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

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Mitochondrial DNA repair and disease

Scientists are beginning to realise the importance of mitochondrial DNA (mtDNA) in health and disease. A European study worked to elucidate how mtDNA repair in particular can cause disease.

Health

Mitochondria, the energy production organelles of the cell, possess their own DNA. MtDNA encodes mainly protein subunits of the mitochondrial respiratory chain as well as transfer RNA molecules. Mutations in mtDNA are associated with a number of conditions including normal ageing and neurodegeneration. In spite of this, our knowledge of the mtDNA repair mechanisms is still very limited. The scope of the EU-funded MITODSBR (The role of mitochondrial DNA double-strand break repair in human disease and normal ageing) project was to investigate the molecular mechanism of mtDNA repair and its functional role in human disease. In this context, researchers studied the response of DNA replication upon encounter of oxidative DNA damage. Results demonstrated that the mtDNA replication system could not deal with certain types of mtDNA damage. MITODSBR work verified the existence of an additional DNA polymerase (PrimPol) located in the mammalian mitochondria. This polymerase has the capacity to assist the mtDNA replisome to bypass certain oxidative damage parameters. Nonetheless, other types of oxidative damage prohibited the progression of the mitochondrial replication machinery. Scientists concluded that mtDNA replication stalling due to oxidative stress was the first step leading to DNA damage. The DNA deletions seen in neurodegenerative disorders could be a consequence of the high levels of mitochondrial reactive oxygen species and could affect disease progression. In another part of the project, scientists successfully isolated mitochondrial proteins that interacted with actively replicating mtDNA. Further characterisation of these proteins is required to elucidate their precise function in DNA metabolism and involvement in mtDNA repair. Collectively, the findings of the MITODSBR study highlight the impact of mitochondrial DNA damage in disease progression and open new therapeutic avenues.

Keywords

Mitochondrial DNA, repair, ageing, neurodegeneration, DNA damage, PrimPol, oxidative stress

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