Molecular machinery regulating mitochondrial calcium levels: The nuts and bolts of mitochondrial calcium dynamics

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 (Ca²⁺) dynamics. Mitochondrial Ca²⁺ regulates three Ca²⁺-sensitive dehydrogenase enzymes involved in tricarboxylic acid cycle (TCA) cycle thereby directly controlling ATP synthesis. On the other hand, excessive Ca²⁺ 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 Ca²⁺ concentration. Since cells can neither synthesize nor metabolize Ca²⁺, it is the dynamic interplay of Ca²⁺ handling proteins involved in mitochondrial Ca²⁺ influx and efflux that take the center stage. In this review we would discuss the key molecular machinery regulating mitochondrial Ca²⁺ concentration. We would focus on the channel complex involved in bringing Ca²⁺ into mitochondrial matrix i.e. Mitochondrial Ca²⁺ Uniporter (MCU) and its key regulators Mitochondrial Ca²⁺ Uptake proteins (MICU1, 2 and 3), MCU regulatory subunit b (MCUb), Essential MCU Regulator (EMRE) and Mitochondrial Ca²⁺ Uniporter Regulator 1 (MCUR1). Further, we would deliberate on major mitochondrial Ca²⁺ efflux proteins i.e. Mitochondrial Na⁺/Ca²⁺/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.