Ferritin uptake by human erythroid precursors is a regulated iron uptake pathway

Iron delivery to mammalian cells is traditionally ascribed to diferric transferrin (Tf). We recently reported that human erythroid precursor cells possess specific membrane receptors that bind and internalize acid isoferritin. Here we show that ferritin uptake by these cells is highly regulated and that the internalized ferritin-iron is used for heme synthesis and thus, this process could constitute a physiological pathway for iron assimilation. Ferritin was internalized by a specific, saturable process, distinct from the uptake of iron associated with albumin. Ferritin uptake downregulated transferrin-receptor expression, indicating that internalized ferritin-iron was recognized as an integral part of the cellular iron content. Ferritin receptor expression was coordinated to cell development and was tightly regulated by cellular iron status. Receptor abundance was increased by iron-depletion and decreased by iron-loading, while the affinity of the ferritin receptor for acid isoferritin remained nearly constant (k(d) = 4.1 ± 0.5 x 10^-8 mol/L). Under all experimental conditions, ferritin- and transferrin-receptor expression was closely coordinated, suggesting that these pathways possess a common regulatory element. It is concluded that ferritin uptake by erythroid cells constitutes an iron uptake pathway in addition to the classical transferrin uptake pathway.