Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis

Faculty of Health Sciences, Linköping University, Sweden.
European Journal of Biochemistry (Impact Factor: 3.58). 10/2003; 270(18):3778-86. DOI: 10.1046/j.1432-1033.2003.03765.x
Source: PubMed

ABSTRACT Exposure of mammalian cells to oxidant stress causes early (iron catalysed) lysosomal rupture followed by apoptosis or necrosis. Enhanced intracellular production of reactive oxygen species (ROS), presumably of mitochondrial origin, is also observed when cells are exposed to nonoxidant pro-apoptotic agonists of cell death. We hypothesized that ROS generation in this latter case might promote the apoptotic cascade and could arise from effects of released lysosomal materials on mitochondria. Indeed, in intact cells (J774 macrophages, HeLa cells and AG1518 fibroblasts) the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH) causes lysosomal rupture, enhanced intracellular ROS production, and apoptosis. Furthermore, in mixtures of rat liver lysosomes and mitochondria, selective rupture of lysosomes by MSDH promotes mitochondrial ROS production and cytochrome c release, whereas MSDH has no direct effect on ROS generation by purifed mitochondria. Intracellular lysosomal rupture is associated with the release of (among other constituents) cathepsins and activation of phospholipase A2 (PLA2). We find that addition of purified cathepsins B or D, or of PLA2, causes substantial increases in ROS generation by purified mitochondria. Furthermore, PLA2 - but not cathepsins B or D - causes rupture of semipurified lysosomes, suggesting an amplification mechanism. Thus, initiation of the apoptotic cascade by nonoxidant agonists may involve early release of lysosomal constituents (such as cathepsins B and D) and activation of PLA2, leading to enhanced mitochondrial oxidant production, further lysosomal rupture and, finally, mitochondrial cytochrome c release. Nonoxidant agonists of apoptosis may, thus, act through oxidant mechanisms.

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Available from: Fernando Antunes, Oct 13, 2014
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    • "[2] According to this concept, oxidative damage of lysosomes could result in released lysosomal enzymes acting on the mitochondria, where ROS formation would be enhanced and/or cytochrome c and other proapoptotic factors would be released. [3] Many related studies have produced data consistent with these reports. For instance, dithiocarbamates (DCs) are sulfur-based metal chelators that are known to exert pro-oxidant and antioxidant effects in both cell-free and biological systems. "
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    • "However, the Type II reaction is considered the most frequent pathway responsible for cell death [14, 16–18]. Oxidative stress caused by PDT is known to cause membrane lipid peroxidation or rupture and DNA damage that may lead to apoptosis or necrosis [19]. Apoptosis occurs through a series of intracellular and extracellular biochemical milieu. "
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    • "In autophagic cell death, lysosomes fuse with autophagosomes to form autophagolysosomes, by which their contents are degraded.54 In apoptosis, cathepsins are released from lysosomes into the cytoplasm and trigger a cascade of intracellular degradation.53,55,56 The involvement of lysosomes in both programmed cell death pathways55–57 may suggest an involvement of cathepsins as a functional link between apoptosis and autophagy. "
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