Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex

Mitochondrial CA(2+) uptake, a process crucial for bioenergetics and CA(2+) signaling, is catalyzed by the mitochondrial calcium uniporter. The uniporter is a multi-subunit CA(2+)-activated CA(2+) channel, with the CA(2+) pore formed by the MCU protein and CA(2+)-dependent activation mediated by MICU subunits. Recently, a mitochondrial inner membrane protein EMRE was identified as a uniporter subunit absolutely required for CA(2+) permeation. However, the molecular mechanism and regulatory purpose of EMRE remain largely unexplored. Here, we determine the transmembrane orientation of EMRE, and show that its known MCU-activating function is mediated by the interaction of transmembrane helices from both proteins. We also reveal a second function of EMRE: to maintain tight MICU regulation of the MCU pore, a role that requires EMRE to bind MICU1 using its conserved C-terminal polyaspartate tail. This dual functionality of EMRE ensures that all transport-competent uniporters are tightly regulated, responding appropriately to a dynamic intracellular CA(2+) landscape.