Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
EMBO Rep. 2020 Mar 4;21(3):e49612. doi: 10.15252/embr.201949612. Epub 2020 Feb 19.
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.
线粒体 DNA（mtDNA）编码一组基因，这些基因负责氧化磷酸化。人类 mtDNA 的致病性突变通常是异质性的，即在野生型 mtDNA 与致病性 mtDNA 共存的情况下，只有当致病性 mtDNA 百分比超过生化表现的阈值时，才会出现生物能量缺陷。生殖系发育过程中的 mtDNA 分离可以解释从一代到下一代异质性的一些极端变化。具有高致病性 mtDNA 异质性的患者可能患有真正的线粒体疾病，目前尚无治愈方法。将 mtDNA 异质性向野生型 mtDNA 转变可能为患者提供治疗选择。线粒体靶向工程核酸酶，如 mitoTALENs 和 mitoZFNs，已在携带致病性患者源性 mtDNA 突变的人类细胞中进行了体外研究，最近在致病性 mtDNA 点突变的小鼠模型中进行了体内研究。这些用于改变 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 从母亲传递给孩子的治疗方法联合使用。
