Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening

Arduino, Daniela M.; Wettmarshausen, Jennifer; Vais, Horia; Navas-Navarro, Paloma; Cheng, Yiming; Leimpek, Anja; Ma, Zhongming; Delrio-Lorenzo, Alba; Giordano, Andrea; Garcia-Perez, Cecilia; Medard, Guillaume; Kuster, Bernhard; Garcia-Sancho, Javier; Mokranjac, Dejana; Foskett, J. Kevin; Teresa Alonso, M. und Perocchi, Fabiana (2017): Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening. In: Molecular Cell, Bd. 67, Nr. 4: S. 711-723

Abstract

The mitochondrial calcium uniporter complex is essential for calcium (Ca2+) uptake into mitochondria of all mammalian tissues, where it regulates bioenergetics, cell death, and Ca2+ signal transduction. Despite its involvement in several human diseases, we currently lack pharmacological agents for targeting uniporter activity. Here we introduce a high-throughput assay that selects for human MCUspecific small-molecule modulators in primary drug screens. Using isolated yeast mitochondria, reconstituted with human MCU, its essential regulator EMRE, and aequorin, and exploiting a D-lactate- and mannitol/sucrose-based bioenergetic shunt that greatly minimizes false-positive hits, we identify mitoxantrone out of more than 600 clinically approved drugs as a direct selective inhibitor of human MCU. We validate mitoxantrone in orthogonal mammalian cell-based assays, demonstrating that our screening approach is an effective and robust tool for MCU-specific drug discovery and, more generally, for the identification of compounds that target mitochondrial functions.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie ; Medizin
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1097-2765
• Sprache: Englisch