Metallothionein protects against oxidative stress-induced lysosomal destabilization.
The introduction of apo-ferritin or the iron chelator DFO (desferrioxamine) conjugated to starch into the lysosomal compartment protects cells against oxidative stress, lysosomal rupture and ensuing apoptosis/necrosis by binding intralysosomal redox-active iron, thus preventing Fenton-type reactions and ensuing peroxidation of lysosomal membranes. Because up-regulation of MTs (metallothioneins) also generates enhanced cellular resistance to oxidative stress, including X-irradiation, and MTs were found to be capable of iron binding in an acidic and reducing lysosomal-like environment, we propose that these proteins might similarly stabilize lysosomes following autophagocytotic delivery to the lysosomal compartment. Here, we report that Zn-mediated MT up-regulation, assayed by Western blotting and immunocytochemistry, results in lysosomal stabilization and decreased apoptosis following oxidative stress, similar to the protection afforded by fluid-phase endocytosis of apo-ferritin or DFO. In contrast, the endocytotic uptake of an iron phosphate complex destabilized lysosomes against oxidative stress, but this was suppressed in cells with up-regulated MT. It is suggested that the resistance against oxidative stress, known to occur in MT-rich cells, may be a consequence of autophagic turnover of MT, resulting in reduced iron-catalysed intralysosomal peroxidative reactions.
Baird
Sarah K
SK
Division of Pharmacology, Faculty of Health Sciences, Linköping University, S-58185 Linköping, Sweden.
Kurz
Tino
T
Brunk
Ulf T
UT
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002460:Cell Line; D007501:Iron / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D009336:Necrosis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology
D008668:Metallothionein; D007501:Iron; D015032:Zinc