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Mol Cell
2017 Aug 17;674:711-723.e7. doi: 10.1016/j.molcel.2017.07.019.
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Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening.
Arduino DM
,
Wettmarshausen J
,
Vais H
,
Navas-Navarro P
,
Cheng Y
,
Leimpek A
,
Ma Z
,
Delrio-Lorenzo A
,
Giordano A
,
Garcia-Perez C
,
Médard G
,
Kuster B
,
García-Sancho J
,
Mokranjac D
,
Foskett JK
,
Alonso MT
,
Perocchi F
.
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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.
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