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The Significance Of Mitochondrial DNA Half-life To The Lifespan Of Post-mitotic Cells

Alan G Holt, Adrian M Davies

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AbstractThe proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging, and age related neurodegenerative conditions. In this study we model effect of mtDNA half-life on mtDNA competition and selection.Individual cells effectively form a closed ecosystem containing a large population of independently replicating mtDNA. We would expect competition and selection to occur between wild type mtDNA and various mutant variants. There is a symbiotic relationship between the cell and the mitochondria, and unrestricted mtDNA replication would be detrimental to the host cell. Deletion mutations of mtDNA are relatively common and give a replication advantage to the shorter sequence, as this could be lethal to the host cell, we would expect to see differences in mtDNA replication in short and long lived cells.In this paper, we use a computer simulation of mtDNA replication, where mtDNA sequences may undergo deletion errors and give rise to mutant species that can compete with the wild type. This study focuses on longer lived cells where the wild type mtDNA is expected to be more susceptible to displacement by mutants. Our simulations confirm that deletion mutations have a replication advantage over the wild type due to decreased replication time. Wild type survival times diminished with increased mutation probabilities. The relationship between survival time and mutation rate was non-linear; a ten-fold increase in mutation probability resulted in a halving in wild type survival time.In contrast a modest increase in the mtDNA half-life had a profound affect on the wild type survival time in the presence of deletion mutants, thereby, mitigating the replicative advantage of shorter sequence mutations. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could be a therapeutic strategy.