U.S. Department of Health and Human Services

Discovery of a New Protein Involved in Intestinal Iron Transport

Scientists have discovered a new protein in rodents involved in intestinal iron transport, which may complement actions of other proteins required for facilitating absorption of this important nutrient. Iron is absorbed from food by cells of the small intestine and used for such essential functions as red blood cell production. In cases where insufficient iron is absorbed, anemia can result. Iron transport out of cells lining the intestine and into the circulation was thought to require an enzyme—hephaestin—that spans the cells’ membranes. This enzyme oxidizes iron into a form that can be transported out of the intestinal cells. But, when scientists created a mouse with a mutated, inactive form of hephaestin, the animals were only mildly iron-deficient, suggesting another protein was compensating for the lost hephaestin. Scientists have since undertaken a search for a new enzyme with iron-oxidizing capabilities similar to those of hephaestin. They also considered the possibility of compensation by another enzyme known to oxidize iron, called ceruloplasmin. For this research, they used rat and mouse models with genetic mutations in these iron-oxidizing enzymes, as well as models with mild, diet-induced deficiencies in either iron or copper, because activity of these enzymes is known to increase when dietary iron levels are low, and both enzymes also happen to require copper in order to perform their functions on iron. Samples of intestinal cells taken from iron-deficient rats with elevated iron-oxidizing enzymes were broken open and processed to separate the cells’ internal contents (the cytosol) from those in the cell membrane. Surprisingly, iron-oxidizing activity was detected in the cytosol, as well as in the cell membrane. Experiments with the rodents that had genetic mutations showed that iron was still oxidized, confirming the presence of a previously unknown iron-oxidizing enzyme in the cytosol of intestinal cells. This discovery of a new iron-oxidizing enzyme inside rodent intestinal cells, which may work in concert with the membrane-bound hephaestin to enable iron transport, deepens understanding of mammalian iron transport processes and related conditions.

Ranganathan PN, Lu Y, Fuqua BK, and Collins JF. Discovery of a cytosolic/soluble ferroxidase in rodent enterocytes. Proc Natl Acad Sci USA 109: 3564-3569, 2012.​