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Relationship: 934


The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Inhibition, NADH-ubiquinone oxidoreductase (complex I) leads to N/A, Mitochondrial dysfunction 1

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 Moderate Andrea Terron (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Inhibited CI is unable to pass off its electron to ubiquinone and it cannot translocate protons across the mitochondrial inner membrane. This creates a back-up of NADH within the mitochondrial matrix (Brown and Borutaite, 2004). This leads to an arrest of the citric acid cycle and a failure to build a proton gradient (mitochondrial membrane potential, Δψm) across the inner membrane. This results in impaired ATP production. In addition, the direct transfer of electrons from CI to oxygen is increased. This leads to oxidative stress as ROS (e.g. superoxide, hydrogen peroxide) are produced, which can damage DNA, proteins, lipids and other cell components and function (Sanders et al., 2014).

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

The weight of evidence supporting the relationship between inhibition of CI and mitochondrial dysfunction is strong. The mechanisms behind this KER are partially understood and well documented based on in vitro as well as in vivo experiments (e.g., Sanders et al., 2014), complemented by data from human post-mortem PD brain evaluations (Parker et al., 1989; Greenamyre et al., 2001; Sherer et al., 2003; Schapira et al., 1989).

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   More help

The biological plausibility that inhibition of CI activity triggers mitochondrial dysfunction is strong. It is well understood, how the inhibition of CI can lead to mitochondrial dysfunction as measured by: a) decreased oxygen consumption, b) decrease or loss of ATP production, c) decrease of Δψm, d) the loss of mitochondrial protein import and protein biosynthesis, e) reduced activities of enzymes of the mitochondrial respiratory chain and the Krebs cycle, f) elevated levels of ROS, g) the loss of mitochondrial motility, causing a failure of mitochondria to re-localize to sites of increased energy demands (such as synapses), h) destruction of the mitochondrial network, i) increased mitochondrial uptake of Ca2+ causing mitochondrial Ca2+ overload (Graier et al., 2007) and opening of mitochondrial PTP, (j) rupture of the mitochondrial inner and outer membranes, leading to release of mitochondrial pro-death factors, including cytochrome c, AIF and endonuclease G (Braun, 2012; Martin, 2011; Correia et al., 2012; Cozzolino et al., 2013). These pathological mechanisms are extremely well studied.

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Some studies suggest that rotenone may have effects other than CI inhibition, and it has been claimed that rotenone induces microtubule disruption, rather than ETC CI inhibition (Feng, 2006; Ren et al., 2005). Some studies suggested that there was no evidence for significant change in mitochondrial CI function in PD patients' brains (Jenner et al., 1992). It is still unclear whether the site of superoxide production in CI inhibited mitochondria is CI itself or not (Singer and Ramsay, 1994).

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

Mitochondrial CI in eukaryotes has highly conserved subunit composition based on protein databases (Cardol, 2011). The characterization of induced mitochondrial dysfunction phenotypes in zebrafish was studied in the presence of CI and CII inhibitors (Pinho et al., 2013). Exposure of Caenorhabditis elegans (C. elegans) to rotenone, reduced bioluminescence (an assay for mitochondrial dysfunction) after both relatively short (2 hr) and longer exposures (24 hr) to a range of concentrations. A sharp decline in bioluminescence (maximal inhibition) relative to controls occurred at the lowest rotenone concentration of 2.5 μM. This decline in bioluminescence was consistent with reduced cellular ATP (Lagido et al., 2015). The results obtained from C. elegans exposed to rotenone suggested that chronic exposure to low concentration (2 or 4 μM) caused mitochondrial damage through persistent suppression of mitochondrial biogenesis and mitochondrial gene expression leading to mitochondrial dysfunction that contributed to DA neuron degeneration (Zhou et al., 2013).

