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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
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 complex I of the electron transport chain leading to chemical induced Fanconi syndrome adjacent Not Specified Not Specified Evgeniia Kazymova (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 Do not cite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

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Key Event Relationship Description

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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

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Evidence Supporting this KER

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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.

Uncertainties and Inconsistencies
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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
Response-response Relationship
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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
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Domain of Applicability

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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.