Evolution of hypoxia responsive cytochrome c oxidase genes in vertebrates

Cytochrome c oxidase (COX) possesses ten nuclear‐encoded subunits, six of which possess isoforms in mammals. Bayesian analysis of vertebrate orthologs suggests independent origins for many of the subunits in fish versus mammals. Both COX4 paralogs in fish are orthologous with the corresponding mammalian genes, with similar tissue distributions: expression of COX4‐1 in muscle and COX4‐2 in respiratory tissue and brain. However, the fish COX4‐2 appears to lack the hypoxia‐responsiveness that typifies the mammalian orthologs. Oxygen conditions that trigger expression of hypoxia markers (e.g., vascular endothelial‐derived growth factor, lactate dehydrogenase) do not stimulate expression of COX4‐2 in (i) zebrafish exposed to 2% atmospheric oxygen (8h) or (ii) isolated zebrafish epithelial cells exposed to 2% or 0% oxygen (8 or 24h). Though yeast and mammals demonstrate a hypoxia‐responsive trigger for one of two COX4 paralogs, the hypoxia‐responsive genes in yeast and mammals are not orthologous. Further studies of the distribution of the hypoxia‐responsiveness amongst vertebrates give insight into the evolutionary origins of the mammalian response. Funded by NSERC Canada (CDM).