Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues
Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues
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DOI：
10.1073/pnas.072670199
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发表时间：
2002-04-16
影响因子：
11.1
通讯作者：
Khrapko, K
中科院分区：
文献类型：
--
作者：
Nekhaeva, E;Bodyak, ND;Khrapko, K
利用单细胞序列分析，我们发现在口腔上皮和心肌等不同组织中，高比例的细胞含有从单个初始突变的mtDNA分子中扩增的克隆突变的mtDNA。我们证明，体细胞点突变的细胞内克隆性扩展在正常人类组织中是常见的事件。这一发现意味着单个细胞内线粒体基因组的有效同质化。然而，在增殖的上皮细胞和有丝分裂后的心肌细胞中观察到的克隆性扩展突变的光谱之间的显著定性差异表明，无论是产生这些突变的过程还是促使它们同质的机制在这两个组织之间可能是根本不同的。此外，体细胞mtDNA突变的扩展能力(表型表达所需)以及它们明显的高发生率，加强了这些突变可能积极参与各种生理过程的可能性，如衰老和退行性疾病。在正常组织的单个细胞中大量克隆扩增的点突变也表明，最近发现的肿瘤中mtDNA突变的积累可能是通过与正常组织中的操作相似或相同的过程来解释的。
Using single-cell sequence analysis, we discovered that a high proportion of cells in tissues as diverse as buccal epithelium and heart muscle contain high proportions of clonal mutant mtDNA expanded from single initial mutant mtDNA molecules. We demonstrate that intracellular clonal expansion of somatic point mutations is a common event in normal human tissues. This finding implies efficient homogenization of mitochondrial genomes within individual cells. Significant qualitative differences observed between the spectra of clonally expanded mutations in proliferating epithelial cells and postmitotic cardiomyocytes suggest, however, that either the processes generating these mutations or mechanisms driving them to homoplasmy are likely to be fundamentally different between the two tissues. Furthermore, the ability of somatic mtDNA mutations to expand (required for their phenotypic expression), as well as their apparently high incidence, reinforces the possibility that these mutations may be involved actively in various physiological processes such as aging and degenerative disease. The abundance of clonally expanded point mutations in individual cells of normal tissues also suggests that the recently discovered accumulation of mtDNA mutations in tumors may be explained by processes that are similar or identical to those operating in the normal tissue.