Molecular identity and functional properties of the mitochondrial Na ⁺/Ca²⁺ exchanger

The mitochondrial membrane potential that powers the generation of ATP also facilitates mitochondrial Ca²⁺ shuttling. This process is fundamental to a wide range of cellular activities, as it regulates ATP production, shapes cytosolic and endoplasmic recticulum Ca²⁺ signaling, and determines cell fate. Mitochondrial Ca²⁺ transport is mediated primarily by two major transporters: a Ca²⁺ uniporter that mediates Ca²⁺ uptake and a Na⁺/Ca²⁺ exchanger that subsequently extrudes mitochondrial Ca²⁺. In this minireview, we focus on the specific role of the mitochondrial Na⁺/Ca²⁺ exchanger and describe its ion exchange mechanism, regulation by ions, and putative partner proteins. We discuss the recent molecular identification of the mitochondrial exchanger and how its activity is linked to physiological and pathophysiological processes.