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Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) leads to Inhibition, NADH-ubiquinone oxidoreductase (complex I)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits||adjacent||High||Low||Andrea Terron (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|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 Do not cite|
|Mitochondrial complex inhibition leading to liver injury||adjacent||Not Specified||Not Specified||Wanda van der Stel (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
It is well documented that binding of an inhibitor to CI inhibits its activity (see MIE). Naturally occurring and synthetic CI inhibitors have been shown to inhibit the catalytic activity of CI, leading to partial or total inhibition of its activity in a dose response manner (Degli Esposti and Ghelli, 1994; Ichimaru et al. 2008; Barrientos and Moraes, 1999; Betarbet et al., 2000). Indeed, binding of inhibitors stops the electron flow from CI to ubiquinone. Therefore, the Fe-S clusters of CI become highly reduced and no further electrons can be transferred from NADH to CI. This leads to the inhibition of the NADH oxido-reductase function, i.e. CI inhibition.
Evidence Supporting this KER
The weight of evidence supporting the relationship between binding of an inhibitor to NADH-ubiquinone oxidoreducatse and its inhibition is strong.
There is an extensive understanding of the functional relationship between binding of an inhibitor to NADH-ubiquinone oxidoreductase (CI) and its inhibition. As the first entry complex of mitochondrial respiratory chain, CI oxidizes NADH and transfers electrons via a flavin mononucleotide cofactor and several Fe-S complexes to ubiquinone. The electron flow is coupled to the translocation of protons from the matrix to the intermembrane space. This helps to establish the electrochemical gradient that is used to fuel ATP synthesis (Greenamyre et al., 2001). If an inhibitor binds to CI, the electron transfer is blocked. This compromises ATP synthesis and maintenance of Δψm, leading to mitochondrial dysfunction. As CI exerts a higher control over oxidative phosphorylation in synaptic mitochondria than in non-synaptic mitochondria in the brain (Davey and Clark, 1996), specific functional defects observed in PD may be explained. It is well documented that CI inhibition is one of the main sites at which electron leakage to oxygen occurs. This results in a production of ROS, such as superoxide (Efremov and Sazanow, 2011) and hydrogen peroxide, which are main contributors to oxidative stress (Greenamyre et al., 2001).
Uncertainties and Inconsistencies
It is not clear the number of subunits constituting CI in mammals, as according to the existing literature different numbers are cited (between 41-46) (Vogel et al., 2007a; Hassinen, 2007). The majority of data claims that mammalian CI is composed of 46 (Greenamyre et al., 2001; Hassinen, 2007) or 45 subunits (Vogel et al., 2007a). It is not sure whether there may exist tissue-specific subunits of CI isoforms (Fearnley et al., 2001). It is unclear, which subunit(s) bind rotenone or other inhibitors of CI. Additionally, it is not clear whether CI has other uncharacterized functions, taking into consideration its size and complexity (43-46 subunits vs. 11 subunits of complex III or 13 subunits of complex IV) (Greenamyre et al., 2001). There is no strict linear relationship between inhibitor binding and reduced mitochondrial function. Low doses of rotenone that inhibit CI activity partially do not alter mitochondrial oxygen consumption. Therefore, bioenergetic defects can not account alone for rotenone-induced neurodegeneration. Instead, under such conditions, rotenone neurotoxicity may result from oxidative stress (Betarbet et al., 2000). Few studies used human brain cells/human brain mitochondria. Therefore, full quantitative data for humans are not available.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The CI is well-conserved across species from lower organism to mammals. The central subunits of CI harboring the bioenergetic core functions are conserved from bacteria to humans. CI from bacteria and from mitochondria of Yarrowia lipolytica, a yeast genetic model for the study of eukaryotic CI (Kerscher et al., 2002) was analyzed by x-ray crystallography (Zickermann et al., 2015). However, the affinity of various chemicals to cause partial or total inhibition of CI activity across species is not well studied (except rotenone).
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Beretta S, et al. 2006. Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON). Neurobiol Dis. 24:308–317.
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3:1301-1306.
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Choi WS, Kruse SE, Palmiter R, Xia Z. 2008. Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP, or paraquat. PNAS. 105(39):15136-15141.
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Vogel RO, van den Brand MA, Rodenburg RJ, van den Heuvel LP, Tsuneoka M, Smeitink JA, Nijtmans LG. (2007a). Investigation of the complex I assembly chaperones B17.2L and NDUFAF1 in a cohort of CI deficient patients. Mol. Genet. Metab. 91:176–182.