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

  • Author(s): Chen, Le
  • Liu, Tingting
  • Tran, Alice
  • Lu, Xiyuan
  • Tomilov, Alexey A
  • Davies, Vanessa
  • Cortopassi, Gino
  • Chiamvimonvat, Nipavan
  • Bers, Donald M
  • Votruba, Marcela
  • Knowlton, Anne A
  • et al.
Abstract

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.

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