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Article Dans Une Revue Cell Chemical Biology Année : 2023

MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors

Résumé

Mitochondrial Ca2+ homeostasis loses its control in many diseases and might provide therapeutic targets. Mitochondrial Ca2+ uptake is mediated by the uniporter channel (mtCU), formed by MCU and is regulated by the Ca2+-sensing gatekeeper, MICU1, which shows tissue-specific stoichiometry. An important gap in knowledge is the molecular mechanism of the mtCU activators and inhibitors. We report that all pharma-cological activators of the mtCU (spermine, kaempferol, SB202190) act in a MICU1-dependent manner, likely by binding to MICU1 and preventing MICU1's gatekeeping activity. These agents also sensitized the mtCU to inhibition by Ru265 and enhanced the Mn2+-induced cytotoxicity as previously seen with MICU1 deletion. Thus, MCU gating by MICU1 is the target of mtCU agonists and is a barrier for inhibitors like RuRed/Ru360/Ru265. The varying MICU1:MCU ratios result in different outcomes for both mtCU ago-nists and antagonists in different tissues, which is relevant for both pre-clinical research and therapeutic efforts
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Dates et versions

hal-04316205 , version 1 (30-11-2023)

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Macarena Rodríguez-Prados, Kai-Ting Huang, Katalin Márta, Melanie Paillard, György Csordás, et al.. MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors. Cell Chemical Biology, 2023, 30 (6), pp.606-617.e4. ⟨10.1016/j.chembiol.2023.05.002⟩. ⟨hal-04316205⟩
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