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Relationship: 3130

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Oxidative Stress leads to Mitochondrial dysfunction

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Do not cite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 Do not cite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 Do not cite Under Development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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties and inconsistencies in this KER are listed below:

  1. 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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

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).

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

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
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

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
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The domain of applicability pertains to only eukaryotic organisms, as prokaryotic organisms do not have mitochondria (Lynch and Marinov, 2017).

References

List of the literature that was cited for this KER description. More help

Almofti, M.R., Ichikawa, T., Yamashita, K., Terada, H., Shinohara, Y. (2003). Silver

ion induces a cyclosporine a-insensitive permeability transition in rat liver mitochondria and release of apoptogenic cytochrome c. J. Biochem., 134, 43–49. doi: 10.1093/jb/mvg111

Belyaeva, E. A., Sokolova, T. V., Emelyanova, L. V., & Zakharova, I. O. (2012). Mitochondrial

electron transport chain in heavy metal-induced neurotoxicity : Effects of cadmium, mercury, and copper. Thescientificworld, 2012, 1-14. doi:10.1100/2012/136063

Bhatti, J. S., Bhatti, G. K., & Reddy, P. H. (2017). Mitochondrial dysfunction and oxidative

stress in metabolic disorders - A step towards mitochondrial based therapeutic strategies. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(5), 1066-1077. doi:10.1016/j.bbadis.2016.11.010

Buelna-Chontal, M., Franco, M., Hernandez-Esquivel, L., Pavon, N., Rodriguez-Zalvala, J. S.,

Correa, F., . . . Chavez, E. (2017). CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction. Cell Biology International, 41, 1356-1366. doi:10.1002/cbin.10871

Forbes, J. M., & Thorburn, D. R. (2018). Mitochondrial dysfunction in diabetic kidney

disease. Nature Review Nephrology, 14(5), 291. doi:10.1038/nrneph.2018.9

Guo, C., Sun, L., Chen, X., & Zhang, D. (2013). Oxidative stress, mitochondrial damage and

neurodegenerative diseases. Neural Regen Rex, 8(21), 2003-2014. doi:0.3969/j.issn.1673-5374.2013.21.009

Hao, Y., Ren, J., Liu, C., Li, H., Liu, J., Yang, Z., . . . Su, Y. (2014). Zinc protects human kidney

cells from depleted uranium induced apoptosis. Basic & Clinical Pharmacology & Toxicology, 114, 271-280. doi:10.1111/bcpt.12167

Huerta-García, E., Perez-Arizti, J. A., Marquez-Ramirez, S. G., Delgado-Buenrostro, N. L.,

Chirino, Y. I., Iglesias, G. G., & Lopez-Marure, R. (2014). Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells. Free Radical Biology and Medicine, 73, 84-94. doi:10.1016/j.freeradbiomed.2014.04.026

Jozefczak, M., Remans, T., Vangronsveld, J., & Cuypers, A. (2012). Glutathione is a key player

in metal-induced oxidative stress defenses. Int.J.Mol.Sci., 13(3), 3145-3175. doi:10.3390/ijms13033145

Kruidering, M., Van De Water, B., De Heer, E., Mulder, G. J., & Nagelkerke, J. F. (1997).

Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: Mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. The Journal of Pharmacology and Experimental Therapeutics, 280(2), 638-649.

Kudryavtseva, A. V., Krasnov, G. S., Dmitriev, A. A., Alekseev, B. Y., Kardymon, O. L.,

Sadritdinova, A. F., . . . Snezhkina, A. V. (2016). Mitochondrial dysfunction and oxidative stress in aging and cancer. Oncotarget, 7(29), 44879-44905. doi:10.18632/oncotarget.9821

Miller, B. F., & Hamilton, K. L. (2012). A perspective on teh determination of mitochondrial

biogenesis. Am. J. Physiol. Endocrinol. Metab., 302(5), 496-499. doi:10.1152/ajpendo.00578.2011

Miyayama, T., Arai, Y., Suzuki, N., & Hirano, S. (2013). Mitochondrial electron transport is

inhibited by disappearance of metallothionein in human bronchial epithelial cells follwoing exposure to silver nitrate. Toxicology, 305, 20-29. doi:10.1016/j.tox.2013.01.004

Nissanka, N., & Moraes, C. T. (2018). Mitochondrial DNA damage and reactive oxygen species

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Lynch, M., & Marinov, G. K. (2017). Membranes, energetics, and evolution across the prokaryote-eukaryote                    divide. eLife6, e20437. 10.7554/eLife.20437

Omidian, K., Rafiei, H., & Bandy, B. (2020). Increased mitochondrial content and function by

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Park, J., Lee, J., & Choi, C. (2011). Mitochondrial network determines intracellular ROS

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Patergnani, S., Bouhamida, E., Leo, S., Pinton, P., & Rimessi, A. (2021). Mitochondrial

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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

Schiffer, T. A., & Friederich-Persson, M. (2017). Mitochondrial reactive oxygen species and

kidney hypoxia in the development of diabetic nephropathy. Front. Physiol., 8:211. doi:10.3389/fphys.2017.00211

Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted

uranium on isolated rat kidney mitochondria. Biochimica Et Biophysica Acta - General Subjects, 1820(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015

Sun, Y., Ge, X., He, J., Wei, X., Du, J., Sum, J., . . . Li, Y. C. (2020). High-fat diet promotes

renal injury by inducing oxidative stress and mitochondrial dysfunction. Cell Death and Disease, 11, 914. doi:10.1038/s41419-020-03122-4

Suski, J. M., Lebiedzinska, M., Bonora, M., Pinton, P., Duszynski, J., & Wieckowski. M.R.

(2012). Relation between mitochondrial membrane potential and ROS formation. Mitochondrial Bioenergetics, 810, 183-205. doi:10.1007/978-1-61779-382-0_12

Wang, Y., Wang, S., Jia, L., Zhang, L., Ba, J., Han, D., . . . Wu, Y. (2016). Nickel-refining

fumes induced DNA damage and apoptosis of NIH/3T3 cells via oxidative stress. International Journal of Environmental Research and Public Health, 13(7), 629-644. doi:10.3390/ijerph13070629

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persists longer than nuclear DNA damage in human cells following oxidative stress. Proc.Natl.Acad.Sci.U.S.A., 94, 514-519. doi:10.1073/pnas.94.2.514

 Zelenka, J., Dvorak, A., & Alan, L. (2015). L-lactate protects skin fibroblasts against aging-

asociated mitochondrial dysfunction via mitohormesis. Oxidative Medicine and Cellular Longevity, 2015 doi:10.1155/2015/351698

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(2018). Nano copper induces apoptosis in PK-15 cells via a mitochondria-mediated pathway. Biological Trace Element Research, 181(1), 62-70. doi:10.1007/s12011-017-1024-0

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An update and review. Biochimica Et Biophysica Acta, 5(1757), 509-517. doi:10.1016/j.bbabio.2006.04.029

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(ROS) and ROS-induced ROS release. Physiol. Rev., 94(3), 909-950. doi:10.1152/physrev.00026.2013