Structures reveal gatekeeping of the mitochondrial Ca²⁺ uniporter by MICU1-MICU2.

The mitochondrial calcium uniporter is a Ca²⁺-gated ion channel complex that controls mitochondrial Ca²⁺ entry and regulates cell metabolism. MCU and EMRE form the channel while Ca²⁺-dependent regulation is conferred by MICU1 and MICU2 through an enigmatic process. We present a cryo-EM structure of an MCU-EMRE-MICU1-MICU2 holocomplex comprising MCU and EMRE subunits from the beetle Tribolium castaneum in complex with a human MICU1-MICU2 heterodimer at 3.3 Å resolution. With analogy to how neuronal channels are blocked by protein toxins, a uniporter interaction domain on MICU1 binds to a channel receptor site comprising MCU and EMRE subunits to inhibit ion flow under resting Ca²⁺ conditions. A Ca²⁺-bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca²⁺-dependent changes enable dynamic response to cytosolic Ca²⁺ signals.

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