2024-03-29T00:41:40Zhttp://uvadoc.uva.es/oai/requestoai:uvadoc.uva.es:10324/351952021-11-15T13:34:46Zcom_10324_32522com_10324_952com_10324_894col_10324_32523
00925njm 22002777a 4500
dc
Arduino, Daniela M.
author
Wettmarshausen, Jennifer
author
Vais, Horia
author
Navas Navarro, Paloma
author
Cheng, Yiming
author
Leimpek, Anja
author
Zhongming Ma
author
Río Lorenzo, Alba del
author
Giordano, Andrea
author
García Pérez, Cecilia
author
Médard, Guillaume
author
Kuster, Bernhard
author
García-Sancho Martín, Francisco Javier
author
Mokranjac, Dejana
author
Foskett, J. Kevin
author
Alonso Alonso, María Teresa
author
Perocchi, Fabiana
author
2017
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.
Molecular Cell, 2017, Volume 67, Issue 4, P711-723.e7
1097-2765
http://uvadoc.uva.es/handle/10324/35195
https://doi.org/10.1016/j.molcel.2017.07.019
Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening