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Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter

De Mario, A; Tosatto, A; Hill, JM; Kriston-Vizi, J; Ketteler, R; Vecellio Reane, D; Cortopassi, G; ... Mammucari, C; + view all (2021) Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter. Cell Reports , 35 (12) , Article 109275. 10.1016/j.celrep.2021.109275. Green open access

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Abstract

The mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+ entry, plays important roles in physiology and pathology. However, only few pharmacological compounds directly and selectively modulate its activity. Here, we perform high-throughput screening on a US Food and Drug Administration (FDA)-approved drug library comprising 1,600 compounds to identify molecules modulating mitochondrial Ca2+ uptake. We find amorolfine and benzethonium to be positive and negative MCU modulators, respectively. In agreement with the positive effect of MCU in muscle trophism, amorolfine increases muscle size, and MCU silencing is sufficient to blunt amorolfine-induced hypertrophy. Conversely, in the triple-negative breast cancer cell line MDA-MB-231, benzethonium delays cell growth and migration in an MCU-dependent manner and protects from ceramide-induced apoptosis, in line with the role of mitochondrial Ca2+ uptake in cancer progression. Overall, we identify amorolfine and benzethonium as effective MCU-targeting drugs applicable to a wide array of experimental and disease conditions.

Type: Article
Title: Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2021.109275
Publisher version: https://doi.org/10.1016/j.celrep.2021.109275
Language: English
Additional information: Copyright © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: FDA-approved drugs, MCU, amorolfine, benzethonium, high-throughput screening, mitochondrial Ca(2+) uptake, mitochondrial calcium uniporter, skeletal muscle hypertrophy, triple-negative breast cancer
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10130419
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