Mitochondrial DNA repair and disease

Apart from nuclear DNA, every cell possesses another source of genetic material located in specialised organelles known as mitochondria. We inherit mitochondrial DNA entirely from our mothers, and mutations are associated with a number of diseases, including neurodegeneration, as well as normal ageing. However, our knowledge on the mechanisms that mediate repair of mitochondrial DNA is limited.

Seeking to address this, the EU-funded project 'The role of mitochondrial DNA double-strand break repair in human disease and normal ageing' (MITODSBR) will investigate how deletions occur in mitochondrial DNA and which factors are implicated in repair. Apart from maintaining mitochondrial DNA integrity, the aim is also to identify new therapeutic pathways for preventing mutations and deletions.

Using RNA interference technology, scientists will downregulate the expression of certain genes, and study their impact following induction of mitochondrial DNA double-strand breaks. In a complementary immunoprecipitation approach, they are in the process of identifying DNA damage repair factors and putative partners.

During the first part of the project, researchers found that oxidative stress stalls mitochondrial DNA replication and can lead to deletions. This could be the case in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, which are associated with high levels of reactive oxygen species.

These findings emphasise the domino effect of mitochondrial DNA damage towards the formation of DNA deletions, and their subsequent involvement in the progression of various diseases. This new insight into the mechanisms of neurodegeneration opens up new avenues for future research and therapeutic exploitation. In the last part of the MITODSBR project, researchers envision the identification of pathways that could be exploited for the design of novel intervention strategies