Red blood cells use a molecule called hemoglobin to transport oxygen around the body. To make hemoglobin, cells require iron to build a component called heme. If an individual does not get enough iron in their diet, the body cannot produce enough red blood cells, or the cells lack hemoglobin. This condition is known as iron deficiency anemia, and it affects around one-third of the world’s population.
Researchers did not know exactly how iron levels control red blood cell production, though several proteins had been identified to play important roles. Heme forms in the cell's mitochondria: the compartments in the cell that supply it with energy. When heme levels in a developing red blood cell are low, a protein called HRI reduces the production of many proteins, most importantly the proteins that make up hemoglobin. HRI also boosts the production of a protein called ATF4, which switches on a set of genes that help both the cell and its mitochondria to adapt to the lack of heme. In turn, HRI and ATF4 reduce the activity of a signaling pathway called mTORC1, which controls the production of proteins that help cells to grow and divide.
To understand in more detail how iron and heme regulate the production of new red blood cells, Zhang et al. looked at immature red blood cells from the livers of developing mice. Some of the mice lacked the gene that produces HRI, and some experienced iron deficiency. Comparing gene activity in the different mice revealed that in the developing blood cells of iron-deficient mice, HRI largely reduces the rate of protein production in both the mitochondria and the wider cell. At the same time, the increased activity of ATF4 allows the mitochondria to carry on releasing energy and the cells to continue developing. Zhang et al. also found that a protein that inhibits the mTORC1 signaling pathway needs to be active for the new red blood cells to mature.
Overall, the results suggest that drugs that activate HRI or block the activity of the mTORC1 pathway could help to treat anemia. The next step is to test the effects that such drugs have in anemic mice and cells from anemic people.