Dissecting the mechanisms underlying the accumulation of mitochondrial DNA deletions in human skeletal muscle.
Dissecting the mechanisms underlying the accumulation of mitochondrial DNA deletions in human skeletal muscle.
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DOI：
10.1093/hmg/ddu176
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发表时间：
2014-09-01
影响因子：
3.5
通讯作者：
Turnbull DM
中科院分区：
文献类型：
--
作者：
Campbell G;Krishnan KJ;Deschauer M;Taylor RW;Turnbull DM
大规模线粒体 DNA (mtDNA) 缺失是线粒体疾病的重要原因，而体细胞 mtDNA 缺失会导致与衰老和神经退行性疾病相关的局灶性呼吸链缺陷。由于 mtDNA 缺失只会在高水平的 mtDNA 异质性下引起细胞病理学，因此 mtDNA 缺失必须累积到可导致生化功能障碍的水平，这一过程称为克隆扩增。对于 mtDNA 缺失的克隆扩增，人们提出了许多假设，包括通过较小的尺寸推断缺失的线粒体基因组的复制优势，这意味着最大的 mtDNA 缺失也将比较小的 mtDNA 缺失表现出复制优势。我们提出，在患有 mtDNA 维持障碍的患者的肌肉纤维中，这会导致多个 mtDNA 缺失的积累，我们将观察到最大的 mtDNA 缺失通过更高的克隆扩张率在单个肌肉纤维中纵向传播最远。我们对骨骼肌纤维中一系列“大”和“小”细胞色素 c 氧化酶 (COX) 缺乏区域的 mtDNA 维持障碍患者的 mtDNA 缺失进行了表征。我们测量了 62 个小的和 60 个大的单个 COX 缺陷 f 区域中克隆扩展缺失的大小。在个体患者或总数据集中没有观察到显着差异（小纤维区域平均 6.59 kb - 大纤维区域平均 6.51 kb）。因此，不同大小的 mtDNA 缺失之间，整个肌肉纤维的克隆扩增速率不存在差异；因此，较小的线粒体基因组似乎在人类肌肉中不具有固有的复制优势。
Large-scale mitochondrial DNA (mtDNA) deletions are an important cause of mitochondrial disease, while somatic mtDNA deletions cause focal respiratory chain deficiency associated with ageing and neurodegenerative disorders. As mtDNA deletions only cause cellular pathology at high levels of mtDNA heteroplasmy, an mtDNA deletion must accumulate to levels which can result in biochemical dysfunction—a process known as clonal expansion. A number of hypotheses have been proposed for clonal expansion of mtDNA deletions, including a replicative advantage for deleted mitochondrial genomes inferred by their smaller size—implying that the largest mtDNA deletions would also display a replicative advantage over smaller mtDNA deletions. We proposed that in muscle fibres from patients with mtDNA maintenance disorders, which lead to the accumulation of multiple mtDNA deletions, we would observe the largest mtDNA deletions spreading the furthest longitudinally through individual muscle fibres by means of a greater rate of clonal expansion. We characterized mtDNA deletions in patients with mtDNA maintenance disorders from a range of ‘large’ and ‘small’ cytochrome c oxidase (COX)-deficient regions in skeletal muscle fibres. We measured the size of clonally expanded deletions in 62 small and 60 large individual COX-deficient f regions. No significant difference was observed in individual patients or in the total dataset (small fibre regions mean 6.59 kb—large fibre regions mean 6.51 kb). Thus no difference existed in the rate of clonal expansion throughout muscle fibres between mtDNA deletions of different sizes; smaller mitochondrial genomes therefore do not appear to have an inherent replicative advantage in human muscle.
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DOI：
10.1038/nrg1606
发表时间：
2005-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
14.9
作者：
Khrapko, K;Bodyak, N;Wei, JY
通讯作者：
Wei, JY
DOI：
10.1111/j.1749-6632.2002.tb02113.x
发表时间：
2002-01-01
期刊：
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影响因子：
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作者：
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通讯作者：
Khrapko, K
影响因子：
3.7
作者：
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通讯作者：
Aiken, Judd M.
影响因子：
4
作者：
deGrey, ADNJ
通讯作者：
deGrey, ADNJ