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Lipid Peroxidation leads to General Apoptosis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|CYP2E1 activation and formation of protein adducts leading to neurodegeneration||adjacent||High||High||Brendan Ferreri-Hanberry (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Lipid peroxidation can induce apoptosis due to two different toxic effects. First of all lipids are responsible for maintaining the integrity of cellular membranes. Due to peroxidation of the lipids in the cellular membrane they lose their composition, structure and dynamics of lipid membranes. Various functions are lost, there is an increase of membrane rigidity, decrease activity of membrane-bound enzymes and altered permeability. Secondly there is the formation of highly reactive compounds such as lipid peroxides (MDA, HNE). These lipid peroxides can generate more ROS or can crosslink with important proteins in the cell. Several apoptosis pathways are started due to increased levels of ROS and HNE. p53 is induced and phosphorylated by HNE, as well as inducement of death receptor Fas (CD95). Also due to lipid peroxidation an energetic disturbance is reached, since the protein pumps lost their function. This can lead to neuronal cell death.
Evidence Supporting this KER
It is biological plausible that lipid peroxidation can lead to apoptosis of cells.
Uncertainties and Inconsistencies
Apoptosis is a mechanism of cell death which occurs during lipid peroxidation. Since cell death is a general term used other mechanisms could also play a role. When enormous levels of ROS and HNE are generated even necrosis can occur. Another form is apoptosis is ferroptosis, which is also linked with lipid peroxidation. Also the defence mechanisms of cells against HNE are not described, which should be taken into account.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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Gaschler, M. M. & Stockwell, B. R. Lipid peroxidation in cell death. Biochemical and Biophysical Research Communications 482, 419–425 (2017).
Dalleau, S., Baradat, M., Guéraud, F. & Huc, L. Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death Differ. 20, 1615–30 (2013).
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Liu, W., Porter, N. A., Schneider, C., Brash, A. R. & Yin, H. Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition. Free Radic. Biol. Med. 50, 166–178 (2011).
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Angelova, P. R. et al. Lipid peroxidation is essential for ??-synuclein-induced cell death. J. Neurochem. 133, 582–589 (2015).
Elharram, A. et al. Deuterium-reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer’s disease. FEBS J. (2017). doi:10.1111/febs.14291