ZFIN ID: ZDB-PUB-141219-10
Evolution of the oxygen sensitivity of cytochrome c oxidase subunit 4
Kocha, K.M., Reilly, K., Porplycia, D.S., McDonald, J., Snider, T., Moyes, C.D.
Date: 2015
Source: American journal of physiology. Regulatory, integrative and comparative physiology   308(4): R305-20 (Journal)
Registered Authors: Kocha, Katrinka
Keywords: none
MeSH Terms:
  • Adaptation, Physiological
  • Adenosine Triphosphate/metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Hypoxia
  • Cell Line
  • Conserved Sequence
  • Cysteine
  • Disulfides/metabolism
  • Electron Transport Complex IV/chemistry
  • Electron Transport Complex IV/genetics
  • Electron Transport Complex IV/metabolism*
  • Evolution, Molecular*
  • Fish Proteins/chemistry
  • Fish Proteins/genetics
  • Fish Proteins/metabolism*
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Isoenzymes
  • Mice
  • Molecular Sequence Data
  • Oxygen/metabolism*
  • Phylogeny
  • Promoter Regions, Genetic
  • RNA, Messenger/metabolism
  • Reptilian Proteins/chemistry
  • Reptilian Proteins/genetics
  • Reptilian Proteins/metabolism*
  • Species Specificity
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
PubMed: 25519729 Full text @ Am. J. Physiol. Regul. Integr. Comp. Physiol.
Vertebrates possess two paralogs of cytochrome oxidase subunit 4: a ubiquitous COX4-1 and a hypoxia-linked COX4-2. Mammalian COX4-2 is thought to have a special role in fine-tuning metabolism in relation to oxygen levels, conferred through both structural differences in the subunit protein structure and regulatory differences in the gene. The ratio of COX4-2 / 4-1 mRNA are generally low in mammals, but this ratio was higher in fish and reptiles, particularly turtles. The COX4-2 gene appeared unresponsive to low oxygen in non-mammalian models (zebrafish, goldfish, tilapia, anoles, turtles) and fish cell lines. Reporter genes constructed from the amphibian and reptile homologues of the mammalian oxygen responsive elements and hypoxia responsive elements did not respond to low oxygen. Unlike the rodent ortholog, the promoter of goldfish COX4-2 did not respond to hypoxia or anoxia. The protein sequences of the COX4-2 peptide showed that the disulfide bridge seen in the human and rodent orthologs would be precluded in other mammalian lineages and lower vertebrates, all of which lack the requisite pair of cysteines. The coordinating ligands of the ATP binding site are largely conserved across mammals and reptiles, but in Xenopus and fish, sequence variations may disrupt the ability of the protein to bind ATP at this site. Collectively, these results suggest that many of the genetic and structural features of COX4-2 that impart responsiveness and benefits in hypoxia may be restricted to the Euarchontoglires lineage that includes primates, lagomorphs and rodents.