Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages

• Published in: FEBS letters 2011-02, Vol.585 (4), p.623-629
• Main Authors: Ghosh, Moumita, Carlsson, Fredrik, Laskar, Amit, Yuan, Xi-Ming, Li, Wei
• Format: Article
• Language: English
• Subjects: Alkalies - pharmacology; Amides - toxicity; Animals; Apoptosis; Apoptosis - drug effects; Cathepsins - antagonists & inhibitors; Cathepsins - metabolism; Cell Line; Detergents - toxicity; Ferritin; Ferritins - metabolism; GSH; Humans; Intracellular Membranes - drug effects; Lysosomes; Lysosomes - drug effects; Lysosomes - enzymology; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; MEDICIN; MEDICINE; Mice; Mitochondria - drug effects; MnSOD; Oxidative stress; Oxidative Stress - drug effects; Permeability - drug effects; RNA, Messenger - metabolism; Serine - analogs & derivatives; Serine - toxicity; Serine Proteinase Inhibitors - pharmacology; Time Factors; Up-Regulation - drug effects
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1016/j.febslet.2010.12.043

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 4Cl 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.