2. Academic Validation
  3. A High-Throughput Screening Identifies MICU1 Targeting Compounds

A High-Throughput Screening Identifies MICU1 Targeting Compounds

  • Cell Rep. 2020 Feb 18;30(7):2321-2331.e6. doi: 10.1016/j.celrep.2020.01.081.
Giulia Di Marco 1,  Francesca Vallese 1,  Benjamin Jourde 2,  Christian Bergsdorf 2,  Mattia Sturlese 3,  Agnese De Mario 1,  Valerie Techer-Etienne 2,  Dorothea Haasen 2,  Berndt Oberhauser 2,  Simone Schleeger 2,  Giulia Minetti 2,  Stefano Moro 3,  Rosario Rizzuto 1,  Diego De Stefani 1,  Mara Fornaro 4,  Cristina Mammucari 5
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy.
  • 2 Novartis Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland.
  • 3 Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy.
  • 4 Novartis Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland. Electronic address: [email protected].
  • 5 Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy. Electronic address: [email protected].
PMID: 32075766 DOI: 10.1016/j.celrep.2020.01.081
Abstract

Mitochondrial Ca2+ uptake depends on the mitochondrial calcium uniporter (MCU) complex, a highly selective channel of the inner mitochondrial membrane (IMM). Here, we screen a library of 44,000 non-proprietary compounds for their ability to modulate mitochondrial Ca2+ uptake. Two of them, named MCU-i4 and MCU-i11, are confirmed to reliably decrease mitochondrial Ca2+ influx. Docking simulations reveal that these molecules directly bind a specific cleft in MICU1, a key element of the MCU complex that controls channel gating. Accordingly, in MICU1-silenced or deleted cells, the inhibitory effect of the two compounds is lost. Moreover, MCU-i4 and MCU-i11 fail to inhibit mitochondrial Ca2+ uptake in cells expressing a MICU1 mutated in the critical Amino acids that forge the predicted binding cleft. Finally, these compounds are tested ex vivo, revealing a primary role for mitochondrial Ca2+ uptake in muscle growth. Overall, MCU-i4 and MCU-i11 represent leading molecules for the development of MICU1-targeting drugs.

Keywords

HTS; MCU; MICU1; active compounds; high-throughput screening; mitochondrial calcium uniporter; mitochondrial calcium uptake; molecular modeling; small molecules.

Figures
Products