Structural and mechanistic insights into MICU 1 regulation of mitochondrial calcium uptake

Mitochondrial calcium uptake is a critical event in various cellular activities. Two recently identified proteins, the mitochondrial Ca 2+ uniporter ( MCU ), which is the pore‐forming subunit of a Ca 2+ channel, and mitochondrial calcium uptake 1 ( MICU 1), which is the regulator of MCU , are essential in this event. However, the molecular mechanism by which MICU 1 regulates MCU remains elusive. In this study, we report the crystal structures of Ca 2+ ‐free and Ca 2+ ‐bound human MICU 1. Our studies reveal that Ca 2+ ‐free MICU 1 forms a hexamer that binds and inhibits MCU . Upon Ca 2+ binding, MICU 1 undergoes large conformational changes, resulting in the formation of multiple oligomers to activate MCU . Furthermore, we demonstrate that the affinity of MICU 1 for Ca 2+ is approximately 15–20 μM. Collectively, our results provide valuable details to decipher the molecular mechanism of MICU 1 regulation of mitochondrial calcium uptake.