Evolution of the nuclear-encoded cytochrome oxidase subunits in vertebrates

Abstract

Vertebrate mitochondrial cytochrome c oxidase (COX) possesses 10 nuclear-encoded subunits. Six subunits have paralogs in mammals, but the origins and distribution of isoforms among vertebrates have not been analyzed. We used Bayesian phylogenetic analysis to interpret the origins of each subunit, inferring the roles of gene and genome duplications. The paralogous ancestries of five genes were identical throughout the major vertebrate taxa: no paralogs of COX6c and COX7c, two paralogs of COX4 and COX6a, and three paralogs of COX7a. Two genes had an extra copy in teleosts (COX5a, COX5b), and three genes had additional copies in mammals (COX6b, COX7b, COX8). Focusing on early vertebrates, we examined structural divergence and explored transcriptional profiles across zebrafish tissues. Quantitative transcript profiles revealed dramatic differences in transcript abundance for different subunits. COX7b and COX4 transcripts were typically present at very low levels, whereas COX5a and COX8 were in vast excess in all tissues. For genes with paralogs, two general patterns emerged. For COX5a and COX8, there was ubiquitous expression of one paralog, with the other paralog in lower abundance in all tissues. COX4 and COX6a shared a distinct expression pattern, with one paralog dominant in brain and gills and the other in muscles. The isoform profiles in combination with phylogenetic analyses show that vertebrate COX isoform patterns are consistent with the hypothesis that early whole genome duplications in basal vertebrates governed the isoform repertoire in modern fish and tetrapods, though more recent lineage-specific gene/genome duplications also play a role in select subunits.

Genomic insights into adaptation to high-altitude environments

“…Instead, analyses of sequence variation of subunit three of the mitochondrial COX gene (COX3) suggest that a single amino-acid substitution (Trp 116-Arg) may alter the interaction between subunits 1 (COX 1) and 3 (COX3) of the catalytic core of COX and this substitution likely contributes to the unique enzyme kinetics in barheaded geese. It is important to note that COX is a heteromeric enzyme that is composed of 10-12 subunits in birds (Kadenbach et al, 1991;Little et al, 2010). The authors only examined sequence variation in those subunits encoded by the mitochondrial genome (COX 1, 2 and 3), and hence it is still unknown whether sequence variation in nuclear-encoded COX subunits also contribute to the altered enzyme kinetics in bar-headed geese.…”

Coordination of cytochrome c oxidase gene expression in the remodelling of skeletal muscle

“…In a previous study on zebrafish (Little et al, 2010), we measured the transcript levels for all nuclear-encoded COX subunits in muscles (white muscle, heart), liver, brain and gills. In the present study on muscle, we focused on the single dominant subunit for each isoform, with the exception of COX6B, where transcripts of two paralogues (COX6B1 and COX6B2) were present at nearequivalent levels in warm zebrafish.…”

“…Of these five gene products, four are amongst the least abundant COX subunit transcripts. COX5A is one of the most abundant transcripts amongst the COX subunits in mammals (Nijtmans et al, 1998;Ugalde et al, 2002) and zebrafish (Little et al, 2010). Transcripts for COX4-1, COX6B1, COX6C and COX7C are among the least abundant of the subunits in zebrafish muscle (Little et al, 2010).…”

“…The mammalian paralogues are tissue-specific variants, with a testes-specific subunit that may be specialized to work with a testes-specific cytochrome c (Hüttemann et al, 2001;Weishaupt and Kadenbach, 1992). The evolutionary relationships between the two fish paralogues and the two mammalian paralogues are not clear (Little et al, 2010). If the fish variants differentially affect COX efficiency, as is the case with the mammalian variants, this might have important ramifications for metabolism in the thermal remodelling of muscle.…”

“…We focused on COX because of its critical role in oxidative phosphorylation (OXPHOS) (Villani and Attardi, 2000), the wealth of knowledge about the function of its individual subunits, and the distinctions between the repertoire of isoforms in fish and mammals (Little et al, 2010). Furthermore, our previous studies have shown that transcripts for COX subunits are present at considerably different levels in muscle (Little et al, 2010), presenting the possibility that a subset of subunits may exert greater control over the rate of synthesis of COX. We assessed transcript levels in three species of minnow (Cyprinidae) exposed to thermal challenges: zebrafish, goldfish and northern redbelly dace.…”