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 HIF homolog
hif-1 and its binding partner
aha-1 (HIF) 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.