Frequent intracellular clonal expansions of somatic mtDNA mutations - Significance and mechanisms
Frequent intracellular clonal expansions of somatic mtDNA mutations - Significance and mechanisms
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DOI：
10.1111/j.1749-6632.2002.tb02113.x
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发表时间：
2002-01-01
期刊：
影响因子：
--
通讯作者：
Khrapko, K
中科院分区：
文献类型：
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作者：
Coller, HA;Bodyak, ND;Khrapko, K
已经提出，线粒体DNA中体细胞突变的年龄依赖性积累是衰老过程的某些方面的原因。然而，大多数细胞含有数百至数千个mtDNA分子。因此，任何新生的体细胞突变体在大多数野生型物种中表现为单一拷贝。单个突变分子不太可能影响细胞的生理机能，因此无法在衰老过程中发挥作用。为了影响细胞生理学，新生体细胞突变体必须以某种方式在细胞中克隆积累到显著水平。支持这一观点的证据，的确，克隆扩张的mtDNA突变是一个广泛的过程中的各种人体组织，克隆扩张可能会影响衰老过程的机制，进行了审查。最初，克隆扩增被证明是在肌肉中具有大缺失的mtDNA。对人心肌细胞和颊上皮细胞的细胞分析显示，克隆扩增影响mtDNA点突变和缺失。扩张并不局限于肌肉，但可能存在于大多数组织中，几乎衰老组织的每个细胞都可能受到扩张的影响。虽然克隆扩张的存在是毫无疑问的，但驱动这一过程的机制在很大程度上是有争议的。解释膨胀的假说包括随机或各种选择性机制，或两者兼而有之。我们发现，在心肌细胞和上皮细胞中，扩展点突变的谱是完全不同的。这表明这些组织中的扩张机制是不同的。特别是，我们提出了随机隔离和积极的选择模型，分别为上皮细胞和肌肉细胞。
It has been proposed that age-dependent accumulation of somatic mutations in mtDNA is responsible for some aspects of the aging process. However, most cells contain hundreds to thousands of mtDNA molecules. Any nascent somatic mutant therefore appears as a single copy among a majority of wild-type species. A single mutant molecule is unlikely to influence the physiology of the cell and thus cannot play a role in the aging process. To affect cellular physiology, the nascent somatic mutants must somehow accumulate clonally in the cell to significant levels. The evidence supporting the view that, indeed, clonal expansion of mtDNA mutations is a widespread process in various human tissues, and the mechanisms by which clonal expansions may affect the aging process, are reviewed. Originally, clonal expansion was demonstrated for mtDNA with large deletions in muscle. Cell-by-cell analysis of human cardiomyocytes and buccal epithelial cells revealed that clonal expansion affects point mtDNA mutations as well as deletions. Expansions are not limited to muscle, but likely are present in most tissues, and almost every cell of an aged tissue is likely to be affected by an expansion. While the very existence of clonal expansion is beyond doubt, the mechanisms driving this process are largely controversial. The hypotheses explaining expansion includes random or various selective mechanisms, or both. We show that the spectra of expanded point mutations are drastically different in cardiomyocytes and epithelial cells. This suggests that the mechanisms of expansion in these tissues are different. In particular, we propose random segregation and positive selection models for epithelial and muscle cells, respectively.