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The response to insufficient oxygen (hypoxia) is orchestrated by the conserved hypoxia-inducible factor (HIF). However, HIF-independent hypoxia response pathways exist that act in parallel with HIF to mediate the physiological hypoxia response. Here, we describe a hypoxia response pathway controlled by  Caenorhabditis elegans  nuclear hormone receptor NHR-49, an orthologue of mammalian peroxisome proliferator-activated receptor alpha (PPARα). We show that  nhr-49  is required for animal survival in hypoxia and is synthetic lethal with  hif-1  in this context, demonstrating that these factors act in parallel. RNA-seq analysis shows that in hypoxia  nhr-49  regulates a set of genes that are  hif-1- independent, including autophagy genes that promote hypoxia survival. We further show that nuclear hormone receptor  nhr-67  is a negative regulator and homeodomain-interacting protein kinase  hpk-1  is a positive regulator of the NHR-49 pathway. Together, our experiments define a new, essential hypoxia response pathway that acts in parallel with the well-known HIF-mediated hypoxia response.

Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans