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Increased reactive oxygen species (in the mitochondria) leads to Mitochondrial Injury
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
High concentrations of mitochondrial ROS can physically damage the mitochondria:
Damage nucleotides Induction mutations in mtDNA
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
It has been well established that increase mitochondrial ROS leads to mitochondrial injury.