HIF- and Non-HIF-Regulated Hypoxic Responses Require the Estrogen-Related Receptor in Drosophila melanogaster

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. © 2013 li et al.