Molecular cell, 2017-08, Vol.67 (4), p.711-723.e7
2017
Details
- Autor(en) / Beteiligte
- Titel
- Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening
- Ist Teil von
- Molecular cell, 2017-08, Vol.67 (4), p.711-723.e7
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Targeting human MCU in yeast mitochondria is an effective drug discovery strategy•A yeast-specific bioenergetic shunt minimizes detection of false-positive hits•An orthogonal, interspecies drug screening can identify specific MCU modulators•Mitoxantrone is a selective and direct inhibitor of MCU Arduino et al. develop a high-throughput drug discovery strategy to identify chemical modulators of the mitochondrial calcium uniporter. They find that mitoxantrone is a selective and direct inhibitor of the MCU channel.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-2765eISSN: 1097-4164DOI: 10.1016/j.molcel.2017.07.019Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5825229
- Format
- –
- Schlagworte
- Aequorin, Aequorin - metabolism, Animal genetics, Animals, Biochemistry, Molecular Biology, bioenergetics, Calcium, Calcium - metabolism, Calcium Channel Blockers, Calcium Channel Blockers - chemistry, Calcium Channel Blockers - pharmacology, Calcium Channels, Calcium Channels - drug effects, Calcium Channels - genetics, Calcium Channels - metabolism, calcium signaling, Dose-Response Relationship, Drug, Drug Discovery, Drug Discovery - methods, drug screening, Energy Metabolism, Energy Metabolism - drug effects, Genetics, HEK293 Cells, HeLa Cells, high-throughput screening, High-Throughput Screening Assays, Humans, Kinetics, Lactic Acid, Lactic Acid - metabolism, Life Sciences, Mannitol, Mannitol - metabolism, MCU, Membrane Potentials, Mice, Transgenic, Mitochondria, Mitochondria - drug effects, Mitochondria - metabolism, mitochondrial calcium uniporter, Mitoxantrone, Mitoxantrone - chemistry, Mitoxantrone - pharmacology, Models, Molecular, Molecular biology, Molecular Structure, Saccharomyces cerevisiae, Saccharomyces cerevisiae - drug effects, Saccharomyces cerevisiae - genetics, Saccharomyces cerevisiae - metabolism, Structure-Activity Relationship, Sucrose, Sucrose - metabolism, Xenopus laevis