Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening

Producción Científica

Detalles Bibliográficos
Autores: Arduino, Daniela M., Wettmarshausen, Jennifer, Vais, Horia, Navas Navarro, Paloma, Cheng, Yiming, Leimpek, Anja, Zhongming Ma, Río Lorenzo, Alba del, Giordano, Andrea, García Pérez, Cecilia, Médard, Guillaume, Kuster, Bernhard, García-Sancho Martín, Francisco Javier, Mokranjac, Dejana, Foskett, J. Kevin, Alonso Alonso, María Teresa, Perocchi, Fabiana
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universidad de Valladolid
Repositorio:UVaDOC. Repositorio Documental de la Universidad de Valladolid
OAI Identifier:oai:uvadoc.uva.es:10324/35195
Acceso en línea:https://doi.org/10.1016/j.molcel.2017.07.019
http://uvadoc.uva.es/handle/10324/35195
Access Level:acceso abierto
Palabra clave:Calcio mitocondrial
Mitochondrial calcium
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spelling Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical ScreeningArduino, Daniela M.Wettmarshausen, JenniferVais, HoriaNavas Navarro, PalomaCheng, YimingLeimpek, AnjaZhongming MaRío Lorenzo, Alba delGiordano, AndreaGarcía Pérez, CeciliaMédard, GuillaumeKuster, BernhardGarcía-Sancho Martín, Francisco JavierMokranjac, DejanaFoskett, J. KevinAlonso Alonso, María TeresaPerocchi, FabianaCalcio mitocondrialMitochondrial calciumProducción CientíficaThe 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.Ministerio de Economía, Industria y Competitividad (Project BFU2014-53469P)Instituto de Saludo Carlos III (grant RD16/0011/0003)Elsevier2017info:eu-repo/semantics/articleapplication/pdfhttps://doi.org/10.1016/j.molcel.2017.07.019http://uvadoc.uva.es/handle/10324/35195reponame:UVaDOC. Repositorio Documental de la Universidad de Valladolidinstname:Universidad de ValladolidIngléshttps://www.cell.com/molecular-cell/fulltext/S1097-2765(17)30537-3info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:uvadoc.uva.es:10324/351952026-06-13T12:44:47Z
dc.title.none.fl_str_mv Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
title Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
spellingShingle Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
Arduino, Daniela M.
Calcio mitocondrial
Mitochondrial calcium
title_short Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
title_full Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
title_fullStr Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
title_full_unstemmed Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
title_sort Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
dc.creator.none.fl_str_mv Arduino, Daniela M.
Wettmarshausen, Jennifer
Vais, Horia
Navas Navarro, Paloma
Cheng, Yiming
Leimpek, Anja
Zhongming Ma
Río Lorenzo, Alba del
Giordano, Andrea
García Pérez, Cecilia
Médard, Guillaume
Kuster, Bernhard
García-Sancho Martín, Francisco Javier
Mokranjac, Dejana
Foskett, J. Kevin
Alonso Alonso, María Teresa
Perocchi, Fabiana
author Arduino, Daniela M.
author_facet Arduino, Daniela M.
Wettmarshausen, Jennifer
Vais, Horia
Navas Navarro, Paloma
Cheng, Yiming
Leimpek, Anja
Zhongming Ma
Río Lorenzo, Alba del
Giordano, Andrea
García Pérez, Cecilia
Médard, Guillaume
Kuster, Bernhard
García-Sancho Martín, Francisco Javier
Mokranjac, Dejana
Foskett, J. Kevin
Alonso Alonso, María Teresa
Perocchi, Fabiana
author_role author
author2 Wettmarshausen, Jennifer
Vais, Horia
Navas Navarro, Paloma
Cheng, Yiming
Leimpek, Anja
Zhongming Ma
Río Lorenzo, Alba del
Giordano, Andrea
García Pérez, Cecilia
Médard, Guillaume
Kuster, Bernhard
García-Sancho Martín, Francisco Javier
Mokranjac, Dejana
Foskett, J. Kevin
Alonso Alonso, María Teresa
Perocchi, Fabiana
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Calcio mitocondrial
Mitochondrial calcium
topic Calcio mitocondrial
Mitochondrial calcium
description Producción Científica
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://doi.org/10.1016/j.molcel.2017.07.019
http://uvadoc.uva.es/handle/10324/35195
url https://doi.org/10.1016/j.molcel.2017.07.019
http://uvadoc.uva.es/handle/10324/35195
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://www.cell.com/molecular-cell/fulltext/S1097-2765(17)30537-3
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:UVaDOC. Repositorio Documental de la Universidad de Valladolid
instname:Universidad de Valladolid
instname_str Universidad de Valladolid
reponame_str UVaDOC. Repositorio Documental de la Universidad de Valladolid
collection UVaDOC. Repositorio Documental de la Universidad de Valladolid
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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