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Arduino, D.M. ; 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, J.K.* ; Alonso, M.T.* ; Perocchi, F.

Systematic identification of MCU modulators by orthogonal Iiterspecies chemical screening.

Mol. Cell 67, 711-723.e7 (2017)
Publ. Version/Full Text Research data DOI
Open Access Green as soon as Postprint is submitted to ZB.
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 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Cambridge
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Monoclonal Antibody (IDO-MAB)