A High-Throughput Screening Identifies MICU1 Targeting Compounds
| Autor: | Simone Schleeger, Mara Fornaro, Christian Bergsdorf, Benjamin Jourde, Valerie Techer-Etienne, Mattia Sturlese, Diego De Stefani, Rosario Rizzuto, Stefano Moro, Agnese De Mario, Cristina Mammucari, Francesca Vallese, Giulia Minetti, Berndt Oberhauser, Dorothea Haasen, Giulia Di Marco |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular 0301 basic medicine Molecular model High-throughput screening mitochondrial calcium uptake Mitochondrial Membrane Transport Proteins high-throughput screening Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Humans active compounds Mitochondrial calcium uptake Inner mitochondrial membrane lcsh:QH301-705.5 Cation Transport Proteins chemistry.chemical_classification molecular modeling Calcium-Binding Proteins Mitochondrial calcium uniporter Small molecule High-Throughput Screening Assays Amino acid Cell biology small molecules MCU 030104 developmental biology lcsh:Biology (General) mitochondrial calcium uniporter chemistry Docking (molecular) MICU1 HTS 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Cell Reports Cell Reports, Vol 30, Iss 7, Pp 2321-2331.e6 (2020) |
| ISSN: | 2211-1247 |
| Popis: | 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. Graphical Abstract Highlights • An HTS identifies MCU-i4 and MCU-i11 as negative modulators of the MCU • MCU-i4 and MCU-i11 bind MICU1 • MICU1 is required for the activity of MCU-i4 and MCU-i11 • MCU-i4 and MCU-i11 impair muscle cell growth 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. |
| Databáze: | OpenAIRE |
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