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Relationship: 1787


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

Decrease in mitochondrial oxidative phosphorylation leads to Mitochondrial Injury

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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

Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Inhibition of the oxidative phosphorylation process will lead to a drop or even an absence of available mitochondrial-produced ATP in the cell. The drop in ATP concentrations limits the capacity of the cell to perform ATP-dependent processes.

Processes affected by decreased ATP levels are amounts others:

  1. Ca2+ homeostasis

  2. ROS homeostasis

  3. Mitochondrial integrity

Ca2+ accumulation

Low ATP -> accumulation Ca2+

Evidence coming from the ischemia field demonstrates that a drop in ATP levels (drop in high energy phosphate levels) will lead to an increase in calcium levels.

The cell will compensate the drop in ATP by upregulating the glycolysis (anaerobic and less efficient production of ATP). The glycolysis has various acid side products leading to a drop in pH. Na+ will be imported to counteract the pH drop. The Na+ overload will be pumped out via the Ca2+/Na+ pump, leading to an increase in intracellular Ca2+ levels.

Loss of ATP production will also lead to malfunctioning of the ATP dependent calcium homeostasis process that should keep the intracellular Ca2+ levels low. The following ATP driven process do not function anymore

  1. Active export: membrane pump,

  2. Exchange of calcium for sodium (Na-K pumps) and

  3. Uptake of Ca2+ into the ER.

The only process that is ATP independent is accumulation of Ca2+ in the mitochondria. Malfunctioning of the mitochondrial oxidative phosphorylation will therefore lead to massive uptake of calcium into the mitochondria.

ROS induction

Accumulation Ca2+ -> ROS

High levels of Ca2+ lead to an attempt of the cell to increase the activity of the oxidative phosphorylation. However, the oxidative phosphorylation is already blocked. This will therefore result in extra release of electrons and ROS formation.

Mitochondrial integrity (mPTP opening)

Ca2+ +ROS -> mPTP opening

Increased mitochondrial Ca2+ levels (in combination with increased ROS in the mitochondria) will eventually lead to decreases mitochondrial integrity and release of mitochondrial content in to the cytoplasm (mPTP opening).

Threshold relationship = The cell can cope with reduced ATP levels depending on duration of the effect at the energy supplies and the number of mitochondria that are injured.

Evidence Collection Strategy

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Evidence Supporting this KER

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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

It is broadly accepted that a partially or complete loss of ATP will lead to perturbation of various ATP-dependent mitochondrial functions.

Uncertainties and Inconsistencies
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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
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
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Domain of Applicability

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