Aluminum exposure affects transferrin-dependent and -independent iron uptake by K562 cells

Abstract

Aluminum (Al) and iron (Fe) share several physicochemical characteristics and they both bind to transferrin (Tf), entering the cell via Tf receptors (TfR). Previously, we found similar values of affinity constant for the binding of TfR to Tf carrying either Al or Fe. The competitive interaction between both metals prevented normal Fe incorporation into K562 cells and triggered the upregulation of Fe transport. In the present work we demonstrated that Al modified Fe uptake without affecting the expression of Tf receptors. Both TfR and TfR2 mRNA levels, evaluated by RT-PCR, and TfR antigenic sites, analyzed by flow cytometry, were found unchanged after Al exposure. In turn, Al did induce upregulation of non-Tf bound Fe (NTBI) uptake. This modulation was not due to intracellular Fe decrease since NTBI transport proved not to be regulated by Fe depletion. Unlike its behavior in the presence of Tf, Al was unable to compete with NTBI uptake, suggesting that both metals do not share the same alternative transport pathway. We propose that Al interference with TfR-mediated Fe incorporation might trigger the upregulation of NTBI uptake, an adaptation aimed at incorporating the essential metal required for cellular metabolism without allowing the simultaneous access of a potentially toxic metal.

Effect of Aluminium on the Levels of Some Essential Elements in Occupationally Exposed Workers

“…Aluminium-induced cytotoxicity due to chronic disruption of cell metabolism was recently described as the cause of these clinical disorders (18,19). In terms of biomonitoring, it is not yet clear which of the two measurements of Al concentration is more suitable for medical evaluation of Al exposure, urine or plasma.…”

“…Not only was aluminium exposure found to decrease serum iron and the percentage of transferrin saturation, but also to interfere with iron incorporation in the hem group, increasing free erythrocytic protoporphyrin and resulting in microcytic hypochromic anaemia (24). A competition between both metals takes place due to the fact that both Al and Fe share certain features in their biochemistry, the common route of absorption, plasma transport protein (transferrin), and metabolism (19,24). It should be mentioned that Al neurotoxicity might be related in part to the disruption of the normal Fe homeostasis and Fe-dependent cellular metabolism in the brain (25).…”

Binding of [Cr(phen)3]3+ to transferrin at extracellular and endosomal pHs: Potential application in photodynamic therapy

“…This structural shift is very important in the iron metabolism, because the transferrin receptor (TfR), located in the cell membrane, is capable of recognizing only the rotated conformation [9]. Therefore, mainly holoTf can penetrate the cell and be incorporated by it, possibly by a mechanism that involves the formation of an endosome [10]. Once the endosome is internalized, its pH decreases from 7.40 (extracellular pH) to 5.60 by a proton pump, acidification that results in the release of the Fe 3+ , and subsequent fusion of the endosome with the cell membrane to release and recycle the apoTf.…”

“…Once the endosome is internalized, its pH decreases from 7.40 (extracellular pH) to 5.60 by a proton pump, acidification that results in the release of the Fe 3+ , and subsequent fusion of the endosome with the cell membrane to release and recycle the apoTf. [10][11][12].…”

Effects of aluminium sulphate in the mouse liver: Similarities to the aging process

“…Once in the liver Al increases cells' iron uptake and oxidative status (Perez et al, 2005). Besides the spleen, the liver is the chief site of iron storage, containing 98% of total iron and a large abundance of transferrin receptors (TfRs).…”