线粒体DNA编辑技术及其在生物医学中的应用

Mitochondrial DNA editing technologies and their applications in biomedicine

线粒体拥有一套独立的基因组,参与维持线粒体功能。对线粒体DNA(mitochondrial DNA,mtDNA)进行编辑,可以为其基因功能、相关疾病机理和治疗研究提供重要线索。但由于mtDNA所处环境和损伤修复机制的特殊性,可用于mtDNA编辑的工具较为有限。近年来,随着核酸酶技术和碱基编辑技术的快速发展,可靶向线粒体的核酸酶工具和碱基编辑器相继问世,为mtDNA编辑提供了有力工具。本文总结了近年来针对动物mtDNA而开发的一系列靶向基因编辑工具的主要进展及其在生物医学领域的应用,重点围绕mtDNA碱基编辑器DdCBE,并对mtDNA编辑目前存在的问题与应用前景做了初步展望,以期为线粒体基因编辑新工具的开发,及其在基础研究、疾病模拟和临床治疗等场景中更广泛的应用提供有益参考。

Mitochondria possess their own genome to maintain mitochondrial functions.Modification of mitochondrial DNA(mtDNA)provides important insights into gene functions,disease mechanisms,and therapeutics.However,the available tools for mtDNA editing are relatively limited because of the nature of the unique environment where mtDNA resides and the mechanism of DNA damage repair in mitochondria.With the rapid progress of nuclease and base-editing technologies in recent years,mitochondrially targeted nuclease tools and base editors have been developed,providing powerful tools for mtDNA editing.In this review,we summarize the recent progress of a series of tools developed for targeted editing of animal mtDNA and their applications in biomedicine,focusing on DdCBE(DddA-derived cytosine base editor),and provide a brief outlook on the existing problems and application prospects of mtDNA editing to provide a useful reference for the development of novel tools for mitochondrial genome editing and their wider applications in basic research,disease modeling,and clinical therapeutics.