Chapter 18:  Oxidative Phosphorylation

The NADH and FADH₂ formed in glycolysis, fatty acid oxidation, and the citric acid cycle are energy-rich molecules because each contains a pair of electrons having a high transfer potential. When these electrons are used to reduce molecular oxygen to water, a large amount of free energy is liberated, which can be used to generate ATP. Oxidative phosphorylation is the process in which ATP is formed as a result of the transfer of electrons from NADH or FADH₂ to O₂ by a series of electron carriers. This process, which takes place in mitochondria, is the major source of ATP in aerobic organisms (Figure 18.1). For example, oxidative phosphorylation generates 26 of the 30 molecules of ATP that are formed when glucose is completely oxidized to CO₂ and H₂O.

Oxidative phosphorylation is conceptually simple and mechanistically complex. Indeed, the unraveling of the mechanism of oxidative phosphorylation has been one of the most challenging problems of biochemistry. The flow of electrons from NADH or FADH₂ to O₂ through protein complexes located in the mitochondrial inner membrane leads to the pumping of protons out of the mitochondrial matrix. The resulting uneven distribution of protons generates a pH gradient and a transmembrane electrical potential that creates a proton-motive force. ATP is synthesized when protons flow back to the mitochondrial matrix through an enzyme complex. Thus, the oxidation of fuels and the phosphorylation of ADP are coupled by a proton gradient across the inner mitochondrial membrane (Figure 18.2).

Oxidative phosphorylation is the culmination of a series of energy transformations that are called cellular respiration or simply respiration in their entirety. First, carbon fuels are oxidized in the citric acid cycle to yield electrons with high transfer potential. Then, this electron-motive force is converted into a proton-motive force and, finally, the proton-motive force is converted into phosphoryl transfer potential. The conversion of electron-motive force into proton-motive force is carried out by three electron-driven proton pumps—NADH-Q oxidoreductase, Q-cytochrome c oxidoreductase, and cytochrome c oxidase. These large transmembrane complexes contain multiple oxidation-reduction centers, including quinones, flavins, iron-sulfur clusters, hemes, and copper ions. The final phase of oxidative phosphorylation is carried out by ATP synthase, an ATP-synthesizing assembly that is driven by the flow of protons back into the mitochondrial matrix. Components of this remarkable enzyme rotate as part of its catalytic mechanism. Oxidative phosphorylation vividly shows that proton gradients are an interconvertible currency of free energy in biological systems.