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.