Electron Transport System and Oxidative Phosphorylation

Glycolysis, the link reaction and the TCA cycle, taken together, generate only a small amount of ATP directly, by substrate-level phosphorylation; what they generate in much greater abundance is a large pool of reduced coenzymes -- NADH and FADH2 -- each carrying a pair of high-energy electrons captured, ultimately, from the original glucose molecule. It is the electron transport system (ETS), embedded in the inner mitochondrial membrane, that extracts the energy from these electrons and uses it to generate the great majority of the ATP that aerobic respiration produces, through a process called oxidative phosphorylation.

The inner mitochondrial membrane is thrown into numerous folds called cristae specifically to maximise the surface area available for this system, and it carries a series of large, membrane-embedded protein complexes, conventionally numbered Complex I through Complex IV, together with two smaller, mobile electron carriers, ubiquinone (coenzyme Q) and cytochrome c, that ferry electrons between the fixed complexes. NADH delivers its pair of electrons to Complex I (NADH dehydrogenase); FADH2, generated at a later point in the sequence and carrying somewhat lower-energy electrons, delivers its electrons instead to Complex II, bypassing Complex I altogether. From either entry point, the electrons are passed onward, via ubiquinone, to Complex III (the cytochrome bc1 complex) and then, via cytochrome c, to Complex IV (cytochrome c oxidase), where they are finally transferred to molecular oxygen -- the terminal electron acceptor of the entire chain -- combining with oxygen and protons to form water. It is this final step, and only this step, that actually requires oxygen, and it is why respiration in its presence is described as aerobic.

As electrons pass through Complexes I, III and IV, the energy released at each step is used to actively pump protons (hydrogen ions, H+) out of the mitochondrial matrix and across the inner membrane into the narrow intermembrane space, progressively building up a much higher concentration of protons outside the matrix than within it. This proton concentration gradient, together with the associated difference in electrical charge across the membrane, together constitute what is called the proton-motive force, or electrochemical gradient.

According to the chemiosmotic hypothesis, first proposed by Peter Mitchell, it is this proton gradient -- not the electron-transport steps themselves -- that directly drives ATP synthesis. Protons that have accumulated in the intermembrane space can re-enter the matrix only through a specific channel provided by a further large enzyme complex, ATP synthase (sometimes called Complex V, or, when seen as small stalked particles studding the inner face of the cristae under the electron microscope, oxysomes or F1 particles). As protons flow back down their concentration gradient through ATP synthase, the energy released drives the enzyme's rotary catalytic mechanism, which phosphorylates ADP to ATP using inorganic phosphate -- the process, coupling the flow of protons to ATP synthesis, that gives oxidative phosphorylation its name. …