Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A→G
Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A→G
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DOI：
10.1086/518901
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发表时间：
2007-07-01
影响因子：
9.8
通讯作者：
Chinnery, Patrick F.
中科院分区：
文献类型：
--
作者：
Durham, Steve E.;Samuels, David C.;Chinnery, Patrick F.
线粒体DNA （mtDNA）突变是人类疾病的常见原因，并作为正常衰老和常见神经退行性疾病的一部分积累。只有当突变mtDNA的比例超过临界阈值时，细胞才会表现出生化缺陷，但目前尚不清楚这种缺陷的实际原因是野生型mtDNA的缺失，还是突变mtDNA的过量，还是两者的结合。在这里，我们表明，人类骨骼肌纤维中含有两种致病性mtDNA突变的片段通过维持最低数量的野生型mtDNA来保持正常的细胞色素c氧化酶（COX）活性。对于这些突变，对同一骨骼肌纤维中突变和野生型mtDNA分子的直接测量与“野生型维持”假说一致，该假说预测，在分子缺陷的反应中，存在突变和野生型mtDNA的非选择性增殖。然而，对于m. 3243A - >g突变，在许多COX活性可忽略的肌肉纤维切片中发现了过量的野生型mtDNA，这表明这种特殊突变的致病机制涉及对野生型mtDNA或野生型基因产物功能的干扰。
Mitochondrial DNA (mtDNA) mutations are a common cause of human disease and accumulate as part of normal ageing and in common neurodegenerative disorders. Cells express a biochemical defect only when the proportion of mutated mtDNA exceeds a critical threshold, but it is not clear whether the actual cause of this defect is a loss of wild-type mtDNA, an excess of mutated mtDNA, or a combination of the two. Here, we show that segments of human skeletal muscle fibers harboring two pathogenic mtDNA mutations retain normal cytochrome c oxidase (COX) activity by maintaining a minimum amount of wild- type mtDNA. For these mutations, direct measurements of mutated and wild- type mtDNA molecules within the same skeletal muscle fiber are consistent with the "maintenance of wild type" hypothesis, which predicts that there is nonselective proliferation of mutated and wild- type mtDNA in response to the molecular defect. However, for the m. 3243A -> G mutation, a superabundance of wild-type mtDNA was found in many muscle-fiber sections with negligible COX activity, indicating that the pathogenic mechanism for this particular mutation involves interference with the function of the wild- type mtDNA or wild-type gene products.