MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.
Nat Commun. 2019 Jul 23;10(1):3280. doi: 10.1038/s41467-019-10857-y.
Somatic mutations in the mitochondrial genome (mtDNA) have been linked to multiple disease conditions and to ageing itself. In Drosophila, knock-in of a proofreading deficient mtDNA polymerase (POLG) generates high levels of somatic point mutations and also small indels, but surprisingly limited impact on organismal longevity or fitness. Here we describe a new mtDNA mutator model based on a mitochondrially-targeted cytidine deaminase, APOBEC1. mito-APOBEC1 acts as a potent mutagen which exclusively induces C:G>T:A transitions with no indels or mtDNA depletion. In these flies, the presence of multiple non-synonymous substitutions, even at modest heteroplasmy, disrupts mitochondrial function and dramatically impacts organismal fitness. A detailed analysis of the mutation profile in the POLG and mito-APOBEC1 models reveals that mutation type (quality) rather than quantity is a critical factor in impacting organismal fitness. The specificity for transition mutations and the severe phenotypes make mito-APOBEC1 an excellent mtDNA mutator model for ageing research.
线粒体基因组（mtDNA）中的体细胞突变与多种疾病状况以及衰老本身有关。在果蝇中，具有校对缺陷的 mtDNA 聚合酶（POLG）的基因敲入会产生高水平的体细胞点突变，并且还会产生小的插入缺失，但对生物体的寿命或适应性的影响却惊人地有限。在这里，我们描述了一种基于靶向线粒体的胞嘧啶脱氨酶 APOBEC1 的新型 mtDNA 诱变剂模型。mito-APOBEC1 是一种有效的诱变剂，它仅诱导 C:G>T:A 转换，而没有插入缺失或 mtDNA 耗竭。在这些果蝇中，即使存在适度的异质型，多种非同义突变的存在也会破坏线粒体功能，并严重影响生物体的适应性。对 POLG 和 mito-APOBEC1 模型中的突变谱进行的详细分析表明，突变类型（质量）而不是数量是影响生物体适应性的关键因素。对转换突变的特异性和严重表型使 mito-APOBEC1 成为衰老研究的出色 mtDNA 诱变剂模型。
