title: Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages.
abstract: Moderate lysosomal membrane permeabilization (LMP) is an important inducer of apoptosis. Macrophages are professional scavengers and are rich in hydrolytic enzymes and iron. In the present study, we found that LMP by lysosomotropic detergent MSDH resulted in early up-regulation of lysosomal cathepsins, oxidative stress and ferritin up-regulation, and cell death. Lysosomotropic base NH(4)Cl reduced the ferritin induction and oxidative stress in apoptotic cells induced by MSDH. Cysteine cathepsin inhibitors significantly protected cell death and oxidative stress, but had less effect on ferritin induction. We conclude that oxidative stress induced by lysosomal rupture causes ferritin induction with concomitant mitochondrial damage, which are the potential target for prevention of cellular oxidative stress and cell death induced by typical lysosomotropic substances in different disorders.
authors.affiliation: Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden.
authors.forename: Moumita
authors.initials: M
authors.lastname: Ghosh
authors.forename: Fredrik
authors.initials: F
authors.lastname: Carlsson
authors.forename: Amit
authors.initials: A
authors.lastname: Laskar
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yuan
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000468:Alkalies / Q000494:pharmacology; D000577:Amides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D003902:Detergents / Q000633:toxicity; D005293:Ferritins / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects*; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives / Q000633:toxicity; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000468:Alkalies; D000577:Amides; D003902:Detergents; C407126:O-methyl-serine dodecylamide hydrochloride; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D012694:Serine; D005293:Ferritins; D002403:Cathepsins