title: OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability.
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.
  
  
  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.
authors: Department of Medicine, University of California, Davis, CA 95616, USA.
authors: Le
authors: L
authors: Chen
authors: Tingting
authors: T
authors: Liu
authors: Alice
authors: A
authors: Tran
authors: Xiyuan
authors: X
authors: Lu
authors: Alexey A
authors: AA
authors: Tomilov
authors: Vanessa
authors: V
authors: Davies
authors: Gino
authors: G
authors: Cortopassi
authors: Nipavan
authors: N
authors: Chiamvimonvat
authors: Donald M
authors: DM
authors: Bers
authors: Marcela
authors: M
authors: Votruba
authors: Anne A
authors: AA
authors: Knowlton
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000235:genetics*; D042822:Genomic Instability; D051379:Mice; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse
keywords: OPA1; ROS; cardiomyopathy; mitochondrial fusion; mtDNA