Abstract
Mitochondria play vital role in regulating the cellular energetics and metabolism. Further, it is a signaling hub for cell survival and apoptotic pathways. One of the key determinants that calibrate both cellular energetics and survival functions is mitochondrial calcium (Ca(2+)) dynamics. Mitochondrial Ca(2+) regulates three Ca(2+)-sensitive dehydrogenase enzymes involved in tricarboxylic acid cycle (TCA) cycle thereby directly controlling ATP synthesis. On the other hand, excessive Ca(2+) concentration within the mitochondrial matrix elevates mitochondrial reactive oxygen species (mROS) levels and causes mitochondrial membrane depolarization. This leads to opening of the mitochondrial permeability transition pore (mPTP) and release of cytochrome c into cytosol eventually triggering apoptosis. Therefore, it is critical for cell to maintain mitochondrial Ca(2+) concentration. Since cells can neither synthesize nor metabolize Ca(2+), it is the dynamic interplay of Ca(2+) handling proteins involved in mitochondrial Ca(2+) influx and efflux that take the center stage. In this review we would discuss the key molecular machinery regulating mitochondrial Ca(2+) concentration. We would focus on the channel complex involved in bringing Ca(2+) into mitochondrial matrix i.e. Mitochondrial Ca(2+) Uniporter (MCU) and its key regulators Mitochondrial Ca(2+) Uptake proteins (MICU1, 2 and 3), MCU regulatory subunit b (MCUb), Essential MCU Regulator (EMRE) and Mitochondrial Ca(2+) Uniporter Regulator 1 (MCUR1). Further, we would deliberate on major mitochondrial Ca(2+) efflux proteins i.e. Mitochondrial Na(+)/Ca(2+)/Li(+) exchanger (NCLX) and Leucine zipper EF hand-containing transmembrane1 (Letm1). Moreover, we would highlight the physiological functions of these proteins and discuss their relevance in human pathophysiology. Finally, we would highlight key outstanding questions in the field.