Structure of intact human MCU supercomplex with the auxiliary MICU subunits

The mitochondrial Ca2+ uniporter (MCU) supercomplex is essential for mitochondrial Ca2+ uptake. Here, we present high-resolution cryo-EM structures of human MCU-EMRE supercomplex (MES, 3.41 A) and MCU-EMRE-MICU1-MICU2 supercomplex (MEMMS, 3.64 A). MES adopts a V-shaped dimer architecture comprising two hetero-octamers, and a pair of MICU1-MICU2 hetero-dimers form a bridge across the two halves of MES to constitute an O-shaped architecture of MEMMS. The MES and MEMMS pore profiles are almost identical, with Ca2+ in the selectivity filters and no obstructions, indicating both channels are conductive. Contrary to the current model in which MICUs block the MCU pore, MICU1-MICU2 dimers are located on the periphery of the MCU pores and do not occlude them. However, MICU1-MICU2 dimers may modulate MCU gating by affecting the matrix gate through the EMRE lever.