Abstract
Among the mechanisms that fine‐tune cytochrome c oxidase (COX) levels/activities is an oxygen‐dependent switch of paralogs for subunit 4. COX4‐1 is constitutively expressed in most tissues; COX4‐2 predominates in brain and lung and is induced by hypoxia in other tissues. Though there is considerable evidence that this isoform switch has advantages in COX regulation under energetic stress, the evolutionary origins of the adaptation are unclear. All vertebrates possess single gene copies of both orthologs, though birds lack a functional COX4‐2 gene. Mammals, amphibians and reptiles display considerable diversity in the distribution, degeneracy and efficacy of canonical hypoxia‐responsive elements (HRE) and oxygen‐responsive elements (ORE). Fish display mammalian‐like tissue expression profiles of COX4‐1 and COX4‐2, but we find no evidence that COX4‐2 is hypoxia responsive; fish and fish cells do not alter COX4‐2 expression under hypoxia or anoxia, and their proximal promoters lack HRE or ORE elements homologous to the human gene. These studies suggest that the COX4‐2 paralog is near ubiquitous in vertebrates, but its oxygen responsiveness is perhaps limited to mammals. Even in mammals, its oxygen sensitivity differs among tissues and between cancer lines. Funded by NSERC Canada.
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