A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast

FEBS J. 2005 Jul;272(14):3583-92. doi: 10.1111/j.1742-4658.2005.04779.x.


Whereas the majority of disease-related mitochondrial DNA mutations exhibit significant biochemical and clinical heterogeneity, mutations within the mitochondrially encoded human cytochrome b gene (MTCYB) are almost exclusively associated with isolated complex III deficiency in muscle and a clinical presentation involving exercise intolerance. Recent studies have shown that a small number of MTCYB mutations are associated with a combined enzyme complex defect involving both complexes I and III, on account of the fact that an absence of assembled complex III results in a dramatic loss of complex I, confirming a structural dependence between these two complexes. We present the biochemical and molecular genetic studies of a patient with both muscle and brain involvement and a severe reduction in the activities of both complexes I and III in skeletal muscle due to a novel mutation in the MTCYB gene that predicts the substitution (Arg318Pro) of a highly conserved amino acid. Consistent with the dramatic biochemical defect, Western blotting and BN-PAGE experiments demonstrated loss of assembled complex I and III subunits. Biochemical studies of the equivalent amino-acid substitution (Lys319Pro) in the yeast enzyme showed a loss of enzyme activity and decrease in the steady-state level of bc1 complex in the mutant confirming pathogenicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Arginine / genetics
  • Arginine / metabolism
  • Base Sequence
  • Biopsy
  • Cytochromes b / chemistry
  • Cytochromes b / genetics*
  • Cytochromes b / metabolism*
  • DNA, Mitochondrial / genetics
  • Female
  • Guanidine / metabolism
  • Humans
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Muscles / enzymology
  • Mutation / genetics*
  • Protein Structure, Quaternary
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*


  • DNA, Mitochondrial
  • Protein Subunits
  • Cytochromes b
  • Arginine
  • Guanidine