An intimate crosstalk between iron homeostasis and oxygen metabolism regulated by the hypoxia-inducible factors (HIFs)

Oxygen and iron are among the most abundant elements and have significant roles in human biology. Iron is essential for oxygen transport and is a component of molecular O-2-carrying proteins, such as hemoglobin and myoglobin. Iron is also a constituent of redox enzymes and can occupy multiple oxidation states. An elaborate system has evolved to stringently regulate the concentrations of both, free iron and oxygen, in various sites of the body. The final destination for iron and oxygen in the cells is the mitochondria. The mitochondria require substantial amounts of iron for heme synthesis and maturation of iron-sulfur clusters, and oxygen, as the electron acceptor in oxidative phosphorylation. Therefore, the balance between the control of iron availability and the physiology of hypoxic responses is critical for maintaining cell homeostasis. Several lines of study have clearly demonstrated that the transcription factors, hypoxia-inducible factors (HIFs), play a central role in cellular adaptation to critically low oxygen levels in both normal and compromised tissues. It has also been shown that several target genes of HIFs are involved in iron homeostasis, reflecting the molecular links between oxygen homeostasis and iron metabolism. Furthermore, HIF activation is modulated by intracellular iron, through regulation of hydroxylase activity, which requires iron as a cofactor. In addition, HIF-2 alpha translation is controlled by iron regulatory protein (IRP) activity, providing another level of interdependence between iron and oxygen homeostasis.