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Relationship: 3629

Title

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

Redox cycling leads to Mito ROS dysfunction

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Redox cycling

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Mito ROS dysfunction

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
Redox cycling of a chemical by mitochondria leads to degeneration of nigrostriatal dopaminergic neurons	adjacent			Stefan Schildknecht (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 Do not cite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

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
rat	Rattus norvegicus	High	NCBI
mice	Mus sp.	High	NCBI
yeast	Saccharomyces cerevisiae	High	NCBI
Drosophila melanogaster	Drosophila melanogaster	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

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

Redox cycling is a process of alternate reduction and reoxidation steps. It is triggered in the presence of chemicals able to accept an electron from a reductant. Compounds with a lower electron reduction potential than O2 will react fastest and the newly formed free radical. These radicals due to their high reactivity may undergo electron transfer to molecular oxygen generating superoxide anion radical (O₂•⁻) (Kappus, 1986). Mitochondria may represent the major site of chemical redox cycling, although several membrane and cytosolic enzymes may trigger this reaction. This has been demonstrated for Paraquat (PQ) where alterations of mitochondrial redox state occurs earlier in mitochondria than in the cytosol (Castello et al., 2007; Rodriguez-Roche et al., 2013; Filograna et al., 2016) and higher protection from its toxicity is reached with mitochondrial, rather than cytosolic, expression of antioxidant enzymes (Mockett et al., 2003; Tien Nguyen-nhu and Knoops, 2003; Rodriguez-Roche et al., 2013; Filograna et al., 2016).

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

The implementation of AOP3 is based on a negotiated procedure with EFSA (reference NP/EFSA/PREV/2024/02). The update to AOP3 includes the upload of a revised version of the proposed AOP published in the EFSA Journal in 2017, which formed the basis for developing this relationship. Moreover, experimental evidence for a causal link between mitochondrial redox cycling of chemicals and elevated mitochondrial reactive oxygen species (ROS) production has been derived from studies using isolated mitochondria, submitochondrial particles, and cellular systems.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The weight of evidence supporting the relationship between the redox cycling of a chemical by mitochondria and the increase of production of ROS in mitochondria is strong thanks to the effects shown by the prototypical stressor (Paraquat) and its radicals.

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 biological plausibility evolves from the measured that (i) PQ is reaching the brain (Prasad, 2007; Yin, 2011; Breckenridge, 2013; Liang, 2013), (ii) PQ is taken up into nigrostriatal neurons (Rappold, 2011) and mitochondria (Castello et al., 2007; Cochemé and Murphy, 2009) (iii) PQ is a redox cycler inducing O₂•⁻ production and a cascade of ROS in isolated rat brain mitochondria (Castello et al., 2007; Cochemé and Murphy, 2008) brain homogenates (Castello et al., 2007), yeast (Cochemé and Murphy, 2008) and brain cell cultures mitochondria (Castello et al., 2007; Cantu et al., 2011; Dranka et al., 2012; Huang et al., 2012; Rodriguez-Rocha et al., 2013).

Existing in vitro and in vivo data shows that compound-induced mitochondrial redox cycling causes mitochondrial ROS formation.

PQ2+ dependent generation of superoxide (O₂•⁻) and hydrogen peroxide (H2O2) has been observed in intact mitochondria (Murakami et al. 1997; Peixoto et al. 2004; McCarthy et al. 2004; James et al. 2005; Castello et al. 2007; Mohammadi-Bardbori et al. 2008; Rodriguez-Rocha et al. 2013; Sandy et al. 1986) as well as in mitochondrial fractions and microsomes (Tomita et al. 1991). Similarly, cellular in vