API

Relationship: 1787

Title

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Decrease in mitochondrial oxidative phosphorylation leads to Mitochondrial Injury

Upstream event

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Decrease in mitochondrial oxidative phosphorylation

Downstream event

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Mitochondrial Injury

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Mitochondrial complex inhibition leading to liver injury adjacent High High

Taxonomic Applicability

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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 Supporting this KER

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Biological Plausibility

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

Empirical Evidence

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Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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