**7. Cytochrome oxidase (complex IV)**

To date, 14 phosphorylation sites have been mapped on complex IV [39]. Tyrosine phosphorylation of the specific subunits of complex IV can lead to both inhibition and activation of complex IV activity [39, 40]. Bender and Kadenbach have shown phosphorylation of complex IV subunits I, II/III, and Vb *in vitro* [41]. cAMP-dependent phosphorylation of Y304 on the catalytic subunit I inhibits, whereas tyrosine phosphorylation of subunit II by c-Src kinase activates complex IV [41, 42]. The latter event is required for the normal function of cells, which are dependent on the efficient production of ATP to maintain their functions [42]. Interestingly, phosphorylation of the same subunit by the receptor tyrosine kinase ERBb2 decreases the activity of complex IV and mitochondrial respiration [43, 44]. Complex IV activity is inhibited in a time-dependent manner after myocardial ischemia, which stimulates multiple phosphorylations of complex IV: (1) subunit I on S115 and S116, (2) subunit IVi1 on T52, and (3) subunit Vb on S40 in the heart [38, 45]. These inhibitory phosphorylations are mediated by PKA and inhibition of PKA reduces I/R injury to the myocardial tissue [45]. Phosphorylation of subunit IV-1 on S58 by PKA increases the activity of complex IV by preventing allosteric inhibition of complex IV by ATP [46]. It was proposed that phosphorylation of S58 switches mitochondrial metabolism from energy utilization to energy storage in pathological conditions including I/R-induced injury [46].
