Regulation of intracellular iron metabolism in human erythroid precursors by internalized extracellular ferritin

Human erythroid precursors grown in culture possess membrane receptors that bind and internalize acid isoferritin. These receptors are regulated by th e iron status of the cell, implying that ferritin iron uptake may represent a normal physiologic pathway. The present studies describe the fate of int ernalized ferritin, the mechanisms involved in the release of its iron, and the recognition of this iron by the cell. Normal human erythroid precursor s were grown in a 2-phase liquid culture that supports the proliferation, d ifferentiation, and maturation of erythroid precursors. At the stage of pol ychromatic normoblasts, cells were briefly incubated with Fe-59- and/or I-1 25-labeled acid isoferritin and chased. The I-125-labeled ferritin protein was rapidly degraded and only 50% of the label remained in intact ferritin protein after 3 to 4 hours. In parallel, Fe-59 decreased in ferritin and in creased in hemoglobin. Extracellular holoferritin uptake elevated the cellu lar labile iron pool (LIP) and reduced iron regulatory protein (IRP) activi ty; this was inhibited by leupeptin or chloroquine. Extracellular apoferrit in taken up by the cell functioned as an iron scavenger: it decreased the l evel of cellular tip and increased IRP activity. We suggest that the iron f rom extracellular is metabolized in a similar fashion by developing erythro id cells as is intracellular ferritin. Following its uptake, extracellular ferritin iron is released by proteolytic degradation of the protein shell i n an acid compartment, The released iron induces an increase in the cellula r LIP and participates in heme synthesis and in intracellular iron regulato ry pathways. (C) 1999 by The American Society of Hematology.