Cell Reports (Feb 2020)

A High-Throughput Screening Identifies MICU1 Targeting Compounds

  • Giulia Di Marco,
  • Francesca Vallese,
  • Benjamin Jourde,
  • Christian Bergsdorf,
  • Mattia Sturlese,
  • Agnese De Mario,
  • Valerie Techer-Etienne,
  • Dorothea Haasen,
  • Berndt Oberhauser,
  • Simone Schleeger,
  • Giulia Minetti,
  • Stefano Moro,
  • Rosario Rizzuto,
  • Diego De Stefani,
  • Mara Fornaro,
  • Cristina Mammucari

Journal volume & issue
Vol. 30, no. 7
pp. 2321 – 2331.e6

Abstract

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Summary: 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. : Di Marco et al. report the discovery of MCU-i4 and MCU-i11, two negative modulators of the MCU that decrease mitochondrial Ca2+ uptake. MCU-i4 and MCU-i11 bind MICU1, the key MCU interactor that controls channel gating, and MICU1 is required for their activity. Thus, these small molecules represent lead MICU1-targeting compounds. Keywords: mitochondrial calcium uptake, MICU1, mitochondrial calcium uniporter, MCU, high-throughput screening, HTS, molecular modeling, active compounds, small molecules