Drosophila melanogaster has been proven suitable to study signaling pathways implicated in the regulation of mitochondrial function and integrity, such as the PINK1/parkin pathway (controlling mitochondrial integrity and maintenance), DJ-1 and Omi/HtrA2 genes (associated with the regulation of mitochondrial functionality). Notably, PINK1, PARKIN, and DJ-1 genes are associated with recessive forms of PD (Guo, 2012). Drosophila flies lacking DJ-1 result to be viable, but show an increased sensitivity to oxidative stress induced upon rotenone or Paraquat (an herbicide inducer of CI-dependent ROS) feeding (Menzies et al. 2005; Meulener et al. 2005; Meulener et al. 2006). Moreover, it has been reported in Drosophila that inhibition of CI by mean of sublethal chronic exposure to rotenone (<750 μM) via the feeding medium caused a selective loss of DA neurons in all of the brain regions and locomotor impairments, while L-dopa (3,4-dihydroxy-L-phenylalanine) rescued the behavioral deficits (but not neuronal death) (Coulom and Birman, 2004). MPTP causes Parkinsonism in primates including humans. However, rodents (rats) are much less susceptible to MPTP+ but are fully susceptible to MPP+ (due to the differences in toxicokineticks). In all species, CI inhibition leads to mitochondrial dysfunction. Mitochondrial dysfunction is an universal event occurring in cells of any species (Farooqui and Farooqui, 2012).


List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Alam ZI, et al. Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem. 1997; 69(3):1196–203.

Ambrosi G, Ghezzi C, Sepe S, Milanese C, Payan-Gomez C, Bombardieri CR, Armentero MT, Zangaglia R, Pacchetti C, Mastroberardino PG, Blandini F. Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease. Biochim Biophys Acta. 2014 Sep;1842(9):1385-94.

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

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.

Bernardi P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev. 1999 Oct; 79(4):1127-55.

Braun RJ. 2012. Mitochondrion-mediated cell death: dissecting yeast apoptosis for a better understanding of neurodegeneration. Front Oncol 2:182.

Brown GC, and Borutaite V. 2004. Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols, Biochimica et Biophysica Acta (BBA) – Bioenergetics 1658, 1–2.

Cardol P. 2011. Mitochondrial NADH:ubiquinone oxidoreductase (complex I) in eukaryotes: a highly conserved subunit composition highlighted by mining of protein databases.". Biochim Biophys Acta 1807 (11): 1390–7.

Chen Y, Zhang DQ, Liao Z, Wang B, Gong S, Wang C, Zhang MZ, Wang GH, Cai H, Liao FF, Xu JP 2015. Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson's disease. Mol Neurodegener. 2;10(1):4.

Cheng B, Guo Y, Li C, Ji B, Pan Y, Chen J, Bai B. .Edaravone protected PC12 cells against MPP(+)-cytoxicity via inhibiting oxidative stress and up-regulating heme oxygenase-1 expression. J Neurol Sci. 2014 Aug 15;343(1-2):115-9.

Chiu CC, Yeh TH, Lai SC, Wu-Chou YH, Chen CH, Mochly-Rosen D, Huang YC, Chen YJ, Chen CL, Chang YM, Wang HL, Lu CS. 2015. Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. Exp Neurol. 263:244-53.

Coulom H, Birman S. Chronic exposure to rotenone models sporadic Parkinson's disease in Drosophila melanogaster. J Neurosci. 2004 Dec 1;24(48):10993-8.

Correia SC, Santos RX, Perry G, Zhu X, Moreira PI, Smith MA. 2012. Mitochondrial importance in Alzheimer's, Huntington's and Parkinson's diseases. Adv Exp Med Biol 724:205221.

Cozzolino M, Ferri A, Valle C, Carri MT. 2013. Mitochondria and ALS: implications from novel genes and pathways. Mol Cell Neurosci 55:44–49.

Dexter DT, et al. Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov Disord. 1994; 9(1):92–7.

Dias V, Junn E. and Mouradian MM. 2013. “The role of oxidative stress in parkinson’s disease,” Journal of Parkinson’s Disease, 3(4)461–491.

Farooqui T. and Farooqui, AA. 2012. Oxidative stress in Vertebrates and Invertebrate: molecular aspects of cell signalling. Wiley-Blackwell, Chapter 27:377- 385

Feng J. Mictrotubule. A common target for parkin and Parkinson's disease toxins. Neuroscientist 2006, 12.469-76.

Filomeni G, Graziani I, de Zio D, Dini L, Centonze D., Rotilio G, Ciriolo MR. 2012. Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: Possible implications for Parkinson’s disease. Neurobiol. Aging. 33:767–785.

Fujita KA, Ostaszewski M, Matsuoka Y, Ghosh S, Glaab E, Trefois C, Crespo I, Perumal TM, Jurkowski W, Antony PM, Diederich N, Buttini M, Kodama A, Satagopam VP,

Eifes S, Del Sol A, Schneider R, Kitano H, Balling R. 2014. Integrating pathways of Parkinson's disease in a molecular interaction map. Mol Neurobiol.49(1):88-102.

