加拿大多伦多大学Thomas R. Hurd研究组和美国纽约大学医学院Ruth Lehmann研究组取得一项新突破。他们提出了母体生殖细胞选择更健康的线粒体传递给后代。 该研究于2019年6月20日发表于国际学术期刊《自然》杂志上。

研究人员用一种等位基因特异性荧光原位杂交方法来观察果蝇的种系选择，以区分野生型和突变型mtDNA。选择首先体现在果蝇卵子发生早期阶段，由前融合蛋白Mitofusin的减少触发。这导致线粒体基因组分离成不同的线粒体片段，这阻止了基因组及其产物的混合，从而减少了粒体传递给后代。线粒体一旦分裂，包含突变基因组的线粒体就不太可能产生ATP, 有缺陷的线粒体通过涉及蛋白Atg1和BNIP3的线粒体自噬加以清除。Atg1或BNIP3的减少减少了野生型mtDNA的数量，这表明线粒体更新和mtDNA复制之间存在联系。分裂不仅是种系组织选择的必要条件，而且也足以诱导通常缺乏选择的体细胞组织进行选择。我们假设，针对有害mtDNA突变的选择有一个可推广的机制，这可能使mtDNA疾病治疗策略的发展成为可能。

据悉，线粒体含有自己的基因组，与细胞核基因组不同，线粒体只能在母系遗传。由于线粒体DNA (mtDNA)的高突变率和低重组率，女性生殖系存在特殊的选择机制，以防止有害突变的积累。然而，支持选择理论的分子机制却知之甚少。

附：英文原文

Title: Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline

Author: Toby Lieber, Swathi P. Jeedigunta, Jonathan M. Palozzi, Ruth Lehmann, Thomas R. Hurd

Issue&Volume: Volume 570 Issue 7761, 20 June 2019

Abstract: Mitochondria contain their own genomes that, unlike nuclear genomes, are inherited only in the maternal line. Owing to a high mutation rate and low levels of recombination of mitrochondrial DNA (mtDNA), special selection mechanisms exist in the female germline to prevent the accumulation of deleterious mutations. However, the molecular mechanisms that underpin selection are poorly understood. Here we visualize germline selection in Drosophila using an allele-specific fluorescent in situ-hybridization approach to distinguish wild-type from mutant mtDNA. Selection first manifests in the early stages of Drosophila oogenesis, triggered by reduction of the pro-fusion protein Mitofusin. This leads to the physical separation of mitochondrial genomes into different mitochondrial fragments, which prevents the mixing of genomes and their products and thereby reduces complementation. Once fragmented, mitochondria that contain mutant genomes are less able to produce ATP, which marks them for selection through a process that requires the mitophagy proteins Atg1 and BNIP3. A reduction in Atg1 or BNIP3 decreases the amount of wild-type mtDNA, which suggests a link between mitochondrial turnover and mtDNA replication. Fragmentation is not only necessary for selection in germline tissues, but is also sufficient to induce selection in somatic tissues in which selection is normally absent. We postulate that there is a generalizable mechanism for selection against deleterious mtDNA mutations, which may enable the development of strategies for the treatment of mtDNA disorders.

DOI: 10.1038/s41586-019-1213-4

Source:https://www.nature.com/articles/s41586-019-1213-4