Systematic identification of MCU modulators by orthogonal interspecies chemical screening

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 t...

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Detalles Bibliográficos
Autores: Arduino, Daniela M., Wettmarshausen, Jennifer, Vais, Horia, Navas-Navarro, Paloma, Cheng, Yiming, Leimpek, Anja, Ma, Zhongming, Delrio-Lorenzo, Alba, Giordano, Yiming, Garcia-Perez, Cecilia, Médard, Guillaume, Kuster, Bernhard, García-Sancho, Javier, Mokranjac, Dejana, Foskett, J. Kevin, Alonso, María Teresa, Perocchi, Fabiana
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/197017
Acceso en línea:http://hdl.handle.net/10261/197017
Access Level:acceso abierto
Palabra clave:Mitochondria
Mitochondrial calcium uniporter
MCU
Calcium
Calcium signaling
Bioenergetics
Descripción
Sumario: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.

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