Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening.

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 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

SUBMITTER: Arduino DM 

PROVIDER: S-EPMC5825229 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature