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Relationship: 922

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

Peptide Oxidation leads to N/A, Mitochondrial dysfunction 1

Upstream event

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

Peptide Oxidation

Downstream event

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

N/A, Mitochondrial dysfunction 1

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
rat	Rattus norvegicus	Moderate	NCBI
mouse	Mus musculus	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 mitochondrion consist of a plethora of antioxidant enzymes to defend against oxidative stress, such as catalases, which has been found in the liver, glutathione peroxidase, and thioredoxin peroxidase ^[1] ^[2]. At the same time, the mitochondrion itself is one of the main sources of intracellular ROS formation ^[3].

NAD(P)H plays a central role in the redox state of the mitochondrion: NADP is reduced, in part, by the activity of the NADH/NADP transhydrogenase that functions as a proton pump ^[1] and has a reductive effect on glutathione and thioredoxin. This directly links mitochondrial coupling and the membrane potential to the redox potential. As a consequence, an imbalance in the NAD(P) redox status can lead to mitochondrial permeability transition (MPT), a nonselective permeabilization of the inner mitochondrial membrane ^[4]. An imbalance of the redox state of these pyridine nucleotides and thus condition of oxidative stress can lead to an increased influx of Ca2+, which in turn facilitates activation of the mitochondrial permeability transition pore, leading to apoptosis ^[5] ^[6].

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

Overwhelming the mitochondrial antioxidant defence system and subsequent uncoupling of the respiratory chain leads to MPT, resulting in loss of matrix components, impairment of mitochondrial functionality and substantial induction of apoptosis ^[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

A direct effect of oxidative stress induction (by using t-butylhydroperoxide TBH) on the opening of the mitochondrial permeability transition pore has been reported using rat liver mitochondria ^[7]. This was found to lead to an increase in the mitochondrial membrane potential, which could be partly inhibited by addition of the antioxidant GSH ^[8]. Cell treatment with a lysosomal inhibitor was found to delay the production of ROS that act on mitochondria, thus mitochondria-related cell death was delayed ^[9]. Superoxide-radical-triggered increase in Ca2+ uptake to the mitochondrion was found to precede loss of mitochondrial membrane potential, which was independent of other oxidants and mitochondrially derived ROS, as determined by using respective inhibitors. This work shows the specific effects of external and not mitochondrially derived ROS on mitochondrial damage ^[10].

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

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?

Quantitative understanding of this KER is low. Inhibition of the ROS source could delay mitochondrial damage, and treatment with an antioxidant could partly inhibit the effect on the mitochondrion.

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

^[10]: rat

^[7]: rat

^[8]: rat

^[9]: mouse

References

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

↑ ^1.0 ^1.1 Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE. Mitochondria and reactive oxygen species. Free Radic Biol Med. 2009 Aug 15;47(4):333-43
↑ M. Salvi, V. Battaglia, A.M. Brunati, N. La Rocca, E. Tibaldi, P. Pietrangeli, L. Marcocci, B. Mondovì, C.A. Rossi, A. Toninello. Catalase takes part in rat liver mitochondria oxidative stress defense. J. Biol. Chem., 282 (2007), pp. 24407–24415
↑ Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007 Jun 15;462(2):245-53
↑ ^4.0 ^4.1 Kowaltowski AJ, Castilho RF, Vercesi AE. Mitochondrial permeability transition and oxidative stress. FEBS Lett. 2001 Apr 20;495(1-2):12-5
↑ Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15;341 (Pt 2):233-49
↑ Hüser J, Rechenmacher CE, Blatter LA. Imaging the permeability pore transition in single mitochondria. Biophys J. 1998 Apr;74(4):2129-37
↑ ^7.0 ^7.1 Halestrap AP, Woodfield KY, Connern CP. Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. J Biol Chem. 1997 Feb 7;272(6):3346-54
↑ ^8.0 ^8.1 Hüser J, Rechenmacher CE, Blatter LA. Imaging the permeability pore transition in single mitochondria. Biophys J. 1998 Apr;74(4):2129-37
↑ ^9.0 ^9.1 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
↑ ^10.0 ^10.1 Madesh M, Hawkins BJ, Milovanova T, Bhanumathy CD, Joseph SK, Ramachandrarao SP, Sharma K, Kurosaki T, Fisher AB. Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis. J Cell Biol. 2005 Sep 26;170(7):1079-90