ALUMINUM ALTERS THE COMPARTMENTALIZATION OF IRON IN FRIEND-ERYTHROLEUKEMIA CELLS

Aluminum (Al) accumulation in renal failure patients can result in enc ephalopathy, osteomalacia, and anemia. Since the cellular mechanisms o f Al toxicity are not completely understood we used cultured Friend er ythroleukemia cells (FEC) as a model system of Al-induced anemia. In t his system Al accumulation leads to decreased cell growth and hemoglob in synthesis despite increased iron (Fe) uptake by transferrin (Tf) en docytosis. In FEC we evaluated the effect of Al on the cellular and su bcellular 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 st udies were done at 24, 48, 72, and 96 hours after plating. The highest concentration of intracellular Al was found in mitochondria with less er amounts in the nucleus, and the least was in cytosol. The rate of F e uptake was higher in Al-loaded FEC without a proportionally increase d rate of exit. This resulted in higher concentrations of Fe in Al-loa ded FEC. Subcellular fractionation following the uptake of Fe-59, I-12 5-Tf in, Al-loaded FEC showed increased uptake of Fe-59 in the nuclear and mitochondrial compartments with no increase in the cytosol. Al-lo aded FEC showed decreased ferritin content and decreased uptake of Fe- 59 by ferritin. Increased membrane lipid peroxidation occurred in Al-l oaded FEC at 96 hours as assessed by cellular malonyldialdehyde accumu lation. These results indicate that Al disrupts Fe metabolism in FEC b y increasing cellular Fe content with increased compartmentalization o f Fe in the mitochondria and nuclei, decreased ferritin content, and d ecreased uptake of Fe by ferritin. The Al-loading of FEC produces an F e depletion-like state as Tf-associated Fe uptake increases and ferrit in synthesis decreases. The Al-induced disturbances in Fe metabolism l ead to membrane lipid peroxidation and irreversible damage to the FEC.