Journal
CELL REPORTS
Volume 35, Issue 12, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109275
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Funding
- French Muscular Dystrophy Association [22493]
- Italian Association for Cancer Research (AIRC) [22759]
- Italian Telethon Association [GGP16029]
- Italian Ministry of Health [RF-2016-02363566]
- Cariparo Foundation
- UK Medical Research Council [MC_U12266B]
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In this study, amorolfine and benzethonium were identified as positive and negative modulators of the mitochondrial calcium uniporter (MCU), demonstrating their potential roles in muscle development and cancer progression.
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.
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