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Relationship: 2565


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

Inhibition, ETC complexes of the respiratory chain leads to Increase, Oxidative Stress

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
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 Do not cite Under Development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

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

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 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
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
  1. 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

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

There are no known modulating factors.

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

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.

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 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
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 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

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).


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

Ferreira, G. K., Cardoso, E., Vuolo, F. S., Michels, M., Zanoni, E. T., Carvalho-Silva, M., . . .

Paula, M. M. S. (2015). Gold nanoparticles alter parameters of oxidative stress and energy metabolism in organs of adult rats. Biochem. Cell Biol., 93, 548-557. doi:10.1139/bcb-2015-0030

García-Niño, W. R., Tapia, E., Zazueta, C., Zatarain-Barrón, Z. L., Hernández-Pando, R., Vega-

García, C. C., & Pedraza-Chaverrí, J. (2013). Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening. Evidence-Based Complementary and Alternative Medicine, (424692), 1-19. doi:10.1155/2013/424692

Gonzalez-Hunt, C. P., Wadhawa, M., Sanders, L. H. (2018). DNA damage by oxidative stress:

Measurement strategies for two genomes. Current Opinion in Toxicology, 7, 87-94. ISSN 2468-2020. doi:10.1016/j.cotox.2017.11.001.

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

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

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.

Li, X., Fang, P., Mai, J., Choi, E. T., Wang, H., & Yang, X. (2013). Targeting mitochondrial

reactive oxygen species as novel therapy for inflammatory diseases and cancers. Journal of Hematology and Oncology, 6(19), 1-19. doi:10.1186/1756-8722-6-19

Lynch, M., & Marinov, G. K. (2017). Membranes, energetics, and evolution across the

prokaryote-eukaryote divide. eLife6, e20437. 10.7554/eLife.20437

Ma, L., Liu, J., Dong, J., Xiao, Q., Zhao, J., & Jiang, F. (2017). Toxicity of Pb2+ on rat liver

mitochondria induced by oxidative stress and mitochondrial permeability transition. Toxicol.Res., 6, 822. doi:10.1039/c7tx00204a

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

Prakash, C., Soni, M., & Kumar, V. (2015). Biochemical and molecular alterations following

arsenic-induced oxidative stress and mitochondrial dysfunction in rat brain. Biol.Trace Elem.Res., 167, 121-129. doi:10.1007/s12011-015-0284-9

Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C.

(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

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

Wang, Y., Fang, J., Leonard, S. S., & Krishna Rao, K. M. (2004). Cadmium inhibits the electron

transfer chain and induces reactive oxygen species. Free Radical Biology and Medicine, 36(11), 1434-1443. doi:10.1016/j.freeradbiomed.2004.03.010

Yu, L., Li, W., Chu, J., Chen, C., Li, X., Tang, W., . . . Xiong, Z. (2021). Uranium inhibits

mammalian mitochondrial cytochrome c oxidase and ATP synthase. Environmental Pollution, 271, 116377. doi:10.1016/j.envpol.2020.116377

Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019). Mitochondrial electron transport chain, ROS

generation and uncoupling (review). International Journal of Molecular Medicine, 44(1), 3-15. doi:10.3892/ijmm.2019.4188

Zmijewski, J. W., Landar, A., Watanabe, N., Dickinson, D. A., Noguchi, N., Darley-Usmar, V.

M. (2005). Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium. Biochem. Soc. Trans., 33(6),1385–1389. doi:10.1042/BST20051385