Calcium uptake protein 2, mitochondrial
cellular response to calcium ion
Structure and mechanism of the mitochondrial Ca<sup>2+</sup> uniporter holocomplex.
Mitochondria take up Ca<sup>2+</sup> through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca<sup>2+</sup> signalling and cell death<sup>1,2</sup>. 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 Ca<sup>2+</sup> transport<sup>3-8</sup>. To prevent detrimental Ca<sup>2+</sup> overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca<sup>2+</sup> concentrations to switch MCU on and off<sup>9,10</sup>. Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca<sup>2+</sup>-activated states. These structures define the architecture of this multicomponent Ca<sup>2+</sup>-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca<sup>2+</sup> uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca<sup>2+</sup> overload.