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Relationship: 362


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

Increased, Intracellular Calcium overload 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
Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment. adjacent High Moderate Allie Always (send email) Open for citation & comment WPHA/WNT Endorsed
Calcium overload in dopaminergic neurons of the substantia nigra leading to parkinsonian motor deficits adjacent Not Specified Not Specified Cataia Ives (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 Do not cite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

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

One of the mitochondrial functions is to buffer intracellular Ca2+ levels facilitating the maintenance of Ca2+ homeostasis in the cell. In the case of Ca2+ overload, mitochondria are not able to buffer the excess of Ca2+ that leads to mitochondrial dysfunction measured by the increased generation of reactive oxygen species (ROS), triggering mitochondrial permeability transition pore opening (Choi et al.,2013) and reduced ATP production (reviewed in Gleichmann and Mattson, 2011).

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

There is functional and structural mechanistic understanding supporting the relationship between KE "Ca2+ influx, increased" and KE "Mitochondrial dysfunction".

The increase in cytoplasmic Ca2+ can cause the activation of plasma membrane and endoplasmic reticulum (ER) Ca2+-ATPases that results in higher ATP demand. At the same time elevated Ca2+ can cause reduced levels of ATP by the direct uptake of the cation into the matrix that utilizes the proton circuit and directly competes with mitochondrial ATP synthesis (reviewed in Nicholls, 2009).

Ca2+ overload besides of being detrimental to mitochondrial energy production can also induce mitochondrial ROS generation. A number of possible mechanisms have been suggested by which Ca2+ overload can increase ROS production including: 1) stimulated increase of metabolic rate by Ca2+, 2) stimulated nitric oxide production by Ca2+, 3) Ca2+ induced cytochrome c dissociation, 4) Ca2+ induced cardiolipin peroxidation, 5) Ca2+ induced mitochondrial permeability transition pore (MPTP)opening with release of cytochrome c (leading to apoptosome formation and caspase-3 activation)and apoptosis inducing factor (AIF), decreased level of reduced glutathione (GSH), the antioxidative enzymes, and 6) Ca2+-calmodulin dependent protein kinase activation (reviewed in Peng and Jou, 2010; Gleichmann and Mattson, 2011). It is worth mentioning that mitochondrial ROS increase is capable of modulating Ca2+ dynamics causing further increase of Ca2+ levels.

The cytoplasmic and mitochondrial Ca2+ levels, the oxidative stress and the energy production are very closely inter-related. For example, decreased (or lack) of ATP production can affect the function of plasma membrane Ca2+ pump activity causing Ca2+ overload, oxidative stress and further restriction in ATP generating capacity (reviewed in Nicholls, 2009). Prolonged oxidative stimuli cause further mitochondrial dysfunction, including the decrease of mitochondrial transmembrane potential (ΔΨm), further overload of mitochondrial calcium, and opening of mitochondrial permeability transition pore (MPTP) (Choi et al., 2013).

Mitochondria within dendrites are elongated and perform extensive directional and lateral movement at physiological conditions. Under an excitotoxic exposure to glutamate, mitochondrial movement has been found to be inhibited and mitochondria change morphology becoming rounded and swollen. Although blocking mitochondrial ATP production is sufficient to inhibit mitochondrial movement (Rintoul et al., 2003), research has shown that the collapse of mitochondrial structure requires extracellular Ca2+ influx via NMDA receptors (Rintoul et al., 2003; Pivovarova et al., 2004; Shalbuyeva et al., 2006), suggesting that structural, mechanistic understanding is also available supporting this KER.

In neurons, the high mitochondrial content in axons and dendrites closely correlates with the high energy demand in these structures that is needed to pump the ions that underlie the generation of action potentials mediated by the electrochemical gradients (Attwell and Laughlin, 2001).

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

DomA toxicosis in California sea lions (CSLs, Zalophus californianus) is accompanied by increased expression of markers of oxidative stress such as malondialdehyde (MDA) and 3-nitrotyrosine (NT) in neurons (Madl et al., 2014).

