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Systematic identification of MCU modulators by orthogonal Iiterspecies chemical screening.
Mol. Cell 67, 711-723.e7 (2017)
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Research data
DOI
PMC
The mitochondrial calcium uniporter complex is essential for calcium (Ca(2+)) uptake into mitochondria of all mammalian tissues, where it regulates bioenergetics, cell death, and Ca(2+) 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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Mcu ; Bioenergetics ; Calcium ; Calcium Signaling ; Drug Discovery ; Drug Screening ; High-throughput Screening ; Mitochondria ; Mitochondrial Calcium Uniporter; Mitochondrial Calcium Uniporter; Rat-kidney Mitochondria; Liver-mitochondria; Essential Component; Respiration; Transport; Cells; Yeast; Ca2+; Mitoxantrone
ISSN (print) / ISBN
1097-2765
e-ISSN
1097-4164
Journal
Molecular Cell
Quellenangaben
Volume: 67,
Issue: 4,
Pages: 711-723.e7
Publisher
Elsevier
Publishing Place
Cambridge
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Obesity (IDO)
CF Monoclonal Antibodies (CF-MAB)
CF Monoclonal Antibodies (CF-MAB)