The mitochondrial Na⁺/Ca²⁺ exchanger

Powered by the steep mitochondrial membrane potential Ca²⁺ permeates into the mitochondria via the Ca²⁺ uniporter and is then extruded by a mitochondrial Na⁺/Ca²⁺ exchanger. This mitochondrial Ca²⁺ shuttling regulates the rate of ATP production and participates in cellular Ca²⁺ signaling. Despite the fact that the exchanger was functionally identified 40 years ago its molecular identity remained a mystery. Early studies on isolated mitochondria and intact cells characterized the functional properties of a mitochondrial Na⁺/Ca²⁺ exchanger, and showed that it possess unique functional fingerprints such as Li⁺/Ca²⁺ exchange and that it is displaying selective sensitivity to inhibitors. Purification of mitochondria proteins combined with functional reconstitution led to the isolation of a polypeptide candidate of the exchanger but failed to molecularly identify it. A turning point in the search for the exchanger molecule came with the recent cloning of the last member of the Na⁺/Ca²⁺ exchanger superfamily termed NCLX (Na⁺/Ca²⁺/Li⁺ exchanger). NCLX is localized in the inner mitochondria membrane and its expression is linked to mitochondria Na⁺/Ca²⁺ exchange matching the functional fingerprints of the putative mitochondrial Na⁺/Ca²⁺ exchanger. Thus NCLX emerges as the long sought mitochondria Na⁺/Ca²⁺ exchanger and provide a critical molecular handle to study mitochondrial Ca²⁺ signaling and transport. Here we summarize some of the main topics related to the molecular properties of the Na⁺/Ca²⁺ exchanger, beginning with the early days of its functional identification, its kinetic properties and regulation, and culminating in its molecular identification.