Iron homeostasis: recently identified proteins provide insight into novel control mechanisms

Abstract

Iron is an essential nutrient required for a variety of biochemical processes. It is a vital component of the heme in hemoglobin, myoglobin, and cytochromes and is also an essential cofactor for non-heme enzymes such as ribonucleotide reductase, the limiting enzyme for DNA synthesis. When in excess, iron is toxic because it generates superoxide anions and hydroxyl radicals that react readily with biological molecules, including proteins, lipids, and DNA. As a result, humans possess elegant control mechanisms to maintain iron homeostasis by coordinately regulating iron absorption, iron recycling, and mobilization of stored iron. Disruption of these processes causes either iron-deficient anemia or iron overload disorders. In this minireview, we focus on the roles of recently identified proteins in the regulation of iron homeostasis.

FIGURE 1.

Model of hepcidin regulation by iron. Central to this model is that hepcidin transcription is regulated by HJV, which acts as a co-receptor for BMP. Upon binding to the BMP receptor (BMPR), a signaling cascade is initiated resulting in the translocation of SMAD4 to the nucleus, where it stimulates hepcidin transcription. The binding of HJV to neogenin (neo) is necessary for the release of HJV from cells. The release is dependent on cleavage by the protease furin. Where in the cell this occurs remains to be determined. In addition, cleavage of HJV is inhibited by Tf. Soluble HJV inhibits BMP-mediated signaling. Mutations in TfR2, HFE, or Tf result in a decreased level of hepcidin mRNA. Tf stabilizes TfR2. The mechanism by which the Tf-TfR2-HFE complex affects hepcidin transcription is unknown.