1. Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter.
- Author
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De Mario A, Tosatto A, Hill JM, Kriston-Vizi J, Ketteler R, Vecellio Reane D, Cortopassi G, Szabadkai G, Rizzuto R, and Mammucari C
- Subjects
- Animals, Apoptosis drug effects, Benzethonium pharmacology, Breast Neoplasms pathology, Calcium metabolism, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Cytoprotection drug effects, Duloxetine Hydrochloride pharmacology, Energy Metabolism drug effects, Female, High-Throughput Screening Assays, Homeostasis drug effects, Humans, Hypertrophy, Mice, Mitochondria drug effects, Mitochondria metabolism, Morpholines pharmacology, Muscle Fibers, Skeletal drug effects, Muscle, Skeletal drug effects, Muscle, Skeletal pathology, Oxygen Consumption drug effects, Reactive Oxygen Species metabolism, Reproducibility of Results, United States, Calcium Channels metabolism, United States Food and Drug Administration
- Abstract
The mitochondrial calcium uniporter (MCU), the highly selective channel responsible for mitochondrial Ca
2+ 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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