Oxidative phosphorylation, mitochondrial proton cycling, free-radical production and aging

The electron transport chain on the inner mitochondrial membrane serves to pump protons into the intermembrane space, from where they can return across the membrane driving generation of either ATP or heat. Oxygen radical species are generated when molecules of oxygen promiscuously interact with electron donors outside of the final complex IV in the electron transport chain. Two sites have been identified as the major producers of superoxide - complex I and complex III, which generate radicals on the matrix and cytosolic sides of the inner membrane, respectively. Debate continues over how much consumed oxygen generates free radicals and which of these sites is quantitatively most significant. Free-radical scavenging mechanisms are present within the matrix and also in the cytosol to ameliorate the potential damage that radical oxygen species might cause to macromolecules. Production of free radicals at complex III is dependent on the mitochondrial membrane potential (ΔΨ) and therefore expression levels of the uncoupling proteins and other factors that influence proton leakage across the membrane (such as respiration state and membrane lipid saturation levels). A simple link between rate of energy expenditure, free-radical production, oxidative damage and lifespan is not expected.