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Relationship: 3130
Title
Increase, Oxidative Stress leads to Mitochondrial dysfunction
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Nrf2 inhibition leading to vascular disrupting effects through activating apoptosis signal pathway and mitochondrial dysfunction | adjacent | High | High | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | |
The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects | adjacent | High | High | Evgeniia Kazymova (send email) | Under development: Not open for comment. Do not cite | |
Inhibition of mitochondrial electron transport chain (ETC) complexes leading to kidney toxicity | adjacent | Not Specified | Not Specified | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Oxidative stress is a cellular state in which there is excess generation of reactive oxygen species (ROS) and oxidation of macromolecules (Guo et al., 2013). The oxidation of macromolecules in particular can lead to many sources of mitochondrial dysfunction, such as the peroxidation of proteins essential to calcium homeostasis within the cell, dysfunction of the mitochondrial permeability transition pore (mPTP), altered mitochondrial membrane potential, and changes in antioxidant gene expression (Kruidering et al., 1997; Belyaeva et al., 2012; Guo et al., 2013).
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
The biological rationale for linking increased oxidative stress with an increase in mitochondrial dysfunction is strong. This is supported by a variety of articles (Bhatti, Bhatti, and Reddy, 2017).
ROS molecules attack proteins, lipids, and nucleic acids non-specifically, which then continues to cause increased mitochondrial dysfunction (Kruidering et al., 1997). One example of a sign of mitochondrial dysfunction is the opening of the MPT pore, which is induced by calcium overload within the mitochondria, elevated phosphate levels, adenine nucleotide depletion, and conditions of oxidative stress (Belyaeva et al., 2012). Calcium homoeostasis proteins are known to be particularly vulnerable to ROS attack, resulting in oxidative stress leading to calcium excess in the mitochondria (Guo et al., 2013). Increased oxidative stress is also known to lead to changes in membrane potential and changes in antioxidant gene expression for genes such as superoxide dismutase (SOD) (Huerta-García et al., 2014). Mitochondrial changes occur in situations of increased oxidative stress due to the increased content of oxidized macromolecules within the cell as oxidative stress progresses (Guo et al., 2013).
Empirical Evidence
Dose concordance
There were several studies which directly assessed the dose concordance between increased oxidative stress and increased mitochondrial dysfunction. One study compared the ROS formation and mitochondrial membrane potential in pig kidney mitochondria when treated with cisplatin concentrations of 100 and 500 μM (Kruidering et al., 1997). They found ROS formation, which was dose-dependant, caused a likewise dose-dependant decrease in mitochondrial membrane potential, which had a lower rate of change than ROS production (Kruidering et al., 1997). Another study found that rat kidney mitochondria treated with uranium acetate for 30 minutes showed significant ROS formation and lipid peroxidation with 100 μM treatment, while mitochondrial membrane potential was not altered significantly until 200 μM (Shaki et al., 2012). In addition, following treatment for an hour, rat kidney mitochondria did not show mitochondrial outer membrane integrity loss until treated with 200 μM uranium acetate. ROS production and GSH depletion were both significant as of 50 μM (Shaki et al., 2012). A study of copper, cadmium, and mercury on human kidney cells found that when treated for 3 hours with cadmium and mercury, significant increases in ROS formation occurred at 10 μM, while proton leakage across the mitochondrial membrane was not significantly increased from the control until 100 or 50 μM (Belyaeva et al., 2012). Another article found that copper nanoparticle treatment for 12 hours resulted in oxidative stress, characterized by increased lipid peroxidation and decreased SOD activity, which occurred at a dose of 20 μg/mL; however,mitochondrial membrane potential was not significantly decreased until 60 μg/mL (Zhang et al., 2018).
Temporal concordance
Very few studies have shown temporal concordance between increased oxidative stress and increased mitochondrial dysfunction. One study found that rat kidney mitochondria treated with 100 μM uranium acetate showed significant ROS formation after 30 minutes of treatment, while mitochondrial membrane potential and mitochondrial membrane permeability were not altered significantly until 40 minutes after treatment, at which point both showed time-dependant decreases (Shaki et al., 2012).
Incidence concordance
Some studies showed incidence concordance for the relationship between increased oxidative stress and increased mitochondrial dysfunction.
