Essential but toxic: Controlling the flux of iron in the body

Iron is an essential nutrient, but, because it is toxic when present in excess, its levels in the body are tightly controlled. This regulation is affected by controlling the release of iron into the plasma. Most iron enters the plasma from macrophages, which recycle iron from senescent erythrocytes, but dietary iron absorption and the release of hepatocyte storage iron are other major sources. Cellular iron export is mediated by the membrane iron transporter ferroportin 1, in conjunction with an iron oxidase. Hephaestin provides this oxidase activity in the intestine, whereas ceruloplasmin is the oxidase used by most other tissues. The liver-derived peptide hepcidin binds to ferroportin 1 and removes it from the cell surface, thus reducing iron donation to the plasma. The levels of hepcidin, in turn, reflect body iron requirements. At the cellular level, ferroportin 1 can also be regulated independently of hepcidin by hypoxia-inducible factors and the iron regulatory proteins. The hepcidinferroportin axis plays a critical role in regulating body iron homeostasis.