Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Free Radic Biol Med ; 80: 48-58, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25532933

ABSTRACT

Several pathologies are associated with elevated levels of serum ferritin, for which growth inhibitory properties have been reported; however, the underlying mechanisms are still poorly defined. Previously we have described cytotoxic properties of isoferritins released from primary hepatocytes in vitro, which induce apoptosis in an iron and oxidative stress-dependent mode. Here we show that this ferritin species stimulates endosome clustering and giant endosome formation in primary hepatocytes accompanied by enhanced lysosomal membrane permeability (LMP). In parallel, protein modification by lipid peroxidation-derived 4-hydroxynonenal (HNE) is strongly promoted by ferritin, the HNE-modified proteins (HNE-P) showing remarkable aggregation. Emphasizing the prooxidant context, GSH is rapidly depleted and the GSH/GSSG ratio is substantially declining in ferritin-treated cells. Furthermore, ferritin triggers a transient upregulation of macroautophagy which is abolished by iron chelation and apparently supports HNE-P clearance. Macroautophagy inhibition by 3-methyladenine strongly amplifies ferritin cytotoxicity in a time- and concentration-dependent mode, suggesting an important role of macroautophagy on cellular responses to ferritin endocytosis. Moreover, pointing at an involvement of lysosomal proteolysis, ferritin cytotoxicity and lysosome fragility are aggravated by the protease inhibitor leupeptin. In contrast, EGF which suppresses ferritin-induced cell death attenuates ferritin-mediated LMP. In conclusion, we propose that HNE-P accumulation, lysosome dysfunction, and macroautophagy stimulated by ferritin endocytosis provoke lysosomal "metastability" in primary hepatocytes which permits cell survival as long as in- and extrinsic determinants (e.g., antioxidant availability, damage repair, EGF signaling) keep the degree of lysosomal destabilization below cell death-inducing thresholds.


Subject(s)
Autophagy/drug effects , Culture Media, Conditioned/pharmacology , Ferritins/pharmacology , Hepatocytes/drug effects , Intracellular Membranes/drug effects , Lysosomes/drug effects , Adenine/analogs & derivatives , Adenine/pharmacology , Aldehydes/pharmacology , Animals , Apoptosis/drug effects , Culture Media, Conditioned/chemistry , Endocytosis , Epidermal Growth Factor/pharmacology , Female , Glutathione/metabolism , Glutathione Disulfide/metabolism , Hepatocytes/metabolism , Hepatocytes/ultrastructure , Intracellular Membranes/metabolism , Intracellular Membranes/ultrastructure , Iron Chelating Agents/pharmacology , Leupeptins/pharmacology , Liver/cytology , Liver/drug effects , Liver/metabolism , Lysosomes/metabolism , Lysosomes/ultrastructure , Molecular Imaging , Permeability/drug effects , Primary Cell Culture , Protease Inhibitors/pharmacology , Protein Aggregates , Rats , Rats, Inbred F344
SELECTION OF CITATIONS
SEARCH DETAIL
...