RT info:eu-repo/semantics/article
T1 Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
A1 Arduino, Daniela M.
A1 Wettmarshausen, Jennifer
A1 Vais, Horia
A1 Navas Navarro, Paloma
A1 Cheng, Yiming
A1 Leimpek, Anja
A1 Zhongming Ma
A1 Río Lorenzo, Alba del
A1 Giordano, Andrea
A1 García Pérez, Cecilia
A1 Médard, Guillaume
A1 Kuster, Bernhard
A1 García-Sancho Martín, Francisco Javier
A1 Mokranjac, Dejana
A1 Foskett, J. Kevin
A1 Alonso Alonso, María Teresa
A1 Perocchi, Fabiana
K1 Calcio mitocondrial
K1 Mitochondrial calcium
AB 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.
PB Elsevier
SN 1097-2765
YR 2017
FD 2017
LK http://uvadoc.uva.es/handle/10324/35195
UL http://uvadoc.uva.es/handle/10324/35195
LA eng
NO Molecular Cell, 2017, Volume 67, Issue 4, P711-723.e7
NO Producción Científica
DS UVaDOC
RD 22-nov-2024