Oxidative Phosphorylation
Overview
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate (ATP). This process takes place in eukaryotes in the mitochondria, and in prokaryotes on the cell membrane. It is the final stage of cellular respiration, following glycolysis and the citric acid cycle.
Biochemical Process
Oxidative phosphorylation involves the transfer of electrons from electron donors to electron acceptors such as oxygen, in redox reactions. These reactions release energy, which is used to form ATP. This process is carried out by a series of protein complexes within the mitochondrion, collectively known as the electron transport chain.
Electron Transport Chain
The electron transport chain is composed of four protein complexes: Complex I (NADH dehydrogenase), Complex II (succinate dehydrogenase), Complex III (cytochrome c reductase), and Complex IV (cytochrome c oxidase). These complexes are embedded in the inner mitochondrial membrane, and work together to transport electrons and pump protons (H+) across the membrane.
Complex I
Complex I, also known as NADH dehydrogenase, is the first complex in the electron transport chain. It oxidizes NADH, releasing two electrons and a proton. The electrons are transferred to a molecule of ubiquinone, reducing it to ubiquinol. This process also pumps four protons across the inner mitochondrial membrane, contributing to the proton gradient.
Complex II
Complex II, or succinate dehydrogenase, is unique among the electron transport chain complexes in that it is also part of the citric acid cycle. It catalyzes the oxidation of succinate to fumarate, and transfers the resulting electrons to ubiquinone, reducing it to ubiquinol.
Complex III
Complex III, or cytochrome c reductase, oxidizes ubiquinol back to ubiquinone, and transfers the electrons to cytochrome c, a small soluble protein found in the intermembrane space of the mitochondria. This process also pumps protons across the membrane, further contributing to the proton gradient.
Complex IV
The final complex in the electron transport chain, Complex IV or cytochrome c oxidase, transfers the electrons from cytochrome c to oxygen, the final electron acceptor. This process also pumps protons across the membrane, and the oxygen is reduced to water.
ATP Synthesis
The proton gradient created by the electron transport chain is used to power ATP synthesis. This process is carried out by ATP synthase, a large protein complex embedded in the inner mitochondrial membrane. As protons flow back across the membrane, down their concentration gradient, they pass through ATP synthase, which uses the energy to phosphorylate ADP, producing ATP.
Regulation
The rate of oxidative phosphorylation is tightly regulated by the availability of substrates (NADH and FADH2), and by the demand for ATP. When ATP demand is high, more NADH is oxidized, and more protons are pumped across the membrane, increasing the rate of ATP synthesis. Conversely, when ATP demand is low, NADH oxidation and proton pumping are reduced, slowing ATP synthesis.
Clinical Significance
Defects in oxidative phosphorylation can lead to a variety of diseases, collectively known as mitochondrial diseases. These can be caused by mutations in the mitochondrial DNA, which encodes some of the proteins involved in oxidative phosphorylation, or in the nuclear DNA, which encodes the rest. Symptoms can vary widely, but often involve the nervous system and muscles, which have high energy demands.