Mechanisms Underlying Metabolic Regulation of Mutant Mitochondrial Genome Dynamics

Mitochondrial dysfunction underlies a variety of metabolic diseases, as well as age-related decline in health. Common sources of mitochondrial dysfunction include mutations in the mitochondrial genome (mtDNA), a small circular chromosome that encodes several genes essential for mitochondrial respiration. Mutant mtDNA (ΔmtDNA) has been implicated in a number of diseases characterized by metabolic dysfunction, including obesity and diabetes. However, ΔmtDNA do not follow the inheritance patterns that are typical of the nuclear genome, making it difficult to predict the risk of developing a ΔmtDNA-associated disease and highlighting the importance of investigating the cellular mechanisms governing the propagation of ΔmtDNA. We have preliminarily found metabolic signals, namely insulin signaling and the ability to metabolize glucose, to be important regulators of ΔmtDNA proliferation in a Caenorhabditis elegans model of mitochondrial disease. Specifically, insulin signaling promotes the proliferation of ΔmtDNA while glycolysis inhibition suppresses it. While these findings are consistent with previous reporting that energy metabolism is an important regulator of mitochondrial networks, the underlying mechanisms are not known. We propose to follow up on these exciting findings by investigating the role of insulin signaling, as well as the utilization of dietary nutrients, on the maintenance and propagation of a pathogenic deletion-bearing mitochondrial genome in the simple animal model, C. elegans. Specifically, our first aim seeks to characterize the downstream mechanisms by which insulin signaling modulates ΔmtDNA levels. Our second aim will characterize the mechanisms underlying the shift in ΔmtDNA levels upon altered utilization of dietary nutrients. This study will yield key insights on the mechanisms governing the propagation of diseasecausing mutations in mtDNA, as well as provide a framework for further research on the potential usage of nutritional and metabolic interventions in combating diseases associated with mitochondrial mutations.