MITODSBR

The role of mitochondrial DNA double-strand break repair in human disease and normal ageing

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 Obiettivo del progetto (Objective)

'Mitochondrial DNA (mtDNA) deletions accumulate in aged post-mitotic tissue and in individuals with neurodegenerative diseases, leading to local energy defects. Understanding the mechanism of mtDNA deletion formation is an essential step in trying to prevent their occurrence. My hypothesis is that mtDNA deletions occur during mtDNA repair via a double strand break (DSB) repair pathway. I will address the different components of this hypothesis by mechanistic studies of cell lines derived from patients, transgenic cell culture and in vitro biochemistry. This project also aims to identify and characterize novel mtDNA DSB repair factors. We will study candidate mtDSB genes by RNAi and confirm that the proteins are recruited to mtDNA after specific induction of mtDSBs. In a complementary approach we will search for protein interactions partners of the already identified mtDSB repair proteins by immunoprecipitations. Identified proteins will be analyzed in vitro, with the long-term goal to reveal the molecular details of human mtDSB repair. Further we will use patient cell lines and transgenic cell culture to identify new therapeutic pathways that can be used to counteract mtDNA deletion formation in neurodegenerative disease and normal ageing. If we can show as I propose that repair is the mechanism underlying mtDNA deletion formation, increasing levels of antioxidants could prevent the induction of DSBs and mtDNA deletions in neurodegenerative disease.'

Introduzione (Teaser)

Mitochondrial DNA deletions are emerging as the underlying cause in many diseases. A European study will unveil how mitochondrial DNA gets damaged and investigate the mechanisms for repair or prevention

Descrizione progetto (Article)

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