Kowald Axel, Kirkwood Thomas B L
Institute of Cell and Molecular Biosciences and Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen 2200, Denmark.
Genes (Basel). 2018 Feb 27;9(3):126. doi: 10.3390/genes9030126.
Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an important role during aging. In both cases, point mutations or large deletions accumulate inside cells, leading to functional impairment once a certain threshold has been surpassed. In most cases, it is a single type of mutant that clonally expands and out-competes the wild type mtDNA, with different mutant molecules being amplified in different cells. The challenge is to explain where the selection advantage for the accumulation comes from, why such a large range of different deletions seem to possess this advantage, and how this process can scale to species with different lifespans such as those of rats and man. From this perspective, we provide an overview of current ideas, present an update of our own proposal, and discuss the wider relevance of the phenomenon for aging.
线粒体是一种特殊的细胞器，因为它们以线粒体DNA（mtDNA）的形式包含自己的遗传物质。mtDNA的损伤和突变不仅与几种人类遗传性疾病有关，而且人们普遍认为其在衰老过程中也起着重要作用。在这两种情况下，点突变或大片段缺失在细胞内积累，一旦超过某个阈值就会导致功能受损。在大多数情况下，是单一类型的突变体进行克隆性扩增并胜过野生型mtDNA，不同的突变分子在不同的细胞中被扩增。挑战在于解释积累的选择优势来自何处，为什么如此大范围的不同缺失似乎都具有这种优势，以及这个过程如何能够扩展到具有不同寿命的物种，如大鼠和人类。从这个角度出发，我们概述了当前的观点，更新了我们自己的提议，并讨论了该现象与衰老更广泛的相关性。
