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|Title:||A study of the selective pressures on inherited mitochondrial DNA mutations in mitotic cell populations|
|Abstract:||Mitochondrial DNA (mtDNA) mutations accumulate somatically with age in normal individuals causing defects in oxidative phosphorylation (OXPHOS), with no selective pressures promoting their accumulation or removal. mtDNA mutations are also inherited through the germline causing mtDNA disease. In contrast to somatic mutations, they are lost in blood over time, suggesting selective pressure against them. This project aims to further investigate the selective loss of inherited mtDNA point mutations in mitotic tissues, using gastrointestinal epithelium as a model. I have determined the mtDNA mutation load and OXPHOS protein levels in various gastrointestinal segments of patients with the inherited m.3243A>G and m.8344A>G mtDNA mutations. The data shows selective loss of these mutations in the mitotic epithelium, but not the post-mitotic smooth muscle and suggests that the selection occurs in the gastrointestinal stem cells. I have further characterised a mouse model of mitochondrial disease carrying the inherited m.5024C>T mutation and have used them to study potential mechanisms of selective mtDNA mutation loss. These mice show: (1) loss of the m.5024C>T in the mitotic spleen and gastrointestinal epithelium with age but not in the post-mitotic tissues; (2) the rate of mutation loss is related to the rate of epithelial cell turnover; (3) the mutation loss in the intestinal epithelium is consistent with maintained levels of OXPHOS proteins with age, in contrast to the accumulation of cells with OXPHOS defects in aged wild-type mice; (4) significantly upregulated mitochondrial proliferation in the intestinal epithelium. These key findings highlight differences in the selective pressures on inherited and somatic mtDNA mutations in mitotic tissue, and the contrasting tissue-specific dynamics of inherited mtDNA mutations in mitotic and post-mitotic tissues. These findings are important to further the understanding of phenotype development, progression and potential treatment of mtDNA disease, and the effect of mtDNA mutations on ageing stem cell biology.|
|Appears in Collections:||Institute of Neuroscience|
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|Su T 2019.pdf||Thesis||17.59 MB||Adobe PDF||View/Open|
|dspacelicence.pdf||Licence||43.82 kB||Adobe PDF||View/Open|
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