The enzyme cytochrome c oxidase or Complex IV, (was EC 1.9.3.1, now reclassified as a translocase EC 7.1.1.9) is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.It is the last enzyme in the respiratory electron transport chain of cells located in the membrane. It receives an electron from each of four cytochrome c molecules and transfers them to one oxygen molecule and four protons, producing two molecules of water. In addition to binding the four protons from the inner aqueous phase, it transports another four protons across the membrane, increasing the transmembrane difference of proton electrochemical potential, which the ATP synthase then uses to synthesize ATP. Structure
The complex
The complex is a large integral membrane protein composed of several metal prosthetic sites and 14  protein subunits in mammals. In mammals, eleven subunits are nuclear in origin, and three are synthesized in the mitochondria. The complex contains two hemes, a cytochrome a and cytochrome a3, and two copper centers, the CuA and CuB centers. In fact, the cytochrome a3 and CuB form a binuclear center that is the site of oxygen reduction. Cytochrome c, which is reduced by the preceding component of the respiratory chain (cytochrome bc1 complex, Complex III), docks near the CuA binuclear center and passes an electron to it, being oxidized back to cytochrome c containing Fe3+. The reduced CuA binuclear center now passes an electron on to cytochrome a, which in turn passes an electron on to the cytochrome a3>-CuB binuclear center.
Among the many classified mitochondrial diseases, those involving dysfunctional COX assembly are thought to be the most severe.The vast majority of COX disorders are linked to mutations in nuclear-encoded proteins referred to as assembly factors, or assembly proteins. These assembly factors contribute to COX structure and functionality, and are involved in several essential processes, including transcription and translation of mitochondrion-encoded subunits, processing of preproteins and membrane insertion, and cofactor biosynthesis and incorporation.Currently, mutations have been identified in seven COX assembly factors: SURF1, SCO1, SCO2, COX10, COX15, COX20, COA5 and LRPPRC. Mutations in these proteins can result in altered functionality of sub-complex assembly, copper transport, or translational regulation. Each gene mutation is associated with the etiology of a specific disease, with some having implications in multiple disorders. Disorders involving dysfunctional COX assembly via gene mutations include Leigh syndrome, cardiomyopathy, leukodystrophy, anemia, and sensorineural deafness. Histochemistry
The increased reliance of neurons on oxidative phosphorylation for energy facilitates the use of COX histochemistry in mapping regional brain metabolism in animals, since it establishes a direct and positive correlation between enzyme activity and neuronal activity. This can be seen in the correlation between COX enzyme amount and activity, which indicates the regulation of COX at the level of gene expression. COX distribution is inconsistent across different regions of the animal brain, but its pattern of its distribution is consistent across animals. This pattern has been observed in the monkey, mouse, and calf brain. One isozyme of COX has been consistently detected in histochemical analysis of the brain.