Iron-mediated oxidative stress plays an essential role in ferritin-induced cell death.
Previously, we have demonstrated an apoptosis-inducing activity of an acidic, H-chain-rich isoferritin secreted from primary rat hepatocytes in vitro. Because this proapoptotic property may be responsible for the growth-inhibitory and immunosuppressive effects described for certain ferritin species, we aimed to address the mechanism by which ferritin can trigger cell death. Suggesting a pivotal role for iron, iron chelation by desferrioxamine significantly abrogates ferritin-mediated apoptosis and necrosis in primary rat hepatocytes and substantially lowers the extent of protein modification by 4-hydroxynonenal (HNE)-a major lipid peroxidation (LPO) product. Furthermore, supplementing the cultures with the radical-scavenging compound trolox also provided significant protection from ferritin-mediated apoptosis. Moreover, a significant increase in micronucleated cells upon exposure to ferritin indicates that ferritin also introduces damage to DNA. Based on these observations we therefore propose that endocytosis of extracellular ferritin increases the level of free ferrous iron in the lysosomal compartment, promoting Fenton chemistry-based oxidative stress involving LPO and increased lysosomal membrane permeability. Subsequently, the release of reactive lysosomal content leads to cellular damage, in particular modification of protein and DNA induced by HNE and other reactive aldehydic LPO products. Together, these effects will trigger apoptosis and necrosis based on the upregulation of p53, increased mitochondrial membrane permeability, and proapoptotic Fas signaling as described recently. In conclusion, based on their iron-storing ability, secreted acidic isoferritins may act as soluble mediators of oxidative stress under certain physiological and pathophysiological conditions.
Bresgen
Nikolaus
N
Department of Cell Biology, University of Salzburg, A-5020 Salzburg, Austria. nikolaus.bresgen@sbg.ac.at
Jaksch
Heidi
H
Lacher
Heide
H
Ohlenschläger
Ingo
I
Uchida
Koji
K
Eckl
Peter M
PM
D000447:Aldehydes / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D005260:Female; D005293:Ferritins / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344
D000447:Aldehydes; D000911:Antibodies, Monoclonal; D002839:Chromans; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine; C027576:4-hydroxy-2-nonenal; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid