Regulatory Complexity of Cytochrome c Oxidase and Its Defective Manifestation in Mitochondrial Diseases

The expenditure of energy in different cells and tissues of mammalian organisms varies, depending on the type of tissue, its developmental stage, and various extracellular signals, like growth factors, hormones, neurotransmitters and metabolites. Because about 95% of the energy (ATP) is synthesized in mitochondria by oxidative phosphorylation, the rate of cellular energy synthesis is roughly proportional to the rate of cell respiration. The reduction of oxygen to water is catalyzed by cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain (complex IV). Like two other enzyme complexes of the respiratory chain, the NADH-dehydrogenase (complex I) and the ubiquinone-cy- tochrome c oxidoreductase (complex III), cytochrome c oxidase converts the redox energy into a proton electrochemical gradient (ΔμH+) across the inner mitochondrial membrane, which is used by the ATP-synthase to drive the endergonic synthesis of ATP from ADP and phosphate (Fig. 1). The activity of cytochrome c oxidase can be principally regulated by three different mechanisms: 1. By isosteric effectors, i.e. the concentration of substrates, namely the concentrations of reduced cytochrome c and oxygen [1], and the ΔμH+ across the inner mitochondrial membrane [2,3]. 2. By allosteric effectors (for review see [4]). Recently ATP and ADP could be identified as allosteric effectors of cytochrome c oxidase (see below). 3. By the cellular enzyme concentration, which is varied by the rate of gene expression and the rate of enzyme degradation.