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Relationship: 933


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

Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I) leads to Inhibition, NADH-ubiquinone oxidoreductase (complex I)

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 the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits adjacent High Low Cataia Ives (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 Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite
Mitochondrial complex inhibition leading to liver injury adjacent Not Specified Not Specified Arthur Author (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 Do not cite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

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 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

The weight of evidence supporting the relationship between binding of an inhibitor to NADH-ubiquinone oxidoreducatse and its inhibition is strong.

Biological Plausibility

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
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

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

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

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).


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

Barrientos A, and Moraes CT. 1999. Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology. 274(23)16188–16197.

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.

Cheville NF. 1994. Ultrastructural Pathology: The Comparative Cellular Basis of Disease Wiley John Wiley & Sons, 09 dic 2009 - 1000 pagine Chinopoulos C, Adam-Vizi V. 2001. Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: Relevance to Parkinson’s disease. J Neurochem. 76:302–306.

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.

Cleeter MW, Cooper JM, Schapira AH. 1992. Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement. J Neurochem. 58(2):786-9.

Davey GP, Clark JB. 1996. Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria, J. Neurochem. 66:1617 24.

Degli Esposti M, Ghelli A. 1994. The mechanism of proton and electron transport in mitochondrial complex I. Biochim Biophys Acta.1187(2):116–120.

Degli Esposti (1998) Inhibitors of NADH-ubiquinone reductase: an overview Biochimica et Biophysica Acta 1364-222-235. Efremov RG, Sazanov LA. Structure of the membrane domain of respiratory complex I. Nature. 2011 Aug 7;476(7361):414-20.

Fearnley IM, Carroll J, Shannon RJ, Runswick MJ, Walker JE, and Hirst J. 2001. GRIM-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH:ubiquinone oxidoreductas (complex I). J. Biol. Chem. 276(42):38345-8.

Greenamyre TJ, Sherer TB, Betarbet R, and Panov AV. 2001. Complex I and Parkinson’s Disease. Critical Review.IUBMB Life, 52: 135–141.

Grivennikova VG, Maklashina EO, Gavrikova EV, Vinogradov AD. 1997. Interaction of the mitochondrial NADH-ubiquinone reductase with rotenone as related to the enzyme active/inactive transition. Biochim et Biophys. Acta. 1319:223–232.

Hassinen I. 2007. Regulation of Mitochondrial Respiration in Heart Muscle. In Mitochondria – The Dynamic Organelle Edited by Schaffer & Suleiman. Springer ISBN-13: 978-0-387-69944-8.

Ichimaru N, Murai M, Kakutani N, Kako J, Ishihara A, Nakagawa Y, Miyoshi H. 2008.. Synthesis and Characterization of New Piperazine-Type Inhibitors for Mitochondrial NADH-Ubiquinone Oxidoreductase (Complex I). Biochemistry. 47(40)10816–10826.

Koopman W, Hink M, Verkaart S, Visch H, Smeitink J, Willems P. 2007. Partial complex I inhibition decreases mitochondrial motility and increases matrix protein diffusion as revealed by fluorescence correlation spectroscopy. Biochimica et Biophysica Acta 1767:940-947. Krug AK, Gutbier S, Zhao L, Pöltl D, Kullmann C, Ivanova V, Förster S, Jagtap S, Meiser J, Leparc G, Schildknecht S, Adam M, Hiller K, Farhan H, Brunner T, Hartung T, Sachinidis A, Leist M (2014) Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+). Cell Death Dis. 8(5):e1222. doi: 10.1038/cddis.2014.166. Lambert AJ, Brand MD. Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem. 2004 Sep 17;279(38):39414-20.

Langston JW. 1996. The etiology of Parkinson’s disease with emphasis on the MPTP story. Neurology. 47, S153–160.

Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sato T, Oya H, Ozawa T, Kagawa Y. 1989. Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem Biophys Res Commun. 29;163(3):1450-5.

Nicklas WJ, Yougster SK, Kindt MV, Heikkila RE. 1987. MPTP, MPP+ and mitochondrial function. Life Sci. 40:721-729.

Okun JG, Lummen PL, Brandt U. 1999. Three Classes of Inhibitors Share a Common Binding Domain in Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) 274(5)2625–2630.

Parker Jr WD, Swerdlow RH. 1998. Mitochondrial dysfunction in idiopathic Parkinson disease. Am J Hum Genet 62:758 –762.

Ramsay RR, Krueger MJ, Youngster SK, Singer TP. Evidence that the inhibition sites of the neurotoxic amine 1-methyl-4-phenylpyridinium (MPP+) and of the respiratory chain inhibitor piericidin A are the same. Biochem J. 1991 Jan 15;273(Pt 2):481-4.

Sayre LM, Arora PK, Feke SC, Urbach FL. 1986. Mechanism of induction of Parkinson’s disease by I-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP). Chemical and electrochemical characterization of a geminal-dimethyl-blocked analogue of a postulated toxic metabolite. J Am Chem Sot. 108:2464-2466.

Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, and Marsden CD. 1989. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet. 1,1269.

Schuler F, Casida JE.The insecticide target in the PSST subunit of complex I. Pest Manag Sci. 2001 Oct;57(10):932-40.

Shults CW. 2004. Mitochondrial dysfunction and possible treatments in Parkinson’s disease–a review. Mitochondrion 4:641– 648.

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.