Mutations of mitochondrial DNA (mtDNA) often underlie mitochondrial disease, one of the most common inherited metabolic disorders. Since the sequencing of the human mitochondrial genome and the discovery of pathogenic mutations in mtDNA more than 30 years ago, a movement towards generating methods for robust manipulation of mtDNA has ensued, although with relatively few advances and some controversy. While developments in the transformation of mammalian mtDNA have stood still for some time, recent demonstrations of programmable nuclease-based technology suggest that clinical manipulation of mtDNA heteroplasmy may be on the horizon for these largely untreatable disorders. Here we review historical and recent developments in mitochondrially targeted nuclease technology and the clinical outlook for treatment of hereditary mitochondrial disease.

线粒体DNA（mtDNA）突变通常是线粒体疾病的基础，而线粒体疾病是最常见的遗传性代谢疾病之一。自人类线粒体基因组测序和发现mtDNA中的致病性突变以来，已有30多年的历史，尽管取得了相对较少的进展和一些争议，但仍在朝着产生对mtDNA进行可靠操纵的方法的方向发展。尽管哺乳动物mtDNA转化的发展已经停滞了一段时间，但最近基于可编程核酸酶技术的论证表明，对于这些很大程度上无法治愈的疾病，mtDNA异质性的临床操作可能即将到来。在这里，我们回顾线粒体靶向核酸酶技术的历史和最新发展以及遗传性线粒体疾病的治疗的临床前景。