Relocation of lysosomal enzymes induces mitochondria-mediated oxidative stress, release of cytochrome c, and apoptosis
(English)Manuscript (preprint) (Other academic)
Oxidative stress induces apoptosis, or necrosis, initiated by iron-catalyzed, intra-lysosomal oxidation leading to lysosomal rupture. Moderate lysosomal disruption induces apoptosis, while more extensive release of lysosomal contents results in necrosis. Enhanced cellular production of reactive oxygen (presumably of mitochondrial origin) also occurs during apoptosis caused by a variety of proapoptotic agonists, raising the question of whether increased oxidant generation is causal or consequential. In mixtures of rat liver lysosomes and mitochondria, selective rupture of the lysosomes by the lysosornotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH) triggers augmented mitochondrial production of reactive oxygen species and release of cytochrome c. These mitochondrial effects are also caused by addition of purified cathepsins B and D, as well as phospholipase A2 (PLA2). We have earlier shown that PLA2 is activated by lysosomal rupture in cells undergoing apoptosis, and we now find that PLA2 - but not cathepsins B or D - causes destabilization of the membranes of semi-purified lysosomes, suggesting an amplification mechanism. In intact cultured fibroblasts, added MSDH induces lysosomal rupture, intracellular oxidant production, and apoptosis. These results suggest that initiation of the apoptotic cascade by agonists other than exogenous oxidants may involve early release of lysosomal constituents (such as cathepsins Band D) and activation of PLA2. These agents may act in concert to promote mitochondrial oxidant production, further lysosomal rupture and, finally, mitochondrial cytochrome c release. Thus, non-oxidant agonists of apoptosis may further amplify the process through oxidant mechanisms.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-81656OAI: oai:DiVA.org:liu-81656DiVA: diva2:555501