Structure of the MICU1-MICU2 heterodimer provides insights into the gatekeeping threshold shift

Mitochondrial calcium uptake proteins 1 and 2 (MICU1 and MICU2) mediate mitochondrial Ca²⁺ influx via the mitochondrial calcium uniporter (MCU). Its molecular action for Ca²⁺ uptake is tightly controlled by the MICU1-MICU2 heterodimer, which comprises Ca²⁺ sensing proteins which act as gatekeepers at low [Ca²⁺] or facilitators at high [Ca²⁺]. However, the mechanism underlying the regulation of the Ca²⁺ gatekeeping threshold for mitochondrial Ca²⁺ uptake through the MCU by the MICU1-MICU2 heterodimer remains unclear. In this study, we determined the crystal structure of the apo form of the human MICU1-MICU2 heterodimer that functions as the MCU gatekeeper. MICU1 and MICU2 assemble in the face-to-face heterodimer with salt bridges and me-thio-nine knobs stabilizing the heterodimer in an apo state. Structural analysis suggests how the heterodimer sets a higher Ca²⁺ threshold than the MICU1 homodimer. The structure of the heterodimer in the apo state provides a framework for understanding the gatekeeping role of the MICU1-MICU2 heterodimer.