The flux of iron through ferritin in erythrocyte development

Terminal differentiation of erythropoietic progenitors requires the rapid accumulation of large amounts of iron, which is transported to the mitochondria, where it is incorporated into heme. Ferritin is the sole site of iron storage present in the cytosol. Yet the role of iron accumulation into ferritin in the context of red cell development had not been clearly defined. Early studies indicated that at the onset of terminal differentiation, iron initially accumulates in ferritin and precedes heme synthesis. Whether this accumulation is physiologically important for red cell development was unclear until recent studies defined an obligatory pathway of iron flux through ferritin.

The iron chaperone functions of poly rC-binding protein 1 (PCBP1) and the autophagic cargo receptor for ferritin, nuclear co-activator 4 (NCOA4) are required for the flux of iron through ferritin in developing red cells. In the absence of these functions, iron delivery to mitochondria for heme synthesis is impaired.

The regulated trafficking of iron through ferritin is important for maintaining a consistent flow of iron to mitochondria without releasing potentially damaging redox-active species in the cell. Other components of the iron trafficking machinery are likely to be important in red cell development.