The Drosophila Hypoxia-inducible factor 1-alpha is required to establish the larval glycolytic program

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 encoding enzymes 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 mimic those observed in dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α stabilize one another, as loss either transcription factor results in loss of the other. Considering that the mammalian homologs of ERR and Hif1α also stabilize one another through heterodimer formation, our findings establish the fly as a powerful genetic model for studying the interaction between these two key metabolic regulators. RNAseq profiling of Sima1/20 mutant Drosophila embryos compared to heterozygous Sima 1/+ controls at 8-12, 12-16, and 16-20 hours post egglay and RNAseq profiling of Sima1/20 mutant Drosophila larvae 60HPE compared to heterozygous Sima 1/+ controls.