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Increased, Intracellular Calcium overload leads to N/A, Mitochondrial dysfunction 1
Key Event Relationship Overview
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||Anna Price (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
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 Supporting this KER
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
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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).
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.