Relationships of some major bioenergetic pools in the neuronal cytosol and mitochondria and their regulation. (A) This schematic shows key bioenergetic processes as waterwheels or gears as well as their interaction with three major bioenergetic reservoirs: the membrane potential across the mitochondrial inner membrane (Δψ_m) and the related electrochemical gradient for protons across the mitochondrial inner membrane (Δμ_H); the mitochondrial NADH/NAD⁺ redox; and the cytosolic NADH/NAD⁺ redox. Both in the mitochondrion and cytosol, ADP and Ca²⁺ are the proximal signals for metabolic demand. As explained in the text, both ADP and Ca²⁺ entry into mitochondria contribute to mitochondrial depolarization; this allows the ETC to consume mitochondrial NADH and O₂ and to restore the mitochondrial Δμ_H. (B) The impact of neuronal stimulation on these pathways as measured experimentally by monitoring NAD(P)H autofluorescence is diagrammed. The consumption of mitochondrial NADH leads to the dip in mitochondrial NADH. The increase in mitochondrial [Ca²⁺] stimulates the TCA cycle and produces an overshoot in NADH production. In the cytosol, NADH/NAD⁺ redox is controlled by glycolysis (which increases NADH), the MAS, which decreases NADH, and the LDH reaction, which can run in either direction.