Abstract
Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1a in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout Drosophila melanogaster development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in sima mutants and that these animals are unable to mobilize glycogen in hypoxia. Furthermore, we find that the estrogen-related receptor (dERR), which is a global regulator of aerobic glycolysis in larvae, is required for a competent hypoxic response. dERR binds to dHIFa and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIFa in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including upregulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs.
Highlights
The ability to adapt to limiting oxygen requires metabolic versatility, with cells transitioning toward glycolytic lactate production for energy production
Using the fruit fly as a model system, we show that hypoxic responses consist of hypoxia-inducible factor (HIF) and non-HIFdependent pathways
We provide evidence that HIF- and non-HIF-dependent pathways are complemented by the actions of the steroid hormone receptor estrogen-related receptor (ERR), which we show is essential in hypoxia
Summary
The ability to adapt to limiting oxygen requires metabolic versatility, with cells transitioning toward glycolytic lactate production for energy production. Complementing this strategic change of metabolism are complex shifts in the transcriptome, which add durability to the initial hypoxic response. At the vanguard of the transcriptional reply to hypoxia is the HIF transcriptional complex, which is comprised of the oxygen-labile hypoxia-inducible factor-1a (HIF-1a) and its stable partner HIF1b. This ancient pathway is central to the hypoxic response and is highly conserved from worms to human [1]. Hypoxia disrupts the degradative cascade, allowing HIF-1a accumulation and activation of the HIF transcription pathway [11,12]
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