Flexibility in energy metabolism supports hypoxia tolerance in Drosophila flight muscle:: metabolomic and computational systems analysis

The fruitfly Drosophila melanogaster offers promise as a genetically tractable model for studying adaptation to hypoxia at the cellular level, but the metabolic basis for extreme hypoxia tolerance in flies is not well known. Using H-1 NMR spectroscopy, metabolomic profiles were collected under hypoxia. Accumulation of lactate, alanine, and acetate suggested that these are the major end products of anaerobic metabolism in the fly. A constraint-based model of ATP-producing pathways was built using the annotated genome, existing models, and the literature. Multiple redundant pathways for producing acetate and alanine were added and simulations were run in order to find a single optimal strategy for producing each end product. System-wide adaptation to hypoxia was then investigated in silico using the refined model. Simulations supported the hypothesis that the ability to flexibly convert pyruvate to these three by-products might convey hypoxia tolerance by improving the ATP/H+ ratio and efficiency of glucose utilization.