Specific iron chelators determine the route of ferritin degradation.
Deferoxamine (DFO) is a high-affinity Fe (III) chelator produced by Streptomyces pilosus. DFO is used clinically to remove iron from patients with iron overload disorders. Orally administered DFO cannot be absorbed, and therefore it must be injected. Here we show that DFO induces ferritin degradation in lysosomes through induction of autophagy. DFO-treated cells show cytosolic accumulation of LC3B, a critical protein involved in autophagosomal-lysosomal degradation. Treatment of cells with the oral iron chelators deferriprone and desferasirox did not show accumulation of LC3B, and degradation of ferritin occurred through the proteasome. Incubation of DFO-treated cells with 3-methyladenine, an autophagy inhibitor, resulted in degradation of ferritin by the proteasome. These results indicate that ferritin degradation occurs by 2 routes: a DFO-induced entry of ferritin into lysosomes and a cytosolic route in which iron is extracted from ferritin before degradation by the proteasome.
De Domenico
Ivana
I
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Ward
Diane McVey
DM
Kaplan
Jerry
J
D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology
D007502:Iron Chelating Agents; D017262:Siderophores; D005293:Ferritins; D046988:Proteasome Endopeptidase Complex; D003676:Deferoxamine