API

Relationship: 1788

Title

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Increased reactive oxygen species (in the mitochondria) leads to Mitochondrial Injury

Upstream event

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Increased reactive oxygen species (in the mitochondria)

Downstream event

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Mitochondrial Injury

Key Event Relationship Overview

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AOPs Referencing Relationship

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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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High concentrations of mitochondrial ROS can physically damage the mitochondria:

  1. Damage nucleotides
    Induction mutations in mtDNA

  2. Damage proteins
    Malfunctioning respiratory chain complexes
    Malfunctioning transporters (affecting for example Ca2+ homeostasis)

 

Malfunctioning the respiratory chain = Perturbation of complexes

mROS interacts with the different subunits of the respiratory chain complexes. Conformational changes in the complexes can lead to a limited- or non-flow of electrons/protons resulting in perturbation of the overall membrane potential necessary for the production of ATP.

 

Malfunctioning transporters (affecting for example Ca2+ homeostasis)

ROS accumulation -> accumulation Ca2+

mROS can damage Ca2+ transporters in the mitochondria leading to perturbed in and outflux of Ca2+ and therefore Ca2+ accumulation in the mitochondria.

 

Mitochondrial integrity (mPTP opening)

Ca2+ +ROS -> decreased mitochondrial integrity (mPTP opening)

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

 

Threshold relationship = Prolonged release of extra radicals in the mitochondria will lead to damaging of mitochondrial components.

Evidence Supporting this KER

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Biological Plausibility

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It has been well established that increase mitochondrial ROS leads to mitochondrial injury.

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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