Proteolytic control of the mitochondrial calcium uniporter complex

Significance Mitochondrial Ca 2+ regulates several basic biological functions, including the efficiency of mitochondrial ATP production and the onset of mitochondria-mediated cell death. Ca 2+ uptake into mitochondria is mediated by the “mitochondrial calcium uniporter,” a multisubunit Ca 2+ channel complex made of four proteins: MCU, EMRE, MICU1, and MICU2. This work reveals a proteolytic pathway that maintains stoichiometrically balanced MCU and EMRE levels in the inner mitochondrial membrane. Without this mechanism, uniporter subunits can assemble into a dysfunctional subcomplex that perturbs mitochondrial Ca 2+ homeostasis by constitutively loading Ca 2+ into the matrix. The results provide new insights into the regulation of the uniporter function crucial for multicellular organisms to handle the highly dynamic intracellular Ca 2+ signaling network.