Di Marco, Giulia, Vallese, Francesca, Jourde, Benjamin, Bergsdorf, Christian, Sturlese, Mattia, De Mario , Agnese, Techer-Etienne, Valerie, Haasen, Dorothea, Oberhauser, Berndt, Schleeger, Simone, Minetti, Giulia, Moro, Stefano, Rizzuto, Rosario, De Stefani, Diego, 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