OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability.
OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability.
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DOI：
10.1161/jaha.112.003012
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发表时间：
2012-10
影响因子：
5.4
通讯作者：
Knowlton AA
中科院分区：
文献类型：
--
作者：
Chen L;Liu T;Tran A;Lu X;Tomilov AA;Davies V;Cortopassi G;Chiamvimonvat N;Bers DM;Votruba M;Knowlton AA
线粒体融合蛋白突变是遗传性神经病（如夏科-玛丽-图思病和显性视神经萎缩）的原因。之前我们报道过融合蛋白视神经萎缩1（OPA1）在心力衰竭中减少。我们研究了 OPA1 突变疾病小鼠模型的心脏功能、线粒体功能和 mtDNA 稳定性。纯合突变是胚胎致死的。杂合 OPA+/- 小鼠在 3 至 4 个月时表现出线粒体 DNA 拷贝数减少和核抗氧化基因表达减少。尽管最初的心功能正常，但在 12 个月时，OPA1+/- 小鼠心脏的缩短分数、心输出量和肌细胞收缩均有所下降。这与失明的发生同时发生。除了线粒体碎片外，与野生型同窝小鼠相比，老年 OPA1+/- 小鼠的心脏线粒体功能也受损。 OPA1 突变导致抗氧化转录本缺陷、活性氧增加、线粒体功能障碍和迟发性心肌病。
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. 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. OPA1 mutation leads to deficiency in antioxidant transcripts, increased reactive oxygen species, mitochondrial dysfunction, and late-onset cardiomyopathy.