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Relationship: 1810

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

Decrease, OXPHOS leads to Decreased Na/K ATPase activity

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decrease, OXPHOS

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decreased Na/K ATPase activity

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 complex I of the electron transport chain leading to chemical induced Fanconi syndrome	adjacent	Not Specified	Not Specified	Marvin Martens (send email)	Under development: Not open for comment. Do not cite

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

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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

A decrease in oxidative phosphorylation results in a limited resource in ATP, which limits the capacity of the cell to perform active transport across the plasma membrane. This, in turn, reduces the capacity for secondary transport, resulting in different rates on water and solutes transport compared to healthy proximal tubule cells.

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

Both mitochondria and the Na/K ATPase are present in most cell types in mammals. Oxidative phosphorylation (OXPHOS) is the process by which the mitochondria produce most of the ATP used by the cell. In OXPHOS, the reducing equivalents (NADH and FADH2) produced during the catabolism of glucose and fatty acids fuel the electron transport chain (ETC) that provides the proton gradient needed ATP synthase to produce ATP from ADP and inorganic phosphate. This ATP can then be consumed by ATP-dependent processes such as the transport of sodium and potassium against their electrochemical gradients by the Na/K ATPase. When ATP levels are decreased in the cell, these ATP-dependent processes cannot take place. In the case of a decrease in Na/K ATPase activity, this results in a depolarisation of the plasma membrane, as well as a reduction in secondary active transport driven by the sodium gradient built up by the Na/K ATPase.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

In purified renal cell membranes, the activity of the Na/K ATPase is directly dependent on the concentration of ATP, Na+ and K+ (Jørgensen, 1986). In those conditions, concentrations of ATP below 1 mM drastically decreased the activity of the pump. Ratios of Na+/K+ also could affect Na/K ATPase activity.

Experiments with the mitochondrial electron transport chain (ETC) complex I blocker rotenone have shown a 30% inhibition of Na/K ATPase coupled to a 20% decrease in ATP in Jurkat cells exposed to 10 μM rotenone for 3h (Yin et al., 2009).

Drugs such as cisplatin (Nowak, 2002) have been shown to cause an inhibition of oxidative phosphorylation and a decrease in intracellular ATP followed by impairment of Na/K ATPase activity and sodium-related secondary transport in rabbit renal proximal tubule cells.

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

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

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

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

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

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

References

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

Jørgensen, P. L. (1986). Structure, function and regulation of Na,K-ATPase in the kidney. Kidney International, 29(1), 10–20. https://doi.org/10.1038/KI.1986.3

Nowak, G. (2002). Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells. The Journal of Biological Chemistry, 277(45), 43377–88. https://doi.org/10.1074/jbc.M206373200

Yin, W., Li, X., Feng, S., Cheng, W., Tang, B., Shi, Y. L., & Hua, Z. C. (2009). Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism. Biochemical Pharmacology, 78(2), 191–202.