A Drosophila Model for the Regulation of Aerobic Glycolysis

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Project Summary The Tennessen Lab uses the fruit fly, Drosophila melanogaster, as a model to understand how carbohydrate metabolism supports the biosynthetic and energetic demands of animal growth and development. Our ongoing studies focus on a metabolic program known as the Warburg effect (aerobic glycolysis). This metabolic program allows growing and proliferating cells to metabolize large quantities of glucose in order to generate biomass and synthesize pro-growth signaling molecules. While aerobic glycolysis is most commonly associated with tumors, where it promotes the growth and survival of cancer cells, healthy animal cells, such as stem cells and activated T cells, also use this metabolic program to drive biosynthesis and regulate cell fate decisions. Therefore, basic studies of aerobic glycolysis have the potential to not only identify metabolic mechanisms that could be targeted to inhibit tumor growth but also to reveal how healthy cells manipulate glycolytic metabolism as a means of supporting normal developmental growth. I have discovered that the fruit fly Drosophila melanogaster also uses aerobic glycolysis to promote growth and have established the fly as a model system for studying the genetic mechanisms that regulate this metabolic program. My initial efforts using this model have proven successful, as I have determined that the Drosophila Estrogen-Related Receptor (dERR) is a master regulator of aerobic glycolysis. My lab will now expand upon these initial observations to identify the molecular mechanisms that both activate and repress aerobic glycolysis in vivo. Furthermore, we have determined that Drosophila larvae use aerobic glycolysis to synthesize the oncometabolite L-2-hydroxyglutarate (L-2HG). This compound is almost exclusively studied in the context of cancer metabolism and endogenous L-2HG function remains largely unexplored. We will determine how L-2HG synthesis is controlled in vivo and explore how this oncometabolite controls normal animal growth. Finally, we will use a combination of genetics, genomics, and metabolomics to determine how the disruption of key reactions in aerobic glycolysis affects growth and physiology. Many of these enzymes represent potential therapuetic targets and our innovative approach provides a rare opportunity to systematically evaluate the effects of inhibiting individual glycolytic enzymes in a whole animal system. Moreover, our studies also explore the compensatory metabolic pathways that are activated in response to decreased glycolytic flux, which in a clinical setting, could render tumors insenstive to drug treatments. Finally, we have uncovered an unexpected correlation between the repression of aerobic glycolysis, increased levels of fatty acid oxidation, and pyrimidine metabolism. My lab will use this unexpected discovery as a foundation to explore the poorly understood role of fatty acid beta-oxidation in nucleotide production. Our studies will allow, for the first time, a genetic dissection of the mechanisms regulating aerobic glycolysis within the context of normal animal development and will potentially uncover novel approaches to control cellular growth at a metabolic level.