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

Agnese De Mario, Anna Tosatto, Julia Marie Hill, Janos Kriston-Vizi, Robin Ketteler, Denis Vecellio Reane, Gino Cortopassi, Gyorgy Szabadkai, Rosario Rizzuto, Cristina Mammucari

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article number109275
JournalCell Reports
Issue number12
StatePublished - Jun 22 2021


  • amorolfine
  • benzethonium
  • FDA-approved drugs
  • high-throughput screening
  • MCU
  • mitochondrial Ca uptake
  • mitochondrial calcium uniporter
  • skeletal muscle hypertrophy
  • triple-negative breast cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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