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Inhibition, ECT complexes of the respiratory chain leads to Increase, Oxidative Stress
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of mitochondrial electron transport chain (ETC) complexes leading to kidney toxicity||adjacent||Not Specified||Not Specified||Baki Sadi (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Reactive oxygen species (ROS) are molecules such as hydrogen peroxide and superoxide, which are highly reactive and are able to oxidize many of the cellular components they interact with (Zhao et al., 2019). Mitochondrial electron transport chain inhibition results in the increased formation of ROS, lipid peroxidation, and protein peroxidation (Shaki et al., 2012; Huerta-García et al., 2014). GSH and other antioxidants are also oxidized by the excess formation of ROS, resulting in an imbalance in the antioxidant and ROS levels (Shaki et al., 2012). These processes are all components of oxidative stress (Shaki et al., 2012; García-Niño et al., 2013; Ma et al., 2017).
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility for this KER is moderate, as some specific stressors showed the dependent change in both events, however there was an inconsistency with one article where KE1 preceded the MIE.
ROS formation occurs mainly in the mitochondria of a cell, specifically by the complexes of the electron transport chain (ETC) (Zhao et al., 2019; Yu et al., 2021; Shaki et al., 2012; Huerta-García et al., 2014). ROS formation is the result of the leaking of electrons from the ETC, which can then interact with oxygen molecules to form hydrogen peroxide and superoxide (Zhao et al., 2019). In particular the superoxide anion is created as a result of the reaction of oxygen with the iron-sulfur centers in complexes I and III (Kruidering et al., 1997). This is a normal function of the mitochondria when ROS formation is only produced at very low levels, as ROS molecules are involved in signalling pathways within the cell (Zhao et al., 2019). These molecules are then scavenged in the cell by antioxidants in order to maintain a balance of ROS levels in the cell (Kruidering et al., 1997, Zhao et al., 2019). However, complex inhibition in the ETC results in a disrupted electron flow and therefore leads to an increased incidence of electron leakage (Zhao et al., 2019). Complex I and III in particular are considered to be the most common sites of ROS formation within the mitochondria (Zhao et al., 2019, Kuridering et al., 1997, Shaki et al., 2012). Superoxide and hydrogen peroxide molecules then further the increase of oxidative stress by oxidizing lipid molecules and protein molecules while depleting antioxidant molecules (Shaki et al., 2012; Santos et al., 2007).
Uncertainties and Inconsistencies
- One of the articles, the Shaki et al.’s 2012 article, did not show dose concordance for this KER when using uranium as a treatment, as oxidative stress was induced before mitochondrial electron transport chain inhibition occurred, at 50 and 100 μM respectively.
Known modulating factors
There are no known modulating factors.
There are currently no articles detailing the response-response relationship between the inhibition of the mitochondrial ETC and an increase in oxidative stress. Further studies will need to be conducted in order to determine a response-response relationship.
There are currently not enough articles which investigate the time-scale over which inhibition of the mitochondrial ETC occurs and instigates oxidative stress and further research must therefore be conducted to identify the time-scale for this relationship.
Known Feedforward/Feedback loops influencing this KER
There is a known feedback loop which influences this key event relationship. Inhibition of the mitochondrial electron transport chain results in increased oxidative stress, which in turn further inhibits the mitochondrial electron transport chain (Guo et al., 2013). The molecular basis behind this is that the ROS molecules are damaging to the macromolecules, such as DNA, proteins, and lipids that they interact with in the mitochondria (Guo et al., 2013). Unrepaired damage to mitochondrial DNA, which is known to be more sensitive than nuclear DNA to ROS molecules due to proximity to the ETC, leads to defective complex I and III function and results in increased reduction of oxygen to it’s reactive forms (Guo et al., 2013; Gonzalez-Hunt et al., 2018). Similarly, damage to the mitochondrial DNA coding for other critical proteins for electron transport can lead to further generation of ROS molecules, all leading to a cycle of ROS molecule generation and organelle dysfunction which ultimately results in the induction of apoptosis (Guo et al., 2013).
Domain of Applicability
The domain of applicability pertains to only eukaryotic organisms, as prokaryotic organisms do not have mitochondria (Lynch and Marinov, 2017).
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(2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Archives of Toxicology, 81(7), 495-504. doi:10.1007/s00204-006-0173-2
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