Fig. 9: Schematic representation of IMS Ca²⁺ homeostasis as fundamental regulator of resting cytosolic and mitochondrial metabolism.

IMS Ca²⁺ modulates citrin/malate-aspartate shuttle activity with basal IMS Ca²⁺ level being set at around 100 nM by ER-mitochondrial Ca²⁺ flux. Main processes that are regulated by basal IMS Ca²⁺ driven MAS activity are shown with blue arrows, and consist of MAS recycling NAD⁺ for glycolysis and glycolytic products going through TCA cycle and ETC. Disruption of this Ca²⁺ homeostasis leads to metabolic rewiring, shown here with red arrows and text. As a result, cells switch to aerobic glycolysis, rely on LDH for NADH recycling, and have reduced OxPhos. OAA, oxaloacetate; OGC, oxoglutarate/malate carrier protein.