EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter.

Summary The mitochondrial uniporter (MCU) is an ion channel that mediates Ca 2+ uptake into the matrix to regulate metabolism, cell death, and cytoplasmic Ca 2+ signaling. Matrix Ca 2+ concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca 2+ overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca 2+ concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix Ca 2+ inhibition of MCU Ca 2+ currents, resulting in MCU channel activation, enhanced mitochondrial Ca 2+ uptake, and constitutively elevated matrix Ca 2+ concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic Ca 2+ . Thus, mitochondria are protected from Ca 2+ depletion and Ca 2+ overload by a unique molecular complex that involves Ca 2+ sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.