Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.
Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.
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DOI：
10.1371/journal.pgen.1004620
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发表时间：
2014-09
期刊：
影响因子：
4.5
通讯作者：
Turnbull DM
中科院分区：
文献类型：
--
作者：
Greaves LC;Nooteboom M;Elson JL;Tuppen HA;Taylor GA;Commane DM;Arasaradnam RP;Khrapko K;Taylor RW;Kirkwood TB;Mathers JC;Turnbull DM
线粒体完整性的下降是人类衰老过程的一个重要因素。在许多老化的干细胞群体中，线粒体功能的这种下降是由于单个细胞内单个线粒体DNA（mtDNA）点突变的克隆扩增。然而，这一过程的动力学以及这些mtDNA突变最初发生的时间却知之甚少。使用人类结直肠上皮作为具有明确干细胞群的样本组织，我们使用多种技术分析了207名年龄在17-78岁的健康参与者的样本。（随机突变捕获，下一代测序和线粒体酶组织化学），并显示：1）非致病性mtDNA突变存在于早期胚胎发生或可通过生殖系传递，而致病性mtDNA突变在体细胞中检测到，为人类的纯化选择提供了证据，2）致病性mtDNA突变从成年早期（<20岁）就存在，以低水平和克隆扩增的形式存在，3）低水平mtDNA突变频率不随年龄显著变化，表明mtDNA突变率不随年龄显著增加，4）克隆扩增的mtDNA突变随年龄显著增加。这些数据证实，mtDNA突变的克隆扩增，其中一些是在生命早期产生的，是与人类结直肠上皮老化相关的线粒体功能障碍背后的主要驱动力。线粒体DNA（mtDNA）突变已被证明在许多人类干细胞群体中随着年龄的增长而积累，并导致个体细胞内的线粒体功能障碍，从而导致细胞能量不足。mtDNA突变发生和积累在单个细胞内的动力学（称为克隆扩增）知之甚少。特别是我们不知道这些mtDNA突变在生命过程中何时发生。在这里，我们使用三种不同的技术测量了mtDNA突变频率：随机突变捕获，测量低水平突变频率作为突变率的间接测量，下一代测序，测量克隆扩展的mtDNA突变频率，线粒体酶组织化学作为克隆扩展的mtDNA突变的标记物，从207名17-78岁的健康参与者的结直肠粘膜活检中获得。我们发现，到17岁时，有大量的mtDNA点突变负担，早期到中年mtDNA突变的克隆扩张可能是与人类结肠衰老相关的线粒体功能障碍的原因。
Age-related decline in the integrity of mitochondria is an important contributor to the human ageing process. In a number of ageing stem cell populations, this decline in mitochondrial function is due to clonal expansion of individual mitochondrial DNA (mtDNA) point mutations within single cells. However the dynamics of this process and when these mtDNA mutations occur initially are poorly understood. Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17–78 years using a combination of techniques (Random Mutation Capture, Next Generation Sequencing and mitochondrial enzyme histochemistry), and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (<20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium. Mitochondrial DNA (mtDNA) mutations have been shown to accumulate with age in a number of human stem cell populations and cause mitochondrial dysfunction within individual cells resulting in a cellular energy deficit. The dynamics by which mtDNA mutations occur and accumulate within individual cells (known as clonal expansion) is poorly understood. In particular we do not know when in the life-course these mtDNA mutations occur. Here we have measured mtDNA mutation frequency using three different techniques; Random Mutation Capture, which measures low level mutation frequency as an indirect measure of mutation rate, Next Generation Sequencing, which measures clonally expanded mtDNA mutation frequency, and mitochondrial enzyme histochemistry as a marker of clonally expanded mtDNA mutations, on colorectal mucosal biopsies obtained from 207 healthy participants aged 17–78 years. We show that, by 17 years of age, there is a substantial mtDNA point mutation burden and that clonal expansion of early to mid-life mtDNA mutations is likely to be the cause of mitochondrial dysfunction associated with ageing in the human colon.
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影响因子：
4.5
作者：
Ameur A;Stewart JB;Freyer C;Hagström E;Ingman M;Larsson NG;Gyllensten U
通讯作者：
Gyllensten U
影响因子：
56.9
作者：
Fan, Weiwei;Waymire, Katrina G.;Wallace, Douglas C.
通讯作者：
Wallace, Douglas C.
DOI：
10.1073/pnas.0505903103
发表时间：
2006-01-17
影响因子：
11.1
作者：
Greaves, LC;Preston, SL;McDonald, SAC
通讯作者：
McDonald, SAC
影响因子：
3.7
作者：
Bigger, Brian W.;Liao, Ai-Yin;Coutelle, Charles
通讯作者：
Coutelle, Charles
影响因子：
29
作者：
Ahlqvist, Kati J.;Hamalainen, Riikka H.;Suomalainen, Anu
通讯作者：
Suomalainen, Anu