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Relationship: 1731

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

Lipid Peroxidation leads to General Apoptosis

Upstream event

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

Lipid Peroxidation

Downstream event

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

General Apoptosis

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

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
CYP2E1 activation and formation of protein adducts leading to neurodegeneration	adjacent	High	High	Jelle Broeders (send email)	Under development: Not open for comment. Do not cite

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

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

Lipid peroxidation can induce apoptosis due to two different toxic effects. First of all lipids are responsible for maintaining the integrity of cellular membranes. Due to peroxidation of the lipids in the cellular membrane they lose their composition, structure and dynamics of lipid membranes. Various functions are lost, there is an increase of membrane rigidity, decrease activity of membrane-bound enzymes and altered permeability. Secondly there is the formation of highly reactive compounds such as lipid peroxides (MDA, HNE). These lipid peroxides can generate more ROS or can crosslink with important proteins in the cell. Several apoptosis pathways are started due to increased levels of ROS and HNE. p53 is induced and phosphorylated by HNE, as well as inducement of death receptor Fas (CD95). Also due to lipid peroxidation an energetic disturbance is reached, since the protein pumps lost their function. This can lead to neuronal cell death.

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

It is biological plausible that lipid peroxidation can lead to apoptosis of cells.

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

There are two mechanisms of apoptosis induced by HNE (main product of lipid peroxidation), which are the extrinsic and the intrinsic pathway. Extrinsic pathway is triggered by the binding of tumour necrosis factor (TNF) to their death receptors (DR) on the cell surface. HNE can induce extrinsic apoptosis in two different ways, but is mainly activated by Fas aggregation by to HNE adduct formation on the cysteins of the Fas. The promotion of Fas/CD95 DR expression, which belong to the TNF-α family, is induced by HNE. Li et al. showed that a higher concentration in HLE B-3 cells leads to a higher expression of Fas. Furthermore knockout GSTA4 mouse, GSTA4 is an antioxidant for HNE, showed a higher expression of Fas since HNE concentration increased. These studies were performed in different organ tissues of mice. After activation and expression of Fas a pathway is started towards apoptosis by ASK1, JNK an Jun proteins. Jun stimulates the intrinsic apoptotic pathway and stimulate AP-1, pro apoptotic genes, expression after phosphorylation. Sharma et al. showed that an increased HNE concentration leads to a higher expression of ASK1 and JNK. When Fas was inhibited apoptosis was stopped. On the other hand HNE can stimulate a negative feedback loop against apoptosis by stimulating the expression of Daxx, which has a negative effect on ASK1-JNK.

In the intrinsic pathway HNE can affect mitochondrial injury, leading to an increased level of Ca²⁺. This induces apoptotic signals as well as cytochrome c which is released from the mitochondria (known as mitochondrial outer membrane permeabilization (MOMP). Also the redox status of mitochondria can be affected by HNE, leading to mitochondrial crisis and activation of caspases. Liu et al. showed that HNE treatment in Jurkat cells induced caspase 8,3 and 9 activity. Caspase 9 is part of the intrinsic apoptotic pathway. HNE can also cause DNA damage since HNE is genotoxic, which induces activation of p53 in combination with oxidative stress. p53 also interacts with the intrinsic apoptotic pathway.

In two more recent studies a more direct link is shown between lipid peroxidation and cell death. With the use of Deuterated Polyunsaturated Fatty Acid (D-PUFA) treatment, which are deuterium-reinforced polyunsaturated fatty acids and are more sensitive against ROS, a significantly decrease in cell death was shown with toxicant inducement. Also a decrease was shown in lipid peroxidation products. D-PUFA works as an inhibitor against lipid peroxidation.

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

Apoptosis is a mechanism of cell death which occurs during lipid peroxidation. Since cell death is a general term used other mechanisms could also play a role. When enormous levels of ROS and HNE are generated even necrosis can occur. Another form is apoptosis is ferroptosis, which is also linked with lipid peroxidation. Also the defence mechanisms of cells against HNE are not described, which should be taken into account.

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

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

References

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

Ayala, A., Muñoz, M. F. & Argüelles, S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Medicine and Cellular Longevity 2014, (2014).

Sultana, R., Perluigi, M. & Butterfield, D. A. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Free Radical Biology and Medicine 62, 157–169 (2013).

Gaschler, M. M. & Stockwell, B. R. Lipid peroxidation in cell death. Biochemical and Biophysical Research Communications 482, 419–425 (2017).

Dalleau, S., Baradat, M., Guéraud, F. & Huc, L. Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death Differ. 20, 1615–30 (2013).

Li, J. et al. Regulation of CD95 (Fas) expression and Fas-mediated apoptotic signaling in HLE B-3 cells by 4-hydroxynonenal. Biochemistry 45, 12253–12264 (2006).

Engle, M. R. et al. Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: Generation and analysis of mGsta4 null mouse. Toxicol. Appl. Pharmacol. 194, 296–308 (2004).

Sharma, R. et al. 4-Hydroxynonenal self-limits Fas-mediated DISC-independent apoptosis by promoting export of Daxx from the nucleus to the cytosol and its binding to Fas. Biochemistry 47, 143–156 (2008).

Salomoni, P. & Khelifi, A. F. Daxx: Death or survival protein? Trends in Cell Biology 16, 97–104 (2006).

Liu, W., Porter, N. A., Schneider, C., Brash, A. R. & Yin, H. Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition. Free Radic. Biol. Med. 50, 166–178 (2011).

Moreira, P. I. et al. Mitochondria: A therapeutic target in neurodegeneration. Biochimica et Biophysica Acta - Molecular Basis of Disease 1802, 212–220 (2010).

Liu, W. et al. 4-Hydroxynonenal Induces a Cellular Redox Status-Related Activation of the Caspase Cascade for Apoptotic Cell Death. J. Cell Sci. 113 ( Pt 4, 635–641 (2000).

Knoll, N. et al. Genotoxicity of 4-hydroxy-2-nonenal in human colon tumor cells is associated with cellular levels of glutathione and the modulation of glutathione S-transferase A4 expression by butyrate. Toxicol. Sci. 86, 27–35 (2005).

Angelova, P. R. et al. Lipid peroxidation is essential for ??-synuclein-induced cell death. J. Neurochem. 133, 582–589 (2015).

Elharram, A. et al. Deuterium-reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer’s disease. FEBS J. (2017). doi:10.1111/febs.14291