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Aop: 273

AOP Title

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Mitochondrial complex inhibition leading to liver injury

Short name:

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Mitochondrial complex inhibition leading to liver injury

Graphical Representation

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Authors

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van der Stel, W. 1

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

Point of Contact

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Wanda van der Stel   (email point of contact)

Contributors

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  • Wanda van der Stel
  • Marvin Martens

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on June 15, 2019 11:09

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Revision dates for related pages

Page Revision Date/Time
Mitochondrial Complex III inhibition March 07, 2019 05:06
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
N/A, Cell injury/death December 05, 2018 08:26
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 12, 2018 11:19
Mitochondrial Complex III inhibition 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 N/A, Cell injury/death June 07, 2019 09:28
N/A, Cell injury/death leads to Necrotic Tissue March 07, 2019 06:05
Binding of inhibitor, mitochondrial complex III leads to Mitochondrial Complex III inhibition 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

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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.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
2 MIE 1542 Mitochondrial Complex III inhibition Mitochondrial Complex III inhibition
3 MIE 1543 Mitochondrial Complex IV inhibition Mitochondrial Complex IV inhibition
4 MIE 1544 Mitochondrial Complex V inhibition Mitochondrial Complex V inhibition
5 MIE 888 Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I)
6 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
7 KE 1545 Decrease in mitochondrial oxidative phosphorylation Decrease in mitochondrial oxidative phosphorylation
8 KE 1546 Increased reactive oxygen species (in the mitochondria) Increased reactive oxygen species (in the mitochondria)
9 KE 1547 Mitochondrial Injury Mitochondrial Injury
KE 889 Impaired, Proteostasis Impaired, Proteostasis
KE 55 N/A, Cell injury/death N/A, Cell injury/death
KE 177 N/A, Mitochondrial dysfunction 1 N/A, Mitochondrial dysfunction 1
10 AO 1548 Necrotic Tissue Necrotic Tissue
11 AO 1549 Liver Injury Liver Injury

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Mitochondrial Complex III inhibition 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 N/A, Cell injury/death adjacent Not Specified Not Specified
N/A, Cell injury/death leads to Necrotic Tissue adjacent Not Specified Not Specified
Binding of inhibitor, mitochondrial complex III leads to Mitochondrial Complex III inhibition 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

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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