Cytochrome c oxidase assembly in primates is sensitive to small evolutionary variations in amino acid sequence

Mol Biol Evol. 2000 Oct;17(10):1508-19. doi: 10.1093/oxfordjournals.molbev.a026250.


Respiring mitochondria require many interactions between nuclear and mitochondrial genomes. Although mitochondrial DNA (mtDNA) from the gorilla and the chimpanzee are able to restore oxidative phosphorylation in a human cell, mtDNAs from more distant primate species are functionally incompatible with human nuclear genes. Using microcell-mediated chromosome and mitochondria transfer, we introduced and maintained a functional orangutan mtDNA in a human nuclear background. However, partial oxidative phosphorylation function was restored only in the presence of most orangutan chromosomes, suggesting that human oxidative phosphorylation-related nuclear-coded genes are not able to replace many orangutan ones. The respiratory capacity of these hybrids was decreased by 65%-80%, and cytochrome c oxidase (COX) activity was decreased by 85%-95%. The function of other respiratory complexes was not significantly altered. The translation of mtDNA-coded COX subunits was normal, but their steady-state levels were approximately 10% of normal ones. Nuclear-coded COX subunits were loosely associated with mitochondrial membranes, a characteristic of COX assembly-defective mutants. Our results suggest that many human nuclear-coded genes not only cannot replace the orangutan counterparts, but also exert a specific interference at the level of COX assembly. This cellular model underscores the precision of COX assembly in mammals and sheds light on the nature of nuclear-mtDNA coevolutionary constraints.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Fusion
  • Cell Nucleus / genetics*
  • Chick Embryo
  • Electron Transport Complex IV / genetics*
  • Evolution, Molecular
  • Gorilla gorilla / genetics
  • Haplorhini / genetics*
  • Hominidae / genetics
  • Humans
  • Hybrid Cells
  • In Situ Hybridization, Fluorescence
  • Karyotyping
  • Mitochondria / enzymology*
  • Mitochondria / genetics*
  • Oxidative Phosphorylation
  • Pongo pygmaeus / genetics
  • Species Specificity


  • Electron Transport Complex IV