FIGURE 1.

Crucial regulators of Ca²⁺ homeostasis in mitochondria. For mitochondrial Ca²⁺ uptake, the major routes include mitochondrial Ca²⁺ uniporter (MCU), mitochondrial ryanodine receptor (mRYR), rapid mode of mitochondrial Ca²⁺ uptake (RaM), and mitochondrial calcium channel type 2 (mCa2). The most crucial regulatory subunits of MCU include mitochondrial calcium uptake 1, 2 (MICU1, MICU2) and essential MCU regulator (EMRE). For mitochondrial Ca²⁺ extrusion, the major routes include Na⁺/Ca²⁺/Li⁺ exchanger (NCLX), mitochondrial H⁺/Ca²⁺ exchanger (LETM1), and mitochondrial permeability transition pore (mPTP). Voltage-dependent anion channel (VDAC) is suggested to be the outer mitochondrial membrane (OMM) component of mPTP. Recently, ATP synthase has been confirmed to be the inner mitochondrial membrane (IMM) component of mPTP. There are still debates about whether mPTP is formed by ATP synthase dimer or monomer. Cyclophilin (Cyp) D is a crucial regulator of mPTP opening and interacts with ATP synthase through the oligomycin sensitivity-conferring protein (OSCP) subunit. As to Ca²⁺ retention in mitochondrial matrix, inorganic phosphate (Pi) helps sequester free Ca²⁺ in solid precipitates, which could serve as an MCU independent source of mitochondrial Ca²⁺ upon matrix acidification.