Wellcome Centre for Mitochondrial Research, Newcastle upon Tyne, U.K.
Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, 9000 Ghent, Belgium.
Essays Biochem. 2018 Jul 20;62(3):455-465. doi: 10.1042/EBC20170113.
Mitochondrial DNA (mtDNA) is a multi-copy genome whose cell copy number varies depending on tissue type. Mutations in mtDNA can cause a wide spectrum of diseases. Mutated mtDNA is often found as a subset of the total mtDNA population in a cell or tissue, a situation known as heteroplasmy. As mitochondrial dysfunction only presents after a certain level of heteroplasmy has been acquired, ways to artificially reduce or replace the mutated species have been attempted. This review addresses recent approaches and advances in this field, focusing on the prevention of pathogenic mtDNA transfer via mitochondrial donation techniques such as maternal spindle transfer and pronuclear transfer in which mutated mtDNA in the oocyte or fertilized embryo is substituted with normal copies of the mitochondrial genome. This review also discusses the molecular targeting and cleavage of pathogenic mtDNA to shift heteroplasmy using antigenomic therapy and genome engineering techniques including Zinc-finger nucleases and transcription activator-like effector nucleases. Finally, it considers CRISPR technology and the unique difficulties that mitochondrial genome editing presents.
线粒体 DNA（mtDNA）是一种多拷贝基因组，其细胞拷贝数取决于组织类型。mtDNA 突变可引起广泛的疾病。突变的 mtDNA 通常在细胞或组织中的总 mtDNA 群体中作为亚群存在，这种情况称为异质性。由于线粒体功能障碍仅在获得一定程度的异质性后才会出现，因此尝试了人工减少或替换突变种的方法。本综述讨论了该领域的最新方法和进展，重点介绍了通过线粒体捐赠技术预防致病性 mtDNA 转移的方法，例如通过母性纺锤体转移和原核转移，在卵母细胞或受精卵中用正常的线粒体基因组替代突变的 mtDNA。本综述还讨论了使用反义基因组治疗和基因组工程技术（包括锌指核酸酶和转录激活因子样效应物核酸酶）靶向和切割致病性 mtDNA 以改变异质性的方法。最后，它考虑了 CRISPR 技术和线粒体基因组编辑带来的独特困难。
