View Program - 63rd Annual Drosophila Research Conference

The dramatic growth that occurs during Drosophila larval development requires the rapid conversion of nutrients into biomass. In response to these biosynthetic demands, larval metabolism exhibits the hallmark features of aerobic glycolysis, a metabolic program ideally suited to synthesize macromolecules from carbohydrates. Central to the biosynthetic potential of aerobic glycolysis is lactate dehydrogenase (LDH), which promotes glycolytic flux by regenerating NAD⁺. We have seen that although Ldh mutants accumulate elevated NADH levels, larvae compensate for this metabolic insult by increasing glycerol-3-phosphate (G3P) production, which serves as a backup mechanism to regenerate NAD⁺, and the cooperative regulation of lactate and G3P metabolism imparts metabolic robustness on the larval glycolytic program. Further, lack of Ldh and Gpdh1 together, exhibit developmental delays, synthetic lethality, and aberrant carbohydrate metabolism. Although we understand the effect of the loss of Ldh and Gpdh1 in the whole body, tissue-specific roles of both enzymes remain unexplored. To address this deficiency, we used RNAi to understand how tissue-specific depletion of Ldh and Gpdh1 affects larval growth and metabolism. Our results demonstrate that while individual loss of either Ldh or Gpdh1 in fat body, muscle and neurons does not affect larval development, loss of both Ldh and Gpdh1 within either the fat body, muscle or neurons leads to systemic growth defects in larvae. Hence, Ldh and Gpdh1 can influence larval growth and metabolism in a cell nonautonomous manner, indicating that the cooperative activity of these two enzymes within individual tissues is capable of inducing systemic signals that coordinate intercellular metabolic states with growth of the entire organism. Finally, our preliminary findings indicate the cytokine Upd3 is a key signal in connecting loss of Ldh/Gpdh1 activity in individual tissues with systemic growth delays. Overall, our findings hint at a mechanism that coordinates larval growth with the rate of glycolytic flux in individual tissues.

Lactate and glycerol-3-phosphate metabolism cooperatively regulate larval growth in a tissue nonautonomous manner