INDUCTION OF FERRITIN SYNTHESIS BY OXIDATIVE STRESS - TRANSCRIPTIONALAND POSTTRANSCRIPTIONAL REGULATION BY EXPANSION OF THE FREE IRON POOL

Ferritin, by regulating the ''free'' intracellular iron pool, controls iron-catalyzed generation of reactive oxygen species, but its role in oxidative damage is still unclear. We show that ferritin synthesis is significantly stimulated in the liver of rats subjected to oxidative stress by treatment with phorone, a glutathione-depleting drug, RNA-ba ndshift assays document reduced activity of iron regulatory factor, in particular of IRF(B), the cytoplasmic protein that post-transcription ally controls ferritin mRNA translation, Furthermore, Northern blot an alysis shows increased accumulation of H and L subunit mRNAs, and nucl ear run-on experiments provide evidence of transcriptional activation, Direct measurements of intracellular free iron levels by EPR indicate that the increased ferritin synthesis can be mediated by an expansion of the free iron pool, An early drop of ferritin content after phoron e treatment indicates that part of the iron that fuels the free pool m ight derive from ferritin degradation, Present data seem to suggest th at, under conditions of oxidative stress, liver ferritin can represent either a pro- or an anti-oxidant in a time-dependent manner, In fact, its early degradation contributes to expand the intracellular free ir on pool that, later on, activates multiple molecular mechanisms to rec onstitute ferritin content, thus Limiting the prooxidant challenge of iron.