Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease

The mitochondrial calcium (_mCa²⁺) uniporter channel (mtCU) resides at the inner mitochondrial membrane and is required for Ca²⁺ to enter the mitochondrial matrix. The mtCU is essential for cellular function, as _mCa²⁺ regulates metabolism, bioenergetics, signaling pathways and cell death. _mCa²⁺ uptake is primarily regulated by the MICU family (MICU1, MICU2, MICU3), EF-hand-containing Ca²⁺-sensing proteins, which respond to cytosolic Ca²⁺ concentrations to modulate mtCU activity. Considering that mitochondrial function and Ca²⁺ signaling are ubiquitously disrupted in cardiovascular disease, mtCU function has been a hot area of investigation for the last decade. Here we provide an in-depth review of MICU-mediated regulation of mtCU structure and function, as well as potential mtCU-independent functions of these proteins. We detail their role in cardiac physiology and cardiovascular disease by highlighting the phenotypes of different mutant animal models, with an emphasis on therapeutic potential and targets of interest in this pathway.