Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex

Mitochondria take up CA²⁺ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic CA²⁺ signalling and cell death^1,2. In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for CA²⁺ transport^3-8. To prevent detrimental CA²⁺ overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic CA²⁺ concentrations to switch MCU on and off^9,10. Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and CA²⁺-activated states. These structures define the architecture of this multicomponent CA²⁺-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated CA²⁺ uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial CA²⁺ overload.