Oxidative Stress Leads to a Rapid Alteration of Transferrin Receptor Intravesicular Trafficking

Several studies have demonstrated that perturbations of intracellular oxidative balance play a key role in numerous physiological as well as pathological conditions leading to various morbidity states. In previous studies we have shown that the free radical inducer menadione rapidly and specifically...

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Bibliographic Details
Published in:Experimental cell research 1998-05, Vol.241 (1), p.102-116
Main Authors: Malorni, Walter, Testa, Ugo, Rainaldi, Gabriella, Tritarelli, Elena, Peschle, Cesare
Format: Article
Language:English
Subjects:
Acetylcysteine - pharmacology
Cell Compartmentation
Down-Regulation - drug effects
Eukaryotic Cells - chemistry
Eukaryotic Cells - drug effects
Exocytosis - drug effects
Free Radical Scavengers - pharmacology
Hemostatics - pharmacology
HL-60 Cells - chemistry
HL-60 Cells - drug effects
HL-60 Cells - metabolism
Humans
Hydrogen Peroxide - pharmacology
Intracellular Membranes - chemistry
Intracellular Membranes - drug effects
Intracellular Membranes - metabolism
Oxidants - pharmacology
Oxidative Stress - physiology
Receptors, Cell Surface - drug effects
Receptors, Cell Surface - metabolism
Receptors, Transferrin - chemistry
Receptors, Transferrin - drug effects
Receptors, Transferrin - metabolism
Signal Transduction - drug effects
Tumor Cells, Cultured - chemistry
Tumor Cells, Cultured - drug effects
Tumor Cells, Cultured - metabolism
Vitamin K - pharmacology
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Summary:Several studies have demonstrated that perturbations of intracellular oxidative balance play a key role in numerous physiological as well as pathological conditions leading to various morbidity states. In previous studies we have shown that the free radical inducer menadione rapidly and specifically downmodulates the membrane transferrin receptor (TfR) by blocking receptor recycling. This modulation is due to receptor redistribution and not to receptor loss. Here we show that other oxidant compounds, such as hydrogen peroxide, also induce a rapid downmodulation of membrane TfR and that pretreatment of cells with the antioxidant, thiol supplier,N-acetylcysteine inhibits the downmodulation of these receptors elicited by either menadione or hydrogen peroxide. This observation suggests that intracellular thiol redox status may be a critical determinant of TfR dowmodulation induced by oxidative stress. Furthermore, immunocytochemical results show that, in menadione-treated cells, TfRs are associated with the Golgi complex, where normally only 20% of total cellular TfRs is found and is mainly detected in the cytoplasm as scattered punctuations. Accordingly, menadione and hydrogen peroxide also elicited a downmodulation of low density lipoprotein receptor (LDLR) which mediates, like TfR, the transport of nutrients to the cell and is endocytosed through clathrin-coated pits. Finally, experiments carried out using okadaic acid, an inhibitor of phosphatases, suggest that H202and menadione downmodulate surface TfR via different biochemical pathways. Taken together these results suggest the existence of a potentially important protective mechanism through which iron uptake is prevented in oxidatively imbalanced cells. Iron uptake can in fact give rise to the formation of highly toxic hydroxyl radicals reacting with hydrogen peroxide and leading to cytotoxicity. Downmodulation of surface TfR may thus represent the physiological control mechanism for reducing iron uptake in diverse pathological conditions including hypoxia-reperfusion injury, acquired immunodeficiency syndrome, and aging.
ISSN:0014-4827
1090-2422
DOI:10.1006/excr.1998.4020