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Disruption, Lysosome leads to Peptide Oxidation
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
The lysosome contains redox-active labile irons which are suggested to be involved in local reactive oxygen species (ROS) formation via a Fenton-type reaction . Many iron containing metallo-proteins are degraded within the lysosomes, leading to an enrichment of this transition metal within this organelle. Iron which is released inside lysosomes due to degradation processes is transported to the cytoplasm and then stored in ferritin, a ubiquitous and highly conserved iron-binding protein . Induction of lysosomal membrane disruption by lysosomotropic detergents has been found to cause an induction of ferritin, together with an increase of cellular ROS and concomitant reduction of the antioxidants MnSOD (manganese superoxide dismutase) and GSH (glutathione). A suggested explanation for this is the release of free iron into the cytosol .
Evidence Collection Strategy
Evidence Supporting this KER
The main lysosomal function is the degradation of macromolecules. To this end, they are filled with more than 50 acid hydrolases  and are additionally enriched with iron, as explained above. Via the Fenton-type reaction, iron can catalyse formation of ROS. Thus, damage of the lysosomal membrane can induce cell death mechanisms such as necrosis and apoptosis, depending on the severity of lysosomal damage .
Include consideration of temporal concordance here
: By using galactosyl dextran-retinal (GDR) nanogels, the authors demonstrated a negative correlation between ROS production and lysosome function in dendritic cells. Neutralizing the lysosomal pH with NH4Cl partially recovered lysosomal fluorescence but dramatically attenuated GDR-induced ROS after 4h of incubation.
: The authors found that active autophagy is related to basal ROS generation in neuronal cells. Using relevant fluorescent probes, localisation of ROS at lysosomes was found. The decrease of lysosomal ROS by treatment of cells with lysosomal inhibitors delayed the mitochondrial ROS burst and thus cell toxicity.
: The authors suggest that ROS is initially produced due to LMP and release of lysosomal contents, which further promotes mitochondrial membrane permeabilisation (MMP) in apoptosis. This was further supported by experiments with NH4Cl pre-exposure, in which intra-lysosomal trapped NH4+ reduced cellular oxidative stress and apoptotic cell death by blocking lysosomal accumulation of the trigger (O-methyl-serine dodecylamide hydrochloride, MSDH). ROS production was found as early as 3 h and clear reduction of antioxidant enzymes took place from 6 h following exposure, prior to alteration of MMP.
: Using positively charged polystyrene nanoparticles (PS-NH2) as initiators, the authors performed a time-resolved experiment where lysosomal damage was found as the first adverse effect, followed by an increase in reactive oxygen species and subsequent loss in mitochondrial membrane potential. They could show that KEup occurred at earlier time points (3-6 hours) than KEdown (starting after 8 hours).
Uncertainties and Inconsistencies
All studies were performed in varying cell types, either immune or brain cells. Applicability in other cell types such as hepatocytes needs to be determined.
Known modulating factors
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
To date, there are no quantitative studies to determine this KER. However, when lysosomal damage is reduced by neutralizing the lysosomal pH with NH4Cl, ROS-induction is strongly decreased .
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- ↑ Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem. 2010 Jan 1;285(1):667-74
- ↑ 2.0 2.1 2.2 2.3 Ghosh M, Carlsson F, Laskar A, Yuan XM, Li W. Lysosomal membrane permeabilization (LMP) causes oxidative stress and ferritin induction in macrophages. FEBS Lett. 2011 Feb 18;585(4):623-9
- ↑ Johansson AC, Appelqvist H, Nilsson C, Kågedal K, Roberg K, Ollinger K. Regulation of apoptosis-associated LMP. Apoptosis. 2010 May;15(5):527-40
- ↑ Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 2001 Jun;8(6):569-81
- ↑ 5.0 5.1 5.2 Wang C, Li P, Liu L, Pan H, Li H, Cai L, Ma Y. Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation. Biomaterials. 2016 Feb;79:88-100
- ↑ 6.0 6.1 Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem. 2010 Jan 1;285(1):667-74
- ↑ 7.0 7.1 Wang F, Bexiga MG, Anguissola S, Boya P, Simpson JC, Salvati A, Dawson KA: Time resolved study of cell death mechanisms induced by amine-modified polystyrene nanoparticles. Nanoscale 2013, 5:10868–76