Genome Evolution and Ageing

Since the 1970's the involvement of mitochondria in the ageing process has been recognized. The accumulation of mitochondrial dysfunction with age is one of the classic hallmarks of the ageing process. Many different analyses have identified the age-related accumulation of cells displaying mitochondrial dysfunction in the tissues of long-lived animals. Molecular analyses have identified the accumulation of mitochondrial DNA point mutations, structural aberrations of the mitochondrial chromosome, and a decrease in the number of mtDNA copies found within each cell. A typical somatic cell can contain 100s to 1000s of mitochondrial chromosomal copies, which under normal circumstances, provide excess wildtype copies of any of the given genes which protects against accumulating point mutations in a process known as the mitochondrial threshold effect. Over time, a deleterious point mutation or large deletion in the mtDNA can, through the stochastic replication mechanisms of mtDNA, become relatively more prevalent within that cell. This, combined with the age-related decrease in total mtDNA copy number may eventually leave the cell lacking sufficient wildtype copies to maintain normal function, leading the mitochondrial dysfunction.

The Stewart lab focuses on these research questions – how do the mitochondria acquire these mutations? How do they clonally expand to lead to mitochondrial deficiency? What effects do these sporadic deficient cells have on organismal health and ageing?

To address these questions using short-lived model organisms, we need to utilized models with accelerated mitochondrial DNA mutagenesis, such as the mtDNA mutator mouse. This model expresses a proofreading-deficient mitochondrial DNA polymerase, which is encoded in the nuclear DNA, expressed in the cytosol, and then imported into the mitochondria where it leads to an increased rate of mtDNA mutagenesis. These mutations can be transmitted through the female germline to study their effects on ageing, or mouse lineages with defined pathogenic mutations can be bred to study both the ageing process due to mitochondrial dysfunction, or as animal models for heritable mitochondrial DNA diseases of humans. Recent collaborative work in our lab has been testing novel, experimental therapies on these models of mitochondrial DNA diseases in hopes of identifying potential therapies for those suffering from mitochondrial disorders.

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