Iron moves through the body in a cycle: it is absorbed from the diet or released from body cells, carried in the plasma, taken up by the cells that need it, stored, and recovered from red cells that have been destroyed. The molecules below run that cycle, and how quickly iron can leave the stores and reach the marrow is one of the things that limits red cell production.
Transferrin and the transferrin receptor
The iron absorbed from the diet, or released from body cells, is transported in the plasma by transferrin, a bilobed protein that can carry one iron ion in each of its two lobes; it therefore exists as mono-ferric and di-ferric transferrin. The di-ferric form has the higher affinity for the transferrin receptor.
The turnover, or half-clearance time, of the iron on transferrin is normally very short, about 60 to 90 minutes, because the bone marrow needs a continuous supply for red cell production. The turnover time depends both on the level of iron in the plasma and on how much the marrow needs.
Transferrin attaches to the transferrin receptor on the surface of a cell. Almost every cell of the body carries the receptor at some point in its life, and the cells with the highest number are the developing erythroblasts, which carry about 300,000 to 400,000 of them.
Iron uptake into the cell
The transferrin with its iron attaches to the transferrin receptor, and two other molecules, DMT1 (divalent metal transporter 1) and Steap3, join the complex. The whole assembly is taken into the cell as a single vesicle formed by a clathrin-coated pit. Inside the cell:
- the vesicle is acidified, which releases the iron atoms from the transferrin;
- Steap3 reduces iron 3+ to iron 2+;
- DMT1 transports the iron into the cytoplasm;
- the vesicle returns to the plasma membrane;
- the transferrin is released, and some of the transferrin receptor is shed into the blood, where it makes up the pool of soluble transferrin receptor.
Storage and recycling of iron
Within the erythroid cells, iron is stored in the ferritin molecules. Red cells live about 120 days, so in normal conditions about 0.8 to 1% of them are phagocytosed each day by the reticuloendothelial (RE) system, the macrophages that clear old red cells; the iron released from their hemoglobin leaves the RE cell through ferroportin on its surface and passes back to the plasma, where transferrin picks it up again.
Daily iron turnover
The mass of the red cells in an adult is about 2 L, and each millilitre of red cells contains about 1 mg of elemental iron. About 1% of the red cells die each day, so about 20 mg of iron is released daily by dying red cells. Any additional iron the body needs comes from the diet: on average, in normal conditions, a man needs about 1 mg/day and a woman of childbearing age about 1.4 mg/day of elemental iron.
Regulation of iron export
Hepcidin inhibits the export of iron. It attaches to ferroportin and leads to its ubiquitination, so the transporter is removed and iron stays inside the cell. When the concentration of iron in the plasma is low, the opposing signal is erythroferrone, which is made by the developing erythroblasts and suppresses hepcidin; erythroferrone can be abundant when the erythroid pool in the marrow is very active.
Where red cells are destroyed and how much iron returns
Where the red cells are destroyed matters for how much of that recycled iron comes back. Iron released at extravascular sites is reutilised efficiently for the production of new red cells, so in extravascular hemolytic anemia the marrow has iron available. In intravascular hemolysis or blood loss anemia the iron is lost to the recycling pool, and the rate of red cell production is limited by the rate at which stored iron can be mobilised. If that mobilisation is too slow for the stimulated marrow, the cells that are produced are microcytic and hypochromic.