Molecular Cell
Molecular Cell
5 years ago

Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening

Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
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 MCU-specific 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.

Graphical abstract

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Teaser

Arduino et al. develop a high-throughput drug discovery strategy to identify chemical modulators of the mitochondrial calcium uniporter. They find that mitoxantrone is a selective and direct inhibitor of the MCU channel.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517305373

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