Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster

The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we discover that Sima, the Drosophila ortholog of Hif1α, is also essential for establishing the larval glycolytic program. Using a multi-omics approach, we demonstrate that sima mutants fail to properly activate aerobic glycolysis and die during larval development with metabolic defects that phenocopy dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein. Considering that the mammalian homologs of ERR and Hif1α also cooperatively regulate aerobic glycolysis in cancer cells, our findings establish the fly as a powerful genetic model for studying the interaction between these two key metabolic regulators.