One article assessed the impact of 500 μM depleted uranium treatment on human proximal tubular cell mitochondria for 24 hours and found that ROS production increased by 4.62 times compared to the control level while mitochondrial membrane potential was reduced by only 3.8 times compared to the control (Hao et al., 2014). Another study investigated the effects of 20 μg/cm2 titanium nanoparticle treatment for 24 h on rat cancerous brain cells (Huerta-García et al., 2014). They found that ROS production increased by 5.5 times the control level and that mitochondrial depolarization was increased by only 3.4 times the control level (Huerta-García et al., 2014). A study of the effects of Au1.4MS gold nanoparticles on HeLa cells found that 100 μM treatment showed a dose-dependant increase in oxidative stress that was seen as early as 12 hours post-treatment and mitochondrial potential was also decreased in a dose-dependant manner at the same time (Pan et al., 2009). Another study conducted on rats treated with mercury at a dose of 3 mg/kg body weight for 24 hours found that kidney mitochondria from treated rats showed an increase of 11.5 times the control level of lipid peroxidation and also showed a decreased ability to accumulate calcium ions within the mitochondria and decreased transmembrane potential of the mitochondria (Buelna-Chontal et al., 2017). This study also showed that there was a decrease in mitochondrial respiratory function that was reflected in the ratio between the oxygen consumption rate after the addition of ADP and the oxygen consumption rate without ADP (the RC). The control RC was 4.7 times higher than the RC of the treated rat mitochondria . A study of the effects of cisplatin on rat kidney mitochondria found that the GSH/GSSG ratio was lower 76% than the control. In treated mitochondria, lipid peroxidation was increased by 1.6 times, and carbonyl protein was increased by 1.9 times the control levels, while a 25% reduction in ATP content was observed compared tothe control (Santos et al., 2007). Mouse embryo fibroblasts treated with 6.25 μg/mL of nickel-refining fumes for 24 hours resulted in GSH content and ATP levels that were both significantly decreased from the control (Wang et al., 2016).
Essentiality
There is evidence that in the absence of the induction of oxidative stress, and particularly of ROS production, mitochondrial dysfunction and cellular death were completely blocked (Almofti et al., 2003; Miyayama et al., 2013). The prevention of oxidative stress was achieved through treatment with thiol-containing antioxidants such as GSH and MT, which are able to chelate metal ions themselves and deplete ROS molecules within the cell to their proper concentration (Almofti et al., 2003; Jozefczak et al., 2012; Miyayama et al., 2013). The induction of changes in mitochondrial membrane potential independent of ROS production, have also been shown to cause changes in ROS production rate (Suski et al., 2012).
Uncertainties and Inconsistencies
Uncertainties and inconsistencies in this KER are listed below:
- One article had data which showed that a decrease in membrane potential preceded ROS formation when investigating temporal concordance (Kruidering et al., 1997). A decrease in mitochondrial membrane potential occurred after 10 or 15 minutes but ROS formation did not occur until 30 or 40 minutes when pig kidney mitochondria were treated with 100 and 500 μM of cisplatin.
Known modulating factors
One modulating factor for the relationship between oxidative stress and mitochondrial dysfunction is age. Many sources have confirmed that mitochondrial ROS production is increased as a result of the mitohormesis hypothesis (Nissanka and Moraes, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016). This theory explains that as organisms undergo cellular stresses, ROS are employed as signalling molecules for the stress response pathway (Nissanka and Moraes, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016). However, as cells age, they eventually reach a threshhold of age-dependant damage whereupon ROS signalling would become chronic and would lead to mitochondrial dysfunction (Nissanka and Morans, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016).
