DNA Polymerase Gamma Subunit 1 Mediates the Selective Elimination of Mutant mtDNA from the Drosophila Female Germline
Year: 2023
Type: dissertation
Abstract: Mitochondrial DNA (mtDNA) encodes essential components of the oxidative phosphorylation machinery which is the major source of cellular ATP. mtDNA is susceptible to accumulating mutations due to its uniparental inheritance and negligible recombination. If left unchecked, these mutations would be passed on over generations and become incapable of supporting the ATP requirement of cells, resulting in a severe decline in the fitness of the species. To counter this, the female germline has evolved a purifying selection mechanism to ensure that a healthy population of mtDNA is passed on to the next generation. Despite its importance, details underlying this process have only recently been coming to light and much remains to be uncovered. In Drosophila melanogaster, the prevailing model for selection posits that wildtype mtDNA replicates more frequently than mutant genomes in the early germline. Here, I present an alternative model in which the degradation of mtDNA drives a bulk of selection in the germline. I show that the bulk of selection takes place earlier in the germline than previously thought, at stages when mtDNA replication is limited. I demonstrate that the exonuclease activity of the mitochondrial DNA polymerase gamma 1 (PolG1) is essential for selection, in support of a degradative mode of selection. I also show that PolG1 preferentially interacts with mutantmtDNA during selection, suggesting its selectivity for mutant mtDNA. I further identify thatmitochondrial ATP levels regulate the exonuclease activity of PolG1, providing a mechanism through which PolG1 may selectively degrade mutant mtDNA. Promisingly, work from ourcollaborators suggests that this regulation of PolG1 exonuclease activity by ATP is conserved in humans, perhaps suggesting a conserved mechanism of selection. In summary, I posit a novel mechanism for selection in which PolG1 degrades mtDNA within mitochondria with low ATP levels to ensure that a healthy population of mtDNA is passed on to sustain the next generation.
Source: TSpace (University of Toronto)
Author: Jeedigunta, Swathi Prabha
Institution: University of Toronto
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7132934397