Purging mutant mitochondrial DNA: from mechanisms to therapies

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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.