Regulation of mitochondrial respiration and ATP synthesis via cytochrome c oxidase

Cytochrome c oxidase (COX) represents the main oxygen acceptor for respiration of aerobic organisms. The energy of respiration is stored via oxidative phosphorylation (OxPhos) in ATP, the general energy intermediate in living cells, or released as heat. During evolution from bacteria to mammals the complexity of OxPhos regulation increased at COX by increasing the number of subunits, by expression of subunit isoforms which are specific for tissues, developmental stages, and oxygen concentrations, and by reversible phosphorylation. The essential function of the “supernumerary” subunits became evident in patients with mitochondrial disease related to COX-deficiency, based on mutations in these subunit genes. While the basic regulation of energy transduction in OxPhos was explained by the Mitchell theory, an additional regulation of respiration and ATP synthesis was discovered in eukaryotic organisms, based on reversible and membrane potential-independent inhibition of COX activity at high ATP/ADP ratios. So far, only some of the complex regulatory functions of nuclear-encoded subunits were uncovered.