Graier WF, Frieden M, Malli R. 2007. Mitochondria and Ca2+ signaling: old guests, new functions. Pflugers Arch 455:375–396.

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

Guo M. Drosophila as a model to study mitochondrial dysfunction in Parkinson's disease. Cold Spring Harb Perspect Med. 2012 Nov 1;2(11). pii: a009944. Halliwell, BaG; JMC. Free Radicals in Biology and Medicine. 4. Oxford University Press; 2007.

Hartman P, Ponder R, Lo HH, Ishii N. Mitochondrial oxidative stress can lead to nuclear hypermutability. Mech Ageing Dev. 2004 Jun;125(6):417-20.

Hensley, K., Pye, Q. N., Maidt, M. L., Stewart, C. A., Robinson, K. A., Jaffrey, F., and Floyd, R. A. (1998) Interaction of alpha-phenyl -N-tert-butyl nitrone and alternative electron acceptor s with complex I indicates a substrate reduction site upstream from the rotenone binding site. J. Neurochem. 71, 2549–2557.

Höglinger GU, Carrard G, Michel PP, Medja F, Lombès A, Ruberg M, Friguet B, Hirsch EC. 2003. Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson’s disease. J. Neurochem. 86, 1297–1307.

Jenner P, Dexter DT, Sian J, Schapira AH, Marsden CD. Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson's Disease Research Group. Ann Neurol. 1992;32 Suppl:S82-7

Lagido C., McLaggan D., and Glover L.A.. A . Screenable In Vivo Assay for Mitochondrial Modulators Using Transgenic Bioluminescent Caenorhabditis elegans. J Vis Exp. 2015; (104): 53083.

Lee DH, Kim CS, Lee YJ. Astaxanthin protects against MPTP/MPP+-induced mitochondrial dysfunction and ROS production in vivo and in vitro. Food Chem Toxicol. 2011 Jan;49(1):271-80.

Liu W, Kong S, Xie Q, Su J, Li W, Guo H, Li S, Feng X, Su Z, Xu Y, Lai X. Protective effects of apigenin against 1-methyl-4-phenylpyridinium ion induced neurotoxicity in PC12 cells. Int J Mol Med. 2015, 35(3):739-46.

Mann VM, Cooper JM, Krige D, Daniel SE, Schapira AH, Marsden CD. 1992. Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. Brain. 115 ( Pt 2):333-42.

Martin LJ. 2011. Mitochondrial pathobiology in ALS. J Bioenerg Biomembr 43:569–579.

Mecocci P, et al. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol. 1993; 34(4):609–16.

Menzies FM, Yenisetti SC, Min KT. 2005. Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Curr Biol 15: 1578–1582.

Meulener M, Whitworth AJ, Armstrong-Gold CE, Rizzu P, Heutink P, Wes PD, Pallanck LJ, Bonini NM. 2005. Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease. Curr Biol 15: 1572–1577.

Meulener MC, Xu K, Thomson L, Ischiropoulos H, Bonini NM. 2006. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc Natl Acad Sci 103: 12517–12522.

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. 163(3):1450-5

Nataraj J, Manivasagam T, Justin Thenmozhi A, Essa MM 2015. Lutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorating mitochondrial disruption and oxidative stress. Nutr Neurosci. 2015 Mar 2. [Epub ahead of print].

Navarro A, et al. Human brain cortex: mitochondrial oxidative damage and adaptive response in Parkinson disease and in dementia with Lewy bodies. Free Radic Biol Med. 2009; 46(12):1574–80.

Ojha S, Javed H, Azimullah S, Abul Khair SB, Haque ME Neuroprotective potential of ferulic acid in the rotenone model of Parkinson's disease. Drug Des Devel Ther. 2015 Oct 7;9:5499-510.

Parker WD Jr, Boyson SJ, Parks JK. 1989. Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol.26(6):719-23.

Piert M, Koeppe RA, Giordani B, Minoshima S, Kuhl DE. Determination of regional rate constants from dynamic FDG-PET studies in Parkinson's disease. J Nucl Med. 1996 Jul;37(7):1115-22.

