FIGURE 15-35 Movement of Ca²⁺ between the cytosol, mitochondrion, and endoplasmic reticulum. (a) The ER is the main intracellular storage depot for Ca²⁺. Binding of IP₃ to IP₃-gated Ca²⁺ channels (IP₃R) in the membrane of the endoplasmic reticulum releases Ca²⁺ into the cytosol (step 1a); binding also opens IP₃-gated Ca²⁺ channels in the mitochondria-associated membranes (MAMs) of the ER (step 1b). Step 2: VDAC channels in the outer mitochondrial membrane adjacent to MAMs are physically linked to IP₃Rs by the GRP75 protein; they efficiently pass the Ca²⁺ released from the MAMs into the intermembrane space. Step 3: The high concentration of Ca²⁺ in the intermembrane space induces the opening of MCUs or other Ca²⁺ channels in the inner membrane, resulting in the flow of Ca²⁺ into the mitochondrial matrix. Step 4: Over time, Ca²⁺ is released from the mitochondria by Ca²⁺/Na⁺ (NCLX) and Ca²⁺/H⁺ (HCX) antiporters in the inner membrane, then transferred into the cytosol through VDAC or other Ca²⁺ channels in the outer membrane. Finally, pumping of Ca²⁺ from the cytosol by ATP-powered Ca²⁺ pumps in the ER membrane (step 5) or plasma membrane restores the high ER Ca²⁺ and low cytosolic Ca²⁺ levels. (b) Model of the mitochondrial calcium uniporter complex. A multimer of MCU subunits forms the regulated Ca²⁺ pore. Additional subunits include the integral membrane protein EMRE and regulatory subunits MICU1 and MICU2. Ca²⁺ binding to the MICU subunits opens the MCU pore, resulting in the flow of the Ca²⁺ from the intermembrane space into the matrix. See M. Schäfer et al., 2014, Cell Tissue Res. 357:395 and K. Kamer and V. Mootha, 2015, Nat. Rev. Mol. Cell Biol. 16:545.