A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy

Am J Hum Genet. 1999 Oct;65(4):1030-9. doi: 10.1086/302590.


We report the first missense mutation in the mtDNA gene for subunit II of cytochrome c oxidase (COX). The mutation was identified in a 14-year-old boy with a proximal myopathy and lactic acidosis. Muscle histochemistry and mitochondrial respiratory-chain enzymology demonstrated a marked reduction in COX activity. Immunohistochemistry and immunoblot analyses with COX subunit-specific monoclonal antibodies showed a pattern suggestive of a primary mtDNA defect, most likely involving CO II, for COX subunit II (COX II). mtDNA-sequence analysis demonstrated a novel heteroplasmic T-->A transversion at nucleotide position 7,671 in CO II. This mutation changes a methionine to a lysine residue in the middle of the first N-terminal membrane-spanning region of COX II. The immunoblot studies demonstrated a severe reduction in cross-reactivity, not only for COX II but also for the mtDNA-encoded subunit COX III and for nuclear-encoded subunits Vb, VIa, VIb, and VIc. Steady-state levels of the mtDNA-encoded subunit COX I showed a mild reduction, but spectrophotometric analysis revealed a dramatic decrease in COX I-associated heme a3 levels. These observations suggest that, in the COX protein, a structural association of COX II with COX I is necessary to stabilize the binding of heme a3 to COX I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis, Lactic / enzymology
  • Acidosis, Lactic / genetics
  • Acidosis, Lactic / metabolism
  • Acidosis, Lactic / pathology
  • Adolescent
  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Base Sequence
  • Blotting, Western
  • Cell Nucleus / enzymology
  • Cell Respiration
  • Cells, Cultured
  • Cytochrome-c Oxidase Deficiency*
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex IV / chemistry*
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Enzyme Stability
  • Heme / analogs & derivatives*
  • Heme / metabolism
  • Holoenzymes / chemistry
  • Holoenzymes / deficiency
  • Holoenzymes / genetics
  • Holoenzymes / metabolism
  • Humans
  • Immunohistochemistry
  • Male
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Models, Molecular
  • Molecular Sequence Data
  • Muscles / enzymology
  • Muscles / metabolism
  • Muscles / pathology
  • Muscular Diseases / enzymology
  • Muscular Diseases / genetics*
  • Muscular Diseases / metabolism
  • Muscular Diseases / pathology
  • Mutation, Missense / genetics*
  • Photolysis
  • Polarography
  • Protein Structure, Quaternary
  • Sequence Alignment


  • DNA, Mitochondrial
  • Holoenzymes
  • heme a
  • Heme
  • cytochrome C oxidase subunit II
  • Electron Transport Complex IV