API

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Relationship: 3273

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

Superoxide generation, increased leads to Increase, Oxidative Stress

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Superoxide generation, increased
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increase, Oxidative Stress

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
Succinate dehydrogenase inhibition leading to increased insulin resistance through reduction in circulating thyroxine adjacent High Low Simon Thomas (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 Do not cite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
Term Scientific Term Evidence Link
mammals mammals High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

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

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

Superoxide, a reactive oxygen radical is produced by one-electron reduction of molecular oxygen by multiple intracellular enzymes. Under normal physiological conditions, superoxide generation and breakdown are held in balance by the enzymatic and non-enzymatic components of the cell, including superoxide dismutase, with the result that dangerous levels of superoxide are not produced; under conditions in which superoxide production exceeds the ability of the cell to catabolise it, reactive oxygen molecules can accumulate, resulting in oxidative damage to cell components, a condition known as oxidative stress.

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

The following pubmed search was performed on 30/05/2023:

"superoxide"[Title] and "oxidative stress"[Title] AND mitochondri*[Title]

which generated 37 hits. The abstracts were read to identify articles that appeared relevant to the development of this KER, resulting in 12 being selected for study.

Evidence Supporting this KER

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

This KER is supported both by its biological plausibility and by empirical data.

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

Superoxide (O2-.) is produced by one-electron reduction of molecular oxygen (O2) by multiple intracellular enzymes, including xanthine oxidase, nitric oxide synthase, aldehyde oxidase, NADPH oxidases, fumarase, and complexes within the mitochondrial electron transport chain, the latter source being quantitatively the most important in most tissues. Superoxide dismutase isozymes in the mitochondria, cytoplasm and extracellular fluid catalyse the disproportionation of superoxide to molecular oxygen and hydrogen peroxide (H2O2):

2O2-. + 2H+ -> H2O2 + O2

Hydogen peroxide can be catabolised by catalase or glutathione peroxidase, reducing the risk of reactions involving the peroxide ion (O22-).

Superoxide can also generate the highly reactive hydroxyl radical (HO.) by Fe2+-catalysed reaction with hydrogen peroxide:

O2-. + H2O2  -> HO. + O2

and peroxynitrite (ONOO.), a strong oxidant, by reaction with nitric oxide (NO.):

O2-. + NO.  -> ONOO.

Under normal physiological conditions, superoxide generation and breakdown are held in balance by the enzymatic and non-enzymatic (such as glutathione) components of the cell's antioxidant capability. Under conditions, however, in which superoxide production exceeds the ability of the cell to catabolise it, reactive oxygen molecules can accumulate with detrimental impact on the cell components, a condition known as oxidative stress. See Indo et al (2015) for a review.

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

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
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

Hinderfield, D. et al (2004), "Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice", Journal of Neurochemistry, Vol 88, pp 657-67.

Indo, H.P. et al (2015), "A mitochondrial superoxide theory for oxidative stress diseases and aging", Journal of Clinical Biochemistry and Nutrition", Vol 56, pp 1-7.

Khand, F.D. et al (2002), "Mitochondrial superoxide production during oxalate-mediated oxidative stress in renal epithelial cells", Free Radicals in Biology and Medicine, Vol 32, pp 1339-50.

Kowrulu, R.A. et al (2006), "Overexpression of mitochondrial superoxide dismutase in mice prevents the retina from diabetes-induced oxidative stress", Free Radicals in Biology and Medicine, Vol 41, pp 1191-6.