Pinho BR, Santos MM, Fonseca-Silva A, Valentão P, Andrade PB, Oliveira JM. How mitochondrial dysfunction affects zebrafish development and cardiovascular function: an in vivo model for testing mitochondria-targeted drugs. Br J Pharmacol. 2013 Jul;169(5):1072-90.

Rango M, Bonifati C, and Bresolin N. 2006. Parkinson’s disease and brain mitochondrial dysfunction: a functional phosphorus magnetic resonance spectroscopy study.Journal of Cerebral Blood Flow & Metabolism. 26(2)283–290.

Ren Y. et al., 2005. Selectivwe vulnerabity of dopaminergic neurons to microtubule depolymerisation. J. Bio. Chem. 280:434105-12.

Ramsay RR, Singer TP. 1992. Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+. Biochem Biophys Res Commun. 189(1):47-52.

Sanders LH, and Greenamyre JT. 2013. Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med.62:111-20.

Sanders LH, McCoy J, Hu X, Mastroberardino PG, Dickinson BC, Chang CJ, Chu CT, Van Houten B, Greenamyre JT. 2014. Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease. Neurobiol Dis. 70:214-23.

Saravanan KS, Sindhu KM, Senthilkumar KS, Mohanakumar KP. 2006. L-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats. Neurochem Int.49(1):28-40.

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.

Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. 1990a. Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem. 54(3):823-7.

Schapira AH, Mann VM, Cooper JM, Dexter D, Daniel SE, Jenner P, Clark JB, Marsden CD. 1990b. Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson's disease. J Neurochem. 55(6):2142-5.

Schapira AH. 1994. Evidence for mitochondrial dysfunction in Parkinson's disease--a critical appraisal. Mov Disord. 9(2):125-38.

Shamoto-Nagai M, Maruyama W, Kato Y, Isobe K, Tanaka M, Naoi M, Osawa T. 2003. An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells. J Neurosci Res. 74:589–97.

Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT. 2002. An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci. 22(16):7006-15.

Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, et al. 2003. Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci. 23:10756–64.

Singer TP, Ramsay RR.The reaction sites of rotenone and ubiquinone with mitochondrial NADH dehydrogenase. Biochim Biophys Acta. 1994 Aug 30;1187(2):198-202.

Takeshige K 1994. Superoxide formation and lipid peroxidation by the mitochondrial electron-transfer chain. Rinsho Shinkeigaku. 34(12):1269-71.

Testa CM, Sherer TB, Greenamyre JT. Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Res Mol Brain Res. 2005; 134(1):109–18.

Thomas B, Banerjee R, Starkova NN, Zhang SF, Calingasan NY, Yang L, Wille E, Lorenzo BJ, Ho DJ, Beal MF, Starkov A. Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease. Antioxid Redox Signal. 2012 May 1;16(9):855-68.

Tseng YT, Chang FR, Lo YC2. 2014. The Chinese herbal formula Liuwei dihuang protects dopaminergic neurons against Parkinson's toxin through enhancing antioxidative defense and preventing apoptotic death. Phytomedicine. 21(5):724-33.

Wang S, He H, Chen L, Zhang W, Zhang X, Chen J. Protective effects of salidroside in the MPTP/MPP(+)-induced model of Parkinson's disease through ROS-NO-related mitochondrion pathway. Mol Neurobiol. 2015, 51(2):718-28.

Wang H, Liu J, Gao G, Wu X, Wang X, Yang H. Protection effect of piperine and piperlonguminine from Piper longum L. alkaloids against rotenone-induced neuronal injury. Brain Res. 2015 Jul 29. pii: S0006-8993(15)00558-2. doi: 10.1016/j.brainres.2015.07.029. [Epub ahead of print].

Wu RM, Mohanakumar KP, Murphy DL, Chiueh CC. 1994. Antioxidant mechanism and protection of nigral neurons against MPP+ toxicity by deprenyl (selegiline). Ann N Y Acad Sci. 17;738:214-21.

Zhou S, Wang Z, Klaunig JE. Caenorhabditis elegans neuron degeneration and mitochondrial suppression caused by selected environmental chemicals. Int J Biochem Mol Biol. 2013 Dec 15;4(4):191-200. eCollection 2013.

Zhu J, and Chu CTT. 2010. Mitochondrial dysfunction in Parkinson’s disease. Journal of Alzheimer’s Disease, 20(2):S325–S334.