Molecular regulation of MCU: Implications in physiology and disease

Ca ²⁺ flux across the inner mitochondrial membrane (IMM) regulates cellular bioenergetics, intra-cellular cytoplasmic Ca ²⁺ signals, and various cell death pathways. Ca ²⁺ entry into the mitochondria occurs due to the highly negative membrane potential (ΔΨ _m ) through a selective inward rectifying MCU channel. In addition to being regulated by various mitochondrial matrix resident proteins such as MICUs, MCUb, MCUR1 and EMRE, the channel is transcriptionally regulated by upstream Ca ²⁺ cascade, post transnational modification and by divalent cations. The mode of regulation either inhibits or enhances MCU channel activity and thus regulates mitochondrial metabolism and cell fate.