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

Cell Rep. 2021 Jun 22;35(12):109275. doi: 10.1016/j.celrep.2021.109275.


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.

Keywords: FDA-approved drugs; MCU; amorolfine; benzethonium; high-throughput screening; mitochondrial Ca(2+) uptake; mitochondrial calcium uniporter; skeletal muscle hypertrophy; triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzethonium / pharmacology
  • Breast Neoplasms / pathology
  • Calcium / metabolism
  • Calcium Channels / 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
  • United States Food and Drug Administration*


  • Calcium Channels
  • Morpholines
  • Reactive Oxygen Species
  • mitochondrial calcium uniporter
  • Benzethonium
  • Duloxetine Hydrochloride
  • amorolfine
  • Calcium