SIGNIFICANCE:Oxygen metabolism and iron homeostasis are closely linked. Iron facilitates the oxygen-carrying capacity of blood, and its deficiency causes anaemia. Conversely, excess free iron is detrimental for stimulating the formation of reactive oxygen species, causing tissue damage. The amount and distribution of iron thus need to be tightly regulated by the liver-expressed hormone hepcidin. This review analyses the roles of key oxygen-sensing pathways in cellular and systemic regulation of iron homeostasis; specifically, the prolyl hydroxylase domain (PHD)/ hypoxia-inducible factor (HIF) and the KEAP1/NRF2 pathways, which mediate tissue adaptation to low and high oxygen, respectively. Recent Advances: In macrophages, NRF2 regulates genes involved in haemoglobin catabolism, iron storage, and iron export. NRF2 was recently identified as the molecular sensor of iron-induced oxidative stress and is responsible for BMP6 expression by liver sinusoidal endothelial cells, which in turn activates hepcidin synthesis by hepatocytes to restore systemic iron levels. Moreover, NRF2 orchestrates the activation of antioxidant defences that are crucial to protect against iron toxicity. On the other hand, low iron/hypoxia stabilize renal HIF-2α via inactivation of iron-dependent PHD dioxygenases, causing an erythropoietic stimulus that represses hepcidin via an inhibitory effect of erythroferrone on bone morphogenetic proteins. Intestinal HIF-2α is also stabilized, increasing the expression of genes involved in dietary iron absorption. CRITICAL ISSUES:An intimate crosstalk between oxygen-sensing pathways and iron regulatory mechanisms ensures that fluctuations in systemic iron levels are promptly detected and restored. FUTURE DIRECTIONS:The realization that redox-sensitive transcription factors regulate systemic iron levels suggests novel therapeutic approaches.
Antioxidants & redox signaling