Cryptic single-cell mitochondrial DNA mutations in human brain aging and neurodegeneration

Background: Mitochondrial DNA (mtDNA) mutations accumulate with age, but it is not clear whether they contribute to common age-related diseases. Analysing thousands of single cells, our preliminary work has revealed an unexpected extraordinary diversity of different mtDNA-mutations that cannot be detected by analysing pooled cells in bulk tissue samples. These ?cryptic? mtDNA-mutations are acquired during life and appear to disrupt expression of genes linked to aging and neurodegeneration. Approach: We will map the single-cell landscape of mtDNA in the human brain throughout the lifecourse, and show how ?cryptic? mutations contribute to cellular ageing and neurodegenerative mechanisms. Modelling our observations in mice, we will determine whether three different interventions reduce the cryptic-mutation burden and thereby modify pathways of neurodegeneration. Impact: This will provide experimental evidence that cryptic-mtDNA-mutations contribute to ageing and neurodegeneration, and give evidence that this can be controlled, opening a new avenue for treatment.