A High-Throughput Screening Identifies MICU1 Targeting Compounds.

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 am

SUBMITTER: Di Marco G 

PROVIDER: S-EPMC7034061 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature