Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages

Abstract

Edited by Vladimir SkulachevKeywords: Apoptosis Ferritin Lysosomes MnSOD GSH Oxidative stress a b s t r a c t 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.

Oxidant-induced autophagy and ferritin degradation contribute to epithelial–mesenchymal transition through lysosomal iron

“…Thus, DFO will permanently bind iron inside lysosomes, and once it is released from the degraded ferritin molecule, the passage of iron over normal intact lysosomal membranes is impaired; and as part of the LIP, ferritin synthesis is hindered 11,12,16,20,21. A less well-known mechanism for lysosomal iron to exit lysosomes, and trigger ferritin synthesis, is through nonintact leaking lysosomal membranes following membrane damage 28,29. If lysosomal membrane damage involves iron-driven oxidative reactions, DFO will maintain iron in a nonreactive state, and leakage of iron and the resulting upregulation of ferritin synthesis will be prevented 11,12,16,20,21…”

Ferritin-stimulated lipid peroxidation, lysosomal leak, and macroautophagy promote lysosomal “metastability” in primary hepatocytes determining in vitro cell survival

“…In addition, the release of ROS and HNE by limited "low-level" LMP may also promote perilysosomal HNE-P generation. Since cytosolic acidification, ROS, iron, HNE, and HNE-P are able to stimulate autophagy as well as antioxidant responses and also interfere with PCD control [18,[44][45][46][47][48][49][50], lowlevel LMP could readily adopt stress signaling properties without seriously affecting cell survival. In contrast, a shift of LMP toward an advanced degree due to enhanced or continued lysosomal stress will also allow the release of larger molecules, such as lysosomal proteases, which more readily stimulate PCD.…”

The Neuroprotection of Lysosomotropic Agents in Experimental Subarachnoid Hemorrhage Probably Involving the Apoptosis Pathway Triggering by Cathepsins via Chelating Intralysosomal Iron

“…Moderate LMP was an important and critical inducer of apoptosis [26]. It is noteworthy that ROS was regarded as a pivotal factor destabilizing the lysosomal membranes within lysosomes, where the acidic condition and the labile iron facilitated a Fenton-type reaction, particularly intralysosomal hydroxyl radicals HO• production [27].…”