Mitochondrial DNA (mtDNA) encodes a subset of the genes which are responsible for oxidative phosphorylation. Pathogenic mutations in the human mtDNA are often heteroplasmic, where wild-type mtDNA species co-exist with the pathogenic mtDNA and a bioenergetic defect is only seen when the pathogenic mtDNA percentage surpasses a threshold for biochemical manifestations. mtDNA segregation during germline development can explain some of the extreme variation in heteroplasmy from one generation to the next. Patients with high heteroplasmy for deleterious mtDNA species will likely suffer from bona-fide mitochondrial diseases, which currently have no cure. Shifting mtDNA heteroplasmy toward the wild-type mtDNA species could provide a therapeutic option to patients. Mitochondrially targeted engineered nucleases, such as mitoTALENs and mitoZFNs, have been used in vitro in human cells harboring pathogenic patient-derived mtDNA mutations and more recently in vivo in a mouse model of a pathogenic mtDNA point mutation. These gene therapy tools for shifting mtDNA heteroplasmy can also be used in conjunction with other therapies aimed at eliminating and/or preventing the transfer of pathogenic mtDNA from mother to child.

中文翻译：

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疾病中的线粒体DNA异质性和基于核酸酶的靶向治疗方法。

线粒体DNA（mtDNA）编码负责氧化磷酸化的基因的子集。人类mtDNA的致病突变通常是异质性的，其中野生型mtDNA物种与致病性mtDNA共存，并且仅在致病性mtDNA百分比超过生化表现的阈值时才能看到生物能缺陷。种系发育过程中的mtDNA分离可以解释一代一代到下一代异质性的一些极端变化。有害的mtDNA种类异质性高的患者很可能患有真正的线粒体疾病，目前尚无法治愈。将mtDNA异质性向野生型mtDNA物种转移可以为患者提供治疗选择。线粒体靶向工程核酸酶，例如mitoTALEN和mitoZFN，已经在具有病原体患者来源的mtDNA突变的人类细胞中进行了体外研究，最近在具有致病性mtDNA点突变的小鼠模型中进行了体内研究。这些用于转移mtDNA异质性的基因治疗工具也可以与其他旨在消除和/或防止致病性mtDNA从母体转移至儿童的疗法结合使用。