Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations

摘要

Calcium (Ca~(2+)) flux into the matrix is tightly controlled by themitochondrial Ca~(2+) uniporter (MCU) due to vital roles in cell death and bioenergetics. However, the precise atomic mechanisms of MCU regulation remain unclear. Here, we solved the crystal structure of the N-terminal matrix domain of human MCU, revealing a b-grasp-like fold with a cluster of negatively charged residues that interacts with divalent cations. Binding of Ca~(2+) or Mg~(2+) destabilizes and shifts the self-association equilibrium of the domain toward monomer. Mutational disruption of the acidic face weakens oligomerization of the isolated matrix domain and full-length human protein similar to cation binding and markedly decreases MCU activity. Moreover, mitochondrial Mg~(2+) loading or blockade of mitochondrial Ca~(2+) extrusion suppresses MCU Ca~(2+)-uptake rates. Collectively, our data reveal that the b-grasp-like matrix region harbors an MCU-regulating acidic patch that inhibits human MCU activity in response to Mg~(2+) and Ca~(2+) binding.