Evolution of cytochrome c oxidase subunit 4 in relation to hypoxia
Kocha, Katrinka Maria
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Cytochrome c oxidase (COX) is complex IV of the electron transport system, and catalyzes the reduction of molecular oxygen to water. It possesses ten nuclear-encoded subunits, the largest of which is COX4. Bayesian analysis suggests the isoform pair for this subunit arose early in vertebrate evolution, and tissue distribution of the COX4 paralogs is similar in mammals and teleosts: COX4-1 is ubiquitously transcribed while COX4-2 is present in large amounts only in brain and respiratory tissue. This subunit is of interest due to its apparent sensitivity to oxygen. During hypoxia, transcription switches from COX4-1 to COX4-2 in some mammalian tissues. However, questions remain about the regulation of this response as well as its pervasiveness across vertebrates. I investigated these uncertainties by measuring the transcriptional response of the COX4 paralogs to hypoxia in a variety of vertebrate models, and assessing the hypoxic induction of putative oxygen-responsive elements (HRE1, HRE2, and ORE) from candidate vertebrate species in a transfection experiment. I also examined the conservation of key elements of the COX4-2 gene and polypeptide in vertebrates. It was found that the hypoxia-responsiveness of COX4-2 may not be vital to the cellular response to hypoxia. COX4-1 transcripts remained in excess during hypoxia in all of the vertebrate models used with the exception of western painted turtle (Chrysemys picta), where COX4-2 transcripts remained in excess during control and hypoxic treatments. Only the HRE2 element from human COX4-2 was activated with hypoxic exposure, yet this along with the other features of the gene and polypeptide were not well conserved across mammals, and nearly absent outside of this lineage. These results provide evidence that COX4-2 may respond to hypoxia in only select few mammalian tissues, or that the function of this gene is not related to the cellular hypoxic response.