Metabolic consequences of a novel missense mutation of the mtDNA CO I gene

Hum Mol Genet. 2002 Aug 1;11(16):1797-805. doi: 10.1093/hmg/11.16.1797.


We have identified a novel heteroplasmic C6489A missense mutation in the mitochondrial DNA (mtDNA) CO I gene encoding the cytochrome c oxidase (COX) subunit I in a 17-year-old girl with epilepsia partialis continua. This point mutation leads to an exchange of the highly conserved Leu196 to Ileu196. Muscle biopsy showed in single fibers decreased COX activity and lowered binding of COX antibodies, indicating decreased stability of the mutated enzyme. The analysis of blood mtDNA revealed about 30% mutant mtDNA in the patients blood but about 90% mutant mtDNA in the blood of two non-affected family members. Quantitative analysis of the mutation gene dose effect on COX activity on single muscle fiber level revealed a very high threshold-a COX deficiency was observed only in fibers containing >95% mutant mtDNA. In apparent contrast to this high mutation gene dose threshold, in vivo investigations of mitochondrial function in saponin-permeabilized muscle fibers of the index patient containing approximately 90% mutated mtDNA showed decreased maximal rates of respiration and an increased sensitivity of fiber respiration to cyanide. This is due to a 2-fold increase of COX flux control on muscle fiber respiration and a 30% decrease of COX metabolic threshold, supporting the concept of tight COX control of oxidative phosphorylation in skeletal muscle.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Conserved Sequence
  • Cytochrome-c Oxidase Deficiency / complications
  • Cytochrome-c Oxidase Deficiency / enzymology*
  • Cytochrome-c Oxidase Deficiency / genetics*
  • DNA / genetics
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics*
  • Drug Resistance
  • Electron Transport Complex IV / genetics*
  • Electron Transport Complex IV / metabolism*
  • Enzyme Stability
  • Epilepsy, Partial, Motor / drug therapy
  • Epilepsy, Partial, Motor / enzymology*
  • Epilepsy, Partial, Motor / etiology
  • Epilepsy, Partial, Motor / genetics*
  • Female
  • Humans
  • Mitochondria, Muscle / enzymology
  • Molecular Sequence Data
  • Muscle, Skeletal / enzymology
  • Mutation, Missense*
  • Oxidative Phosphorylation
  • Sequence Homology, Amino Acid


  • DNA, Mitochondrial
  • DNA
  • Electron Transport Complex IV