Aop: 273

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Mitochondrial complex inhibition leading to liver injury

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Mitochondrial complex inhibition leading to liver injury

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

van der Stel, W. 1

1Leiden Academic Center for Drug Research, Leiden Univeristy, Leiden, The Netherlands

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Wanda van der Stel
  • Marvin Martens
  • Arthur Author

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Increase, Mitochondrial complex III antagonism December 04, 2020 17:24
Mitochondrial Complex IV inhibition March 07, 2019 05:15
Mitochondrial Complex V inhibition March 07, 2019 05:21
Decrease in mitochondrial oxidative phosphorylation December 19, 2018 09:36
Increased reactive oxygen species (in the mitochondria) December 19, 2018 09:37
Mitochondrial Injury December 19, 2018 09:37
Necrotic Tissue March 07, 2019 04:19
Liver Injury March 07, 2019 04:23
Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) March 28, 2018 04:51
Inhibition, NADH-ubiquinone oxidoreductase (complex I) March 12, 2018 11:03
Impaired, Proteostasis March 15, 2018 12:46
Cell injury/death July 15, 2022 09:46
Binding of inhibitor to mitochondrial complex III June 07, 2019 09:31
Binding of inhibitor to mitochondrial complex IV June 07, 2019 09:31
Binding of inhibitor to mitochondrial complex V June 07, 2019 09:31
N/A, Mitochondrial dysfunction 1 March 07, 2022 07:12
Increase, Mitochondrial complex III antagonism leads to Decrease in mitochondrial oxidative phosphorylation March 07, 2019 08:37
Mitochondrial Complex IV inhibition leads to Decrease in mitochondrial oxidative phosphorylation March 07, 2019 08:38
Mitochondrial Complex V inhibition leads to Decrease in mitochondrial oxidative phosphorylation March 07, 2019 08:38
Necrotic Tissue leads to Liver Injury March 07, 2019 06:07
Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) leads to Inhibition, NADH-ubiquinone oxidoreductase (complex I) August 25, 2017 09:35
Inhibition, NADH-ubiquinone oxidoreductase (complex I) leads to Decrease in mitochondrial oxidative phosphorylation June 07, 2019 09:12
Impaired, Proteostasis leads to Cell injury/death June 07, 2019 09:28
Cell injury/death leads to Necrotic Tissue March 07, 2019 06:05
Binding of inhibitor, mitochondrial complex III leads to Increase, Mitochondrial complex III antagonism June 07, 2019 09:31
Binding of inhibitor, mitochondrial complex IV leads to Mitochondrial Complex IV inhibition June 07, 2019 09:32
Binding of inhibitor, mitochondrial complex V leads to Mitochondrial Complex V inhibition June 07, 2019 09:32
Decrease in mitochondrial oxidative phosphorylation leads to N/A, Mitochondrial dysfunction 1 June 15, 2019 11:06
Increased reactive oxygen species (in the mitochondria) leads to N/A, Mitochondrial dysfunction 1 June 15, 2019 11:07
N/A, Mitochondrial dysfunction 1 leads to Increased reactive oxygen species (in the mitochondria) June 15, 2019 11:08
N/A, Mitochondrial dysfunction 1 leads to Impaired, Proteostasis August 25, 2017 08:35

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP focusses on the inhibition of any of the mitochondrial complexes (I,II,III,IV or V) which eventually leads to the initiation of liver injury. In short, inhibition (fully or partially) of mitochondrial complexes that form the OXPHOS will lead to perturbation of the OXPHOS itself. OXPHOS perturbation will manifest as lower or no production of ATP via the mitochondria. Besides OXPHOS perturbation, the inhibition of the complexes will also lead to accumulation of the unused electrons and therefore ROS formation. Both process combined will trigger mitochondrial injury. One the most important additions to the AOPwiki by us would be to improve the mitochondrial injury key event with more detail, more method descriptions and more evidence. Finally when a certain threshold is reached mitochondria cannot coop with the induced stress and will trigger the cell death pathways (apoptosis and necrosis depending on ATP availability). Evidently, the cell death will proceed to necrotic tissue and in the end to liver injury.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1542 Increase, Mitochondrial complex III antagonism Increase, Mitochondrial complex III antagonism
MIE 1543 Mitochondrial Complex IV inhibition Mitochondrial Complex IV inhibition
MIE 1544 Mitochondrial Complex V inhibition Mitochondrial Complex V inhibition
MIE 888 Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I)
MIE 887 Inhibition, NADH-ubiquinone oxidoreductase (complex I) Inhibition, NADH-ubiquinone oxidoreductase (complex I)
MIE 1653 Binding of inhibitor to mitochondrial complex III Binding of inhibitor, mitochondrial complex III
MIE 1654 Binding of inhibitor to mitochondrial complex IV Binding of inhibitor, mitochondrial complex IV
MIE 1655 Binding of inhibitor to mitochondrial complex V Binding of inhibitor, mitochondrial complex V
KE 1545 Decrease in mitochondrial oxidative phosphorylation Decrease in mitochondrial oxidative phosphorylation
KE 1546 Increased reactive oxygen species (in the mitochondria) Increased reactive oxygen species (in the mitochondria)
KE 1547 Mitochondrial Injury Mitochondrial Injury
KE 889 Impaired, Proteostasis Impaired, Proteostasis
KE 55 Cell injury/death Cell injury/death
KE 177 N/A, Mitochondrial dysfunction 1 N/A, Mitochondrial dysfunction 1
AO 1548 Necrotic Tissue Necrotic Tissue
AO 1549 Liver Injury Liver Injury

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding
Increase, Mitochondrial complex III antagonism leads to Decrease in mitochondrial oxidative phosphorylation adjacent High High
Mitochondrial Complex IV inhibition leads to Decrease in mitochondrial oxidative phosphorylation adjacent High High
Mitochondrial Complex V inhibition leads to Decrease in mitochondrial oxidative phosphorylation adjacent High High
Necrotic Tissue leads to Liver Injury adjacent High High
Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) leads to Inhibition, NADH-ubiquinone oxidoreductase (complex I) adjacent Not Specified Not Specified
Inhibition, NADH-ubiquinone oxidoreductase (complex I) leads to Decrease in mitochondrial oxidative phosphorylation adjacent Not Specified Not Specified
Impaired, Proteostasis leads to Cell injury/death adjacent Not Specified Not Specified
Cell injury/death leads to Necrotic Tissue adjacent Not Specified Not Specified
Binding of inhibitor, mitochondrial complex III leads to Increase, Mitochondrial complex III antagonism adjacent Not Specified Not Specified
Binding of inhibitor, mitochondrial complex IV leads to Mitochondrial Complex IV inhibition adjacent Not Specified Not Specified
Binding of inhibitor, mitochondrial complex V leads to Mitochondrial Complex V inhibition adjacent Not Specified Not Specified
Decrease in mitochondrial oxidative phosphorylation leads to N/A, Mitochondrial dysfunction 1 adjacent Not Specified Not Specified
Increased reactive oxygen species (in the mitochondria) leads to N/A, Mitochondrial dysfunction 1 adjacent High High
N/A, Mitochondrial dysfunction 1 leads to Increased reactive oxygen species (in the mitochondria) adjacent High High
N/A, Mitochondrial dysfunction 1 leads to Impaired, Proteostasis adjacent Not Specified Not Specified

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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