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Relationship: 921

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Disruption, Lysosome leads to Peptide Oxidation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Disruption, Lysosome

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Peptide Oxidation

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mouse	Mus musculus	Moderate	NCBI
human	Homo sapiens	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 ^[1]. 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 ^[2]. 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 ^[2].

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The main lysosomal function is the degradation of macromolecules. To this end, they are filled with more than 50 acid hydrolases ^[3] 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 ^[4].

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Include consideration of temporal concordance here

^[5]: 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.

^[6]: 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.

^[2]: 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.

^[7]: 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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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 ^[5].

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

^[5]: murine

^[6]: murine

^[2]: murine, human

^[7]: human

References

List of the literature that was cited for this KER description. More help

↑ 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