UC Santa Barbara

The endosymbiotic theory explains the origin of eukaryotic cells, in which one bacterium engulfed another bacterium resulting in the creation of mitochondria. Over time the engulfed bacterium transferred parts of its genome to the genome of the engulfing cell, eventually resulting in a dependence of the host on the organelle, and vice versa. However, with this theory, one must consider the problem of selfish DNA. Mitochondria contain their own DNA, containing a small set of essential genes that are involved in the oxidative phosphorylation machinery. How the host cell keeps this mtDNA in check is a large area of research, since if the population of mtDNA accumulates mutations, it results in mitochondrial disease. The general process by which mutated mtDNA is removed is known as purifying selection, but the various mechanisms through which this process operates are largely unknown.

My project tested various levels at which purifying selection may be operating using the genetically tractable nematode C. elegans and the mtDNA deletion mutant uaDf5. In this thesis, I describe foundational work to characterize mitochondrial dynamics and maintenance of mtDNA over the lifespan of the animal, focused primarily on the germline. Our data shows that there are three mechanisms through which purifying selection is operating: asymmetric segregation in early embryonic divisions, PCD in the mature female germline, and insulin signaling. In addition to the discovery of these mechanisms, I also characterized the dynamics of mtDNA selection during development and aging, as well as the dynamics of mitochondrial activity in response to the environment. Lastly, I discovered a potent epigenetically activated mtDNA quality control mechanism that is activated in response to an initiating genetic event, or “IGE”. Altogether, my work shows how C. elegans is an extremely useful system for examining mtDNA dynamics and for the further elucidation of the various ways in which the mtDNA population is maintained.