Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening.
Mol Cell
; 67(4): 711-723.e7, 2017 Aug 17.
Article
en En
| MEDLINE
| ID: mdl-28820965
ABSTRACT
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Saccharomyces cerevisiae
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Bloqueadores de los Canales de Calcio
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Canales de Calcio
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Calcio
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Mitoxantrona
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Descubrimiento de Drogas
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Ensayos Analíticos de Alto Rendimiento
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Mitocondrias
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
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Screening_studies
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2017
Tipo del documento:
Article