The molecular era of the mitochondrial calcium uniporter

The molecular identity of the human mitochondrial calcium uniporter has now been elucidated using integrative genomics. The mammalian uniporter is a protein complex consisting of the inner membrane-spanning subunits mitochondrial calcium uniporter protein (MCU), MCUb and essential MCU regulator (EMRE), together with mitochondrial calcium uptake protein 1 (MICU1) and MICU2 in the intermembrane space.Expression of human MCU and EMRE is sufficient to reconstitute uniporter pore activity in vivo.MICU1 and MICU2 operate together in the intermembrane space to sense calcium concentration and regulate the uniporter.Loss of uniporter activity can be tolerated in vivo in organisms including trypanosomes, worms and mice.Genetic studies in cells and in model organisms are converging on a key function for this channel in the coupling of cellular ATP consumption with its production (termed excitation–energetic coupling). The role of the channel in cell death and apoptosis remains controversial.Inherited mutations in the uniporter machinery have been identified in patients with neuromuscular disease.Next steps include using structural biology to gain mechanistic insights into the uniporter and investigating pathologies associated with the manipulation of uniporter activity, which may suggest a therapeutic strategy for targeting the uniporter.