DOI：10.1038/nature18618 作者：José Antonio Enríquez
摘要 : José Antonio Enríquez及同事使用核基因组相同、但线粒体DNA不同的同源小鼠品系，对线粒体DNA序列变异的影响进行了研究。
José Antonio Enríquez及同事使用核基因组相同、但线粒体DNA不同的同源小鼠品系，对线粒体DNA序列变异的影响进行了研究。他们显示，线粒体基因组对生理的许多层面(包括胰岛素信号传导、肥胖和端粒缩短)有着深远的影响，并导致了寿命中位数的差异。因此，非病理性线粒体DNA变异对代谢影响广泛，这种差异在生命后期更加明显。作者提出，线粒体基因组与核基因组之间的相互作用可能是影响这一现象的一个重要因素，这对线粒体置换领域或许有参考价值。
Human mitochondrial DNA (mtDNA) shows extensive within-population sequence variability1. Many studies suggest that mtDNA variants may be associated with ageing or diseases2, 3, 4, although mechanistic evidence at the molecular level is lacking5, 6. Mitochondrial replacement has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nuclear-encoded mitochondrial genes. Studies in conplastic animals7, 8, 9 allow comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies did not confirm the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria. Here we systematically characterized conplastic mice throughout their lifespan using transcriptomic, proteomic, metabolomic, biochemical, physiological and phenotyping studies. We show that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation, insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.
来源： Nature 浏览次数：1