ALUMINUM ALTERS THE COMPARTMENTALIZATION OF IRON IN FRIEND-ERYTHROLEUKEMIA CELLS

Aluminum (Al) accumulation in renal failure patients can result in encephalopathy, osteomalacia, and anemia. Since the cellular mechanisms of Al toxicity are not completely understood we used cultured Friend erythroleukemia cells (FEC) as a model system of Al-induced anemia. In this system Al accumulation leads to decreased cell growth and hemoglobin synthesis despite increased iron (Fe) uptake by transferrin (Tf) endocytosis. In FEC we evaluated the effect of Al on the cellular and subcellular accumulation of Fe, ferritin concentration, the uptake of Fe by ferritin, the exit of cellular Fe, and membrane lipid peroxidation. FEC were grown in media with or without the addition of Al-Tf and studies were done at 24, 48, 72, and 96 hours after plating. The highest concentration of intracellular Al was found in mitochondria with lesser amounts in the nucleus, and the least was in cytosol. The rate of Fe uptake was higher in Al-loaded FEC without a proportionally increased rate of exit. This resulted in higher concentrations of Fe in Al-loaded FEC. Subcellular fractionation following the uptake of Fe-59, I-125-Tf in, Al-loaded FEC showed increased uptake of Fe-59 in the nuclear and mitochondrial compartments with no increase in the cytosol. Al-loaded FEC showed decreased ferritin content and decreased uptake of Fe-59 by ferritin. Increased membrane lipid peroxidation occurred in Al-loaded FEC at 96 hours as assessed by cellular malonyldialdehyde accumulation. These results indicate that Al disrupts Fe metabolism in FEC by increasing cellular Fe content with increased compartmentalization of Fe in the mitochondria and nuclei, decreased ferritin content, and decreased uptake of Fe by ferritin. The Al-loading of FEC produces an Fe depletion-like state as Tf-associated Fe uptake increases and ferritin synthesis decreases. The Al-induced disturbances in Fe metabolism lead to membrane lipid peroxidation and irreversible damage to the FEC.