Another known modulating factor between oxidative stress and mitochondrial dysfunction is diabetes. Several studies show that mitochondrial ROS generation, mitochondrial calcium accumulation leading to mitochondrial swelling, and the opening of the mitochondrial permeability transition pore are increased in renal mitochondria from diabetic cases compared to non-diabetic renal mitochondria, and result in a quicker progression from oxidative stress to mitochondrial dysfunction (Forbes and Thorburn, 2018; Schiffer and Friederich-Persson, 2017). Diabetes causes changes in ROS generation due to the fact that cellular hyperglycemia induces increased pyruvate concentrations in the mitochondria (Forbes and Thorburn, 2018; Schiffer and Friederich-Persson, 2017). When pyruvate is used too quickly to supply the ETC with electrons the mitochondrial membrane becomes hyperpolarized and there is a resulting increase in ROS production (Schiffer and Friederich-Persson, 2017). Excessive nutrients in the cell also results in an increased need for insulin production that affects the endoplasmic reticulum (ER).because a large number of sulfide bonds must be formed to create insulin molecules and these reactions increase ROS production as a byproduct (Patergnani et al., 2021). This causes ER dysfunction and impaired protein folding, leading to a vicious cycle of mitochondrial stress leading to ER stress which leads to further mitochondrial stress, eventually inducing apoptosis. The hyperglycemic state of the cells also becomes chronic, leading to the further development of diabetes . These increases in oxidative stress are thereby able to induce heightened mitochondrial dysfunction at a faster rate than in a non-diabetic cell (Patergnani et al., 2021).
Similarly, high fat diets (HFD) have been known to induce renal dysfunction through mitochondrial dysfunction and oxidative stress (Sun et al., 2020). HFD-fed mice developed oxidative stress and mitochondrial dysfunction as a result of the upregulated expression of Gp91, a subunit of NADPH oxidase that is commonly identified as a marker of oxidative stress . Mitochondria were also more numerous in the HFD-fed mice and were releasing increased cytochrome c content, indicating that mitochondrial dysfunction was present and that it was initiating apoptosis (Sun et al., 2020).
Quantitative Understanding of the Linkage
Response-response Relationship
There are not many studies showing a response-response relationship for oxidative stress leading to mitochondrial dysfunction. There is one study which shows the relationship between mitochondrial superoxide production and mitochondrial content in mouse embryo fibroblasts using benzo[a]pyrene (B[a]P) to induce mitochondrial superoxides with varying polyphenols to modulate the response (Omidian, Rafiei, and Bandy, 2020). The mitochondrial content can be used to observe changes in the rate of mitochondrial biogenesis and mitophagy, allowing for observation of mitochondrial dysfunction in the cell (Miller and Hamilton, 2012; Omidian, Rafiei, and Bandy, 2020). As mtROS content increased, the mitochondrial content in the cells decreased, with the relationship being strongly negative (r = -0.86) (Omidian, Rafiei, and Bandy, 2020). There was one other study which also showed the correlation between superoxide concentration and decreased mitochondrial function in human fibroblasts (Yakes and Van Houten, 1997). The mitochondrial function in the treated cells was assessed via the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) . This study found that when the fibroblasts were treated with H2O2 concentrations from 0 to 400 μM, the cells showed a steep linear reduction of MTT up to 200 μM reaching approximately 20% of the MTT unreduced in comparison with the control . Further examination of their figure revealed that the correlation coefficient for the treatments up to 200 μM showed a very strong negative correlation (r = -0.99). Treatment with 400 μM H2O2 did not result in a significant further reduction of MTT (Yakes and Van Houten, 1997).
Time-scale
There are too few studies showing the temporal aspect of the relationship between oxidative stress and mitochondrial dysfunction to identify a time-scale. Further research will be required in order to understand the timing of this relationship.
Known Feedforward/Feedback loops influencing this KER
There is a known feedback loop for the relationship between oxidative stress and calcium homeostasis. The formation of ROS within the mitochondria leads to the disruption of homeostasis, causing the opening of the mitochondrial permeability transition pore and a decrease in membrane permeability when sufficient ROS is accumulated to reach the mPTP ROS threshold (Rottenberg and Hoek, 2017; Zorov, Juhaszova, and Sollott, 2006; Zorov, Juhaszova, and Sollott, 2014; Park, Lee, and Choi, 2011). The opening of the mPTP also induces a burst of ROS formation, which is delayed by a few seconds from the loss of mitochondrial membrane potential, and is a result of conformational changes to complex I of the mitochondrial electron transport chain (Zorov, Juhaszova, and Sollott, 2006; Park, Lee, and Choi, 2011). This ROS burst is able to leave the affected mitochondria due to the open mPTP and the decrease in membrane permeability. These molecules then go on to interact with other mitochondria . These ROS molecules act as secondary messengers, activating the RIRR process in neighbouring mitochondria until the cell eventually undergoes apoptosis (Zorov, Juhaszova, and Sollott, 2006; Zorov, Juhaszova, and Sollott, 2014; Park, Lee, and Choi, 2011).
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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