Coller Hilary A, Bodyak Natalya D, Khrapko Konstantin
Fred Hutchinson Cancer Research Center, Seattle, Washington 98119, USA.
Ann N Y Acad Sci. 2002 Apr;959:434-47. doi: 10.1111/j.1749-6632.2002.tb02113.x.
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.
有人提出，线粒体DNA（mtDNA）中与年龄相关的体细胞突变积累是衰老过程某些方面的原因。然而，大多数细胞含有数百到数千个mtDNA分子。因此，任何新出现的体细胞突变体在大多数野生型分子中都表现为单拷贝。单个突变分子不太可能影响细胞的生理功能，因此不能在衰老过程中发挥作用。为了影响细胞生理功能，新出现的体细胞突变体必须以某种方式在细胞中克隆性积累到显著水平。本文综述了支持mtDNA突变的克隆性扩增确实是人类各种组织中广泛存在的过程这一观点的证据，以及克隆性扩增可能影响衰老过程的机制。最初，在肌肉中具有大片段缺失的mtDNA被证明存在克隆性扩增。对人类心肌细胞和颊上皮细胞进行逐个细胞分析发现，克隆性扩增既影响mtDNA点突变，也影响缺失。扩增不仅限于肌肉，可能存在于大多数组织中，而且老年组织中的几乎每个细胞都可能受到扩增的影响。虽然克隆性扩增的存在毋庸置疑，但驱动这一过程的机制在很大程度上存在争议。解释扩增的假说是随机或各种选择机制，或两者兼而有之。我们表明，在心肌细胞和上皮细胞中，扩增的点突变谱有很大差异。这表明这些组织中的扩增机制不同。特别是，我们分别为上皮细胞和肌肉细胞提出了随机分离和正选择模型。