In Atlantic salmon (Salmo salar), the cognition function has been investigated after exposure to sub-lethal doses of DomA (6 mg DA/kg bw). In addition, 14C-2-deoxyglucose has been injected i.m. to measure brain metabolic activity by autoradiography. The three brain regions investigated telencephalon, optic tectum and cerebellum have demonstrated a clear increase of metabolic activity in DomA exposed brains (Bakke and Horsberg, 2007).


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

Ananth C, Gopalakrishnakone P, Kaur C., Protective role of melatonin in domoic acid-induced neuronal damage in the hippocampus of adult rats. Hippocampus, 2003, 13: 375-87.

Attwell D, Laughlin SB, An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab., 2001, 21: 1133–1145.

Bakke MJ, Horsberg TE., Effects of algal-produced neurotoxins on metabolic activity in telencephalon, optic tectum and cerebellum of Atlantic salmon (Salmo salar). Aquat Toxicol., 2007, 85: 96-103.

Choi IY, Lim JH, Kim C, Song HY, Ju C, Kim WK., 4-hydroxy-2(E)-Nonenal facilitates NMDA-Induced Neurotoxicity via Triggering Mitochondrial Permeability Transition Pore Opening and Mitochondrial Calcium Overload. Exp Neurobiol., 2013, 22 :200-207.

Giordano G, White CC, McConnachie LA, Fernandez C, Kavanagh TJ, Costa LG. Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Mol Pharmacol., 2006, 70 :2116-26.

Giordano G, White CC, Mohar I, Kavanagh TJ, Costa LG. Glutathione levels modulate domoic acid-induced apoptosis in mouse cerebellar granule cells. Toxicol Sci., 2007, 100: 433-444.

Gleichmann M, Mattson MP., Neuronal calcium homeostasis and dysregulation. Antioxid Redox Signal., 2011, 14 :1261-1273.

Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF. Purple sweet potato color attenuates domoic acid-induced cognitive deficits by promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice. Free Radic Biol Med., 2012, 52: 646-59.

Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF, Li MQ., Troxerutin counteracts domoic acid-induced memory deficits in mice by inhibiting CCAAT/enhancer binding protein β-mediated inflammatory response and oxidative stress. J Immunol., 2013, 190: 3466-3479.

Madl JE, Duncan CG, Stanhill JE, Tai PY, Spraker TR, Gulland FM., Oxidative stress and redistribution of glutamine synthetase in California sea lions (Zalophus californianus) with domoic acid toxicosis. J Comp Pathol., 2014, 150: 306-315.

Nicholls DG., Mitochondrial calcium function and dysfunction in the central nervous system. Biochim Biophys Acta., 2009, 1787: 1416-1424.

Peng TI, Jou MJ. Oxidative stress caused by mitochondrial calcium overload. Ann N Y Acad Sci., 2010, 201: 183-188.

Pivovarova NB, Nguyen HV, Winters CA, Brantner CA, Smith CL, Andrews SB., Excitotoxic calcium overload in a subpopulation of mitochondria triggers delayed death in hippocampal neurons. J Neurosci., 2004, 24: 5611-5622.

Rintoul GL, Filiano AJ, Brocard JB, Kress GJ, Reynolds IJ., Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J Neurosci., 2003, 23: 7881-7888.

Shalbuyeva N, Brustovetsky T, Bolshakov A, Brustovetsky N. Calcium-dependent spontaneously reversible remodeling of brain mitochondria. J Biol Chem., 2006, 281: 37547-37558.

Shuttleworth CW, Connor JA. Strain-dependent differences in calcium signaling predict excitotoxicity in murine hippocampal neurons. J Neurosci., 2001, 15:21(12):4225-36.

Wu DM, Lu J, Zhang YQ, Zheng YL, Hu B, Cheng W, Zhang ZF, Li MQ., Ursolic acid improves domoic acid-induced cognitive deficits in mice. Toxicol Appl Pharmacol., 2013, 271: 127-36.