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Iron plays an essential role in many biological processes, but also catalyzes the formation of reactive oxygen species (ROS), which can cause molecular damage. Iron homeostasis is therefore a critical determinant of fitness. In  Caenorhabditis elegans , insulin/IGF-1 signaling (IIS) promotes growth and reproduction but limits stress resistance and lifespan through inactivation of the DAF-16/FoxO transcription factor (TF). We report that long-lived  daf-2  insulin/IGF-1 receptor mutants show a  daf-16 –dependent increase in expression of  ftn-1 , which encodes the iron storage protein H-ferritin. To better understand the regulation of iron homeostasis, we performed a TF–limited genetic screen for factors influencing  ftn-1  gene expression. The screen identified the heat-shock TF  hsf-1 , the MAD bHLH TF  mdl-1 , and the putative histone acetyl transferase  ada-2  as activators of  ftn-1  expression. It also revealed that the HIFα homolog  hif-1  and its binding partner  aha-1  (HIFβ) are potent repressors of  ftn-1  expression.  ftn-1  expression is induced by exposure to iron, and we found that  hif-1  was required for this induction. In addition, we found that the prolyl hydroxylase EGL-9, which represses HIF-1 via the von Hippel-Lindau tumor suppressor VHL-1, can also act antagonistically to VHL-1 in regulating  ftn-1 . This suggests a novel mechanism for HIF target gene regulation by these evolutionarily conserved and clinically important hydroxylases. Our findings imply that the IIS and HIF pathways act together to regulate iron homeostasis in  C. elegans . We suggest that IIS/DAF-16 regulation of  ftn-1  modulates a trade-off between growth and stress resistance, as elevated iron availability supports growth but also increases ROS production.

Insulin/IGF-1 and Hypoxia Signaling Act in Concert to Regulate Iron Homeostasis in Caenorhabditis elegans