HYPOXIA ALTERS IRON HOMEOSTASIS AND INDUCES FERRITIN SYNTHESIS IN OLIGODENDROCYTES

Both iron and the major iron-binding protein ferritin are enriched in oligodendrocytes compared with astrocytes and neurons, but their funct ional role remains to be determined. Progressive hypoxia dramatically induces the synthesis of ferritin in both neonatal rat oligodendrocyte s and a human oligodendroglioma cell line. We now report that the rele ase of iron from either transferrin or ferritin-bound iron, after a de crease in intracellular pH, also leads to the induction of ferritin sy nthesis. The hypoxic induction of ferritin synthesis can be blocked ei ther with iron chelators (deferoxamine or phenanthroline) or by preven ting intracellular acidification (which is required for the release of transferrin-bound iron) with weak base treatment (ammonium chloride a nd amantadine). Two sources of exogenous iron (hemin and ferric ammoni um citrate) were able to stimulate ferritin synthesis in both oligoden drocytes and HOG in the absence of hypoxia. This was not additive to t he hypoxic stimulation, suggesting a common mechanism. We also show th at ferritin induction may require intracellular free radical formation because hypoxia-mediated ferritin synthesis can be further enhanced b y cotreatment with hydrogen peroxide, This in turn was blocked by the addition of exogenous catalase to the culture medium. Our data suggest that disruption of intracellular free iron homeostasis is an early ev ent in hypoxic oligodendrocytes and that ferritin may serve as an iron sequestrator and antioxidant to protect cells from subsequent iron-ca talyzed lipid peroxidation injury.