and Mammucari, Cristina (2020) A high throughput screening identifies MICU1 targeting compounds. Cell Reports, 30. pp. 1-11.

Abstract

Mitochondrial Ca2+ uptake depends on the mitochondrial calcium uniporter (MCU), a highly selective tetrameric channel of the inner mitochondrial membrane (IMM), composed of pore forming and of regulatory subunits. Here, we screened a library of 44k non-proprietary compounds for their ability to modulate mitochondrial Ca2+ uptake. Two of them decreased mitochondrial Ca2+ influx both in cell lines and in isolated mouse skeletal muscle fibers. A closer inspection revealed that these molecules directly bound a specific cleft in the MCU complex component and positive regulator MICU1. In MICU1-silenced or deleted cells, the inhibitory effect of the two compounds on Ca2+ influx was lost, demonstrating that MICU1 is required for compound activity. Moreover, in MICU1-KO cells overexpressing a mutant isoform of MICU1, in which critical amino acids of the predicted binding cleft were mutated, the two compounds were unable to decrease mitochondrial Ca2+ uptake. Finally, the compounds were tested ex vivo unravelling a role for mitochondrial Ca2+ uptake in muscle growth. These compounds represent leading molecules for the development of MICU1-targeting drugs.

Item Type: Article
Date Deposited: 21 Feb 2020 00:45
Last Modified: 21 Feb 2020 00:45
URI: https://oak.novartis.com/id/eprint/41199

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