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

ABSTRACT: 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 pharmacological 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 th

SUBMITTER: Rodriguez-Prados M 

PROVIDER: S-EPMC10370359 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature