OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability

J Am Heart Assoc. 2012 Oct;1(5):e003012. doi: 10.1161/JAHA.112.003012. Epub 2012 Oct 25.


Background: Mitochondrial fusion protein mutations are a cause of inherited neuropathies such as Charcot-Marie-Tooth disease and dominant optic atrophy. Previously we reported that the fusion protein optic atrophy 1 (OPA1) is decreased in heart failure.

Methods and results: We investigated cardiac function, mitochondrial function, and mtDNA stability in a mouse model of the disease with OPA1 mutation. The homozygous mutation is embryonic lethal. Heterozygous OPA(+/-) mice exhibit reduced mtDNA copy number and decreased expression of nuclear antioxidant genes at 3 to 4 months. Although initial cardiac function was normal, at 12 months the OPA1(+/-) mouse hearts had decreased fractional shortening, cardiac output, and myocyte contraction. This coincided with the onset of blindness. In addition to small fragmented mitochondria, aged OPA1(+/-) mice had impaired cardiac mitochondrial function compared with wild-type littermates.

Conclusions: OPA1 mutation leads to deficiency in antioxidant transcripts, increased reactive oxygen species, mitochondrial dysfunction, and late-onset cardiomyopathy.

Keywords: OPA1; ROS; cardiomyopathy; mitochondrial fusion; mtDNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cardiomyopathies / genetics*
  • DNA, Mitochondrial / genetics*
  • Disease Models, Animal
  • GTP Phosphohydrolases / genetics*
  • Genomic Instability
  • Mice
  • Mitochondria / genetics*
  • Mutation
  • Polymerase Chain Reaction
  • Reactive Oxygen Species


  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • GTP Phosphohydrolases
  • Opa1 protein, mouse