The Mechanism of MICU-Dependent Gating of theMitochondrial Ca2+ Uniporter

BioRxiv : the Preprint Server for Biology
V. GargYuriy Kirichok

Abstract

Mitochondrial Ca2+ uniporter (MCU) mediates mitochondrial Ca2+ uptake, regulating ATP production and cell death. According to the existing paradigm, MCU is occluded at the resting cytosolic [Ca2+] and only opens above an ~400 nM threshold. This Ca2+-dependent gating is putatively conferred by MICUs, EF hand-containing auxiliary subunits that block/unblock the MCU pore depending on cytosolic [Ca2+]. Here we provide the first direct, patch-clamp based analysis of the Ca2+-dependent MCU gating and the role played by MICUs. Surprisingly, MICUs do not occlude the MCU pore, and MCU is a constitutively active channel without cytosolic [Ca2+] activation threshold. Instead, MICUs potentiate MCU activity when cytosolic Ca2+ binds to their EF hands. MICUs cause this potentiation by increasing the probability of open state of the MCU channel.

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