Purging mutant mitochondrial DNA: from mechanisms to therapies

线粒体是细胞中产生我们从食物中产生的大部分能量的部分，这一过程依赖于它们包含的许多小环DNA--线粒体DNA。线粒体DNA突变是遗传病最常见的原因之一，目前还没有有效的治疗方法。一般来说，一个人、一个器官或一个细胞必须携带许多突变的线粒体DNA来显示线粒体功能障碍和疾病，因此一个长期的目标是找到一种方法来减少突变分子的数量，因为这可能从根本上改变疾病的进程。最近我们发现，我们可以用突变的线粒体DNA削弱线粒体，同时通过使用限制细胞内营养供应的小分子，让那些线粒体DNA复制良好的人茁壮成长。这代表着线粒体医学的一项重要突破，因为这些小分子可能被用来治疗许多线粒体DNA疾病。然而，尽管结果非常有希望，但到目前为止，该策略被证明只对实验室培养的皮肤细胞中最常见的导致线粒体DNA突变的疾病有效。因此，该项目旨在解决重要的悬而未决的问题，旨在为线粒体疾病患者的测试设计和监测提供信息并提供便利。首先，我们计划确定有多少种突变的线粒体DNA对我们的小分子敏感。其次，我们能否清除其他细胞类型的突变线粒体DNA，尤其是神经元和肌肉细胞，因为肌肉和大脑经常受到线粒体疾病的影响？第三，小分子在混合了正常和突变线粒体DNA的小鼠身上有同样的效果吗？由于我们对对抗突变的线粒体DNA的潜在机制有很好的了解，而且我们和其他人有证据表明，我们的一个小分子改变了两个富含线粒体的器官中的营养代谢和线粒体的能力，我们预计会产生积极的结果。此外，我们还计划进一步剖析影响突变线粒体DNA的途径和细胞过程，因为这可以识别新的、也许更好的小分子，并有助于我们了解任何不容易治疗的细胞、组织或突变线粒体变体。因此，该项目有可能在为目前无法治愈的人类疾病的重要群体开发第一个小分子疗法方面迈出实质性的一步。它还将通过营养和代谢物操作推进线粒体DNA复制调控的新领域，这可能有助于解释为什么线粒体(DNA)功能障碍与许多人类疾病和衰老有关。

Mitochondria are the parts of the cell that produce most of the energy we generate from food, and this process depends on the many small circles of DNA they contain - mitochondrial DNAs. Mutations in mitochondrial DNA are among the most frequent causes of genetic disease, and currently, there are no effective treatments for these types of disease. Generally, an individual person, organ or cell has to carry many mutant mitochondrial DNAs to display mitochondrial malfunction and disease, and so a long-standing goal has been to find a means of reducing the number of mutant molecules, as this could radically change the course of the disease. Recently we have discovered that we can cripple the mitochondria with mutant mitochondrial DNAs, while permitting those with good copies of mitochondrial DNA to thrive, using small molecules that restrict nutrient supply inside the cell. This represents an important breakthrough in mitochondrial medicine as these small molecules could potentially be used to treat many mitochondrial DNA disorders. However, while the results are highly promising, to date the strategy has been shown to be effective only against the most common disease causing mitochondrial DNA mutant, in skin cells cultured in the laboratory. Hence this project aims to address important outstanding questions that aim to inform and facilitate the design and monitoring of tests in patients with mitochondrial disease. First, we plan to determine how many types of mutant mitochondrial DNA are susceptible to our small molecules. Second, can we purge other cell types of mutant mitochondrial DNA, most pertinently neurons and muscle cells, as muscle and brain are frequently affected in mitochondrial disease? Third, do the small molecules have the same effect in a mouse that has a mixture of normal and mutant mitochondrial DNAs? Because we have a good understanding of the underlying mechanism which acts against the mutant mitochondrial DNAs and because we and others have evidence that one of our small molecules changes nutrient metabolism and mitochondrial capacity in two organs rich in mitochondria, we expect to produce positive results. Moreover, we plan also to further dissect the pathways and cell processes that affect mutant mitochondrial DNAs, as this can identify new, perhaps better, small molecules, and it can help us to understand any cell, tissue or mutant mitochondrial variant that is not susceptible to treatment. Therefore, this project has the potential to make substantial steps towards developing the first small molecule therapies for an important group of currently incurable human disorders. It will also advance the new area of regulation of mitochondrial DNA replication via nutrient and metabolite manipulation that could help to explain why mitochondrial (DNA) dysfunction has been implicated in many human disorders and ageing.