线粒体DNA靶向治疗

线粒体(mitochondrion)是真核生物细胞中的一种非常重要的细胞器,含有独立于细胞核染色体外的遗传物质,通过氧化磷酸化产生ATP,是细胞的能量工厂,与细胞分化、信号转导、代谢稳态等过程密切联系。线粒体功能的紊乱与癌症、神经退行性疾病、糖尿病等许多疾病的发生、发展及治疗息息相关。线粒体在细胞命运中扮演的关键角色,使对线粒体这一特殊细胞器的探索成为生命科学研究热点之一。人线粒体DNA(mitochondrial DNA, mtDNA)是一相对保守且仅16 kb的环状双链DNA分子,只含37个基因,但这些基因都是维持线粒体功能稳定必不可少的部分。随着对线粒体功能认识的不断深入,研究人员发现mtDNA突变,会导致活性氧自由基过量产生,从而引起细胞衰老,甚至引发诸多疾病,例如遗传性视神经病变、线粒体脑肌病伴高乳酸血症和卒中样发作综合征等。但是,目前针对这些线粒体基因疾病尚无非常有效的治疗手段。为了进一步了解这一关键细胞器,研究人员开发了一些有效的方法来突破线粒体的复杂屏障。本文将重点介绍并讨论近几年靶向mtDNA的研究进展,主要从药物修饰、材料递送、基因编辑等方面进行了总结,希望能为推动线粒体的研究提供一些新的思路。

Mitochondrial DNA Targeting Therapies

The mitochondrion is a particularly important organelle in eukaryotic cells. It contains its own genetic material and is coined as “the powerhouse of cells”. Mitochondria are involved in many cellular progresses such as cell signaling and metabolic homeostasis. Its dysfunction is linked to various human diseases, including cancer, neurodegenerative diseases, and diabetes. Mitochondrion has a unique DNA, a small size with 16 569 bp circular genome, encoding only 37 genes, which are key components of the electron transport chain (ETC) and translational machinery. Furthermore, the mutations of mitochondrion DNA correlate with some inherited disease such as Leber's hereditary optic neuropathy (LHON) andmitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). There are very few treatments to fully cure these diseases. As a result, researchers are interested in developing a wide range of methods to understand mitochondrial functions. In this review, we mainly focus on works in targetingmitochondrial DNA, including drug modification, material delivery and gene editing.