Upstream eventMitochondrial Complex IV inhibition
Decrease in mitochondrial oxidative phosphorylation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Mitochondrial complex inhibition leading to liver injury||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
The initiation event is the reversibly or irreversibly interaction to any of the subunits in the mitochondrial complex I, III or IV.
Inhibition of complex I, III or IV leads to a reduction in proton gradient and therefore impair or completely prevent the production of mitochondrial membrane dependent ATP production.
Threshold relationship = The cell can cope with inhibition of the various mitochondrial complexes and the following decreased OXPHOS depending on the number of mitochondria affected. The more mitochondria within a cell are perturbed, the lower the concentration of available ATP will become. The cell can influence the threshold at which these low ATP levels will become lethal, for example by upregulating the number of available mitochondria (biogenesis).
Evidence Supporting this KER
It is broadly accepted that complex inhibition leads to decreased mitochondrial oxidative phosphorylation.
Deficiencies in complex I in patient leads to decreased activity of the complex