Three-dimensional representation of variable amino acid in mammalian cytochrome c oxidase subunits I, II and III. Sites within COX subunits showing a high number of amino acid properties positive selected [see Additional file 1, Fig. S4] mapped into the bovine structure (pdb code: 1V54 ). Side-chains with over 5 amino acid properties positive selected are presented as black spheres. Sites showing particular mutational trends are shown in white (see text for further details). Mutations in sites shown in red have been related to exercise intolerance in humans (see Table 1). Prosthetic groups are presented as grey spheres. The side chains of the hydrophobic loop in COXII that is involved in cytochrome c docking and electron transfer are depicted as sticks together with their van der Waals surface. The nuclear encoded subunits of Complex IV are shown as in silver. MM: mitochondria matrix; IM: intermembrane space.