Oxidative phosphorylation: regulation and role in cellular and tissue metabolism.

Oxidative phosphorylation provides most of the ATP that higher animals and plants use to support life and is responsible for setting and maintaining metabolic homeostasis. The pathway incorporates three consecutive near equilibrium steps for moving reducing equivalents between the intramitochondrial [NAD+ ]/[NADH] pool to molecular oxygen, with irreversible reduction of oxygen to bound peroxide at cytochrome c oxidase determining the net flux. Net flux (oxygen consumption rate) is determined by demand for ATP, with feedback by the energy state ([ATP]/[ADP][Pi ]) regulating the pathway. This feedback affects the reversible steps equally and independently, resulting in the rate being coupled to ([ATP]/[ADP][Pi ])3 . With increasing energy state, oxygen consumption decreases rapidly until a threshold is reached, above which there is little further decrease. In most cells, [ATP] and [Pi ] are much higher than [ADP] and change in [ADP] is primarily responsible for the change in energy state. As a result, the rate of ATP synthesis, plotted against [ADP], remains low until [ADP] reaches about 30 μm and then increases rapidly with further increase in [ADP]. The dependencies on energy state and [ADP] near the threshold can be fitted by the Hill equation with a Hill coefficients of about -2.6 and 4.2, respectively. The homeostatic set point for metabolism is determined by the threshold, which can be modulated by the PO2 and intramitochondrial [NAD+ ]/[NADH]. The ability of oxidative phosphorylation to precisely set and maintain metabolic homeostasis is consistent with it being permissive of, and essential to, development of higher plants and animals.