A High-Throughput Screening Identifies MICU1 Targeting Compounds

作者：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 · 发表于：Cell Reports · 年份：2020 · DOI：10.1016/j.celrep.2020.01.081 · 被引用次数：103 · 研究领域：Macrophage Migration Inhibitory Factor、ATP Synthase and ATPases Research、Protein Tyrosine Phosphatases

Mitochondrial Ca 2+ 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 Ca 2+ uptake. Two of them, named MCU-i4 and MCU-i11, are confirmed to reliably decrease mitochondrial Ca 2+ 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 Ca 2+ 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 Ca 2+ uptake in muscle growth. Overall, MCU-i4 and MCU-i11 represent leading molecules for the development of MICU1-targeting drugs.