Box 2. Box 2 Fuel metabolism and oxidative phosphorylation

Energy is released when food is combusted to carbon dioxide and water. The organism controls this combustion such that energy can be channelled to perform work within the cell. This is accomplished by enzymatically controlled fuel metabolism and mitochondrial oxidative phosphorylation, step-by-step processes in which a portion of the energy content of fuels (fat, carbohydrate and protein) is converted to ATP. Energy stored in the form of ATP is then used to perform biological work within the cell.

Fuel metabolism and oxidative phosphorylation represent a series of reactions that are shown schematically in Fig. 2. The key task of the cell is to match rates of ATP production to rates of ATP consumption. This is made more complex by the fact that sites of ATP production and ATP use are spatially distinct within cells. It was suggested many years ago that ADP, the by-product of ATP use, controls rates of ATP production⁸⁴. This was based upon the observation that addition of ADP to isolated mitochondria stimulates fuel oxidation, mitochondrial oxygen consumption and ATP synthesis. Such regulation provided a mechanism whereby rates of ATP production might be matched to rates of ATP utilization. The molecular mechanism for this regulation was explained by the chemiosmotic hypothesis of Peter Mitchell, to whom the Nobel prize in chemistry was awarded in 1978⁸⁵.

Metabolism of fuel leads to the production of NADH and FADH₂, which in turn donate electrons to the electron transport chain ( Fig. 2). As electrons move down through the complexes of the electron transport chain, protons are pumped outside of the mitochondrial inner membrane, creating an electrochemical potential gradient (_H ⁺). Protons then re-enter the mitochondrial matrix through F ₀/F₁-ATP synthase in a reaction that is linked tightly to the synthesis of ATP from ADP. If ADP is unavailable, protons are unable to enter through ATP synthase. The three key features of the chemiosmotic hypothesis are as follows: (1) energy derived from fuel oxidation and mitochondrial respiration is converted to _H⁺; (2) when ADP is available, protons enter via ATP synthase, converting ADP to ATP; and (3) elevated _H⁺ puts 'backpressure' on proton pumps in the electron transport chain, inhibiting further fuel oxidation. Thus, when ADP is unavailable, fuel oxidation and mitochondrial respiration decreases.

Although the model has many compelling features, several observations indicate that the chemiosmotic hypothesis, when applied to the in vivo state, is an oversimplification and that additional layers of regulation must exist. Perhaps the strongest argument comes from observations of increased mitochondrial respiration in the absence of proportional increases in ADP^{86, 87}. Such observations have led to the proposal that rates of ATP production increase simultaneously with rates of ATP utilization, possibly as a result of a common activator such as intracellular calcium levels^{88, 89}. The mechanism by which such regulation allows precise matching of ATP production and utilization rates, however, is presently unknown.