Figure 4.

ER Ca²⁺ release stimulates oxidative phosphorylation. Mitochondria-associated membranes (MAMs) are points of contact between the ER and mitochondria that have various functions, including Ca²⁺ signaling between the two organelles. MAMs are stabilized by protein pairs that bind to each other, serving as molecular tethers. The VAPB-PTPIP51 and MFN1/2-MFN2 binding pairs are two such examples. IP₃R exists in MAMs and is linked via GPR75 to porin 1, which is found in the outer mitochondrial membrane (OMM). In this arrangement, IP₃-mediated Ca²⁺ release enables efficient transfer of Ca²⁺ into the intermembrane space, where the low-affinity mitochondrial Ca²⁺ uniporter (MCU) can be overcome by concentrated Ca²⁺ microdomains. Ca²⁺ that enters the mitochondrial matrix stimulates the tricarboxylic acid (TCA) cycle by activating pyruvate-dehydrogenase (PDH), isocitrate-dehydrogenase (IDH), and alpha-ketoglutarate dehydrogenase (KGDH). The TCA cycles produces the reducing equivalents (NADH and FADH₂) that power the electron transport chain (ETC), which produces a protein gradient in the intermembrane space. Protons (H⁺) flow down their concentration gradient through ATP synthase leading to biogenesis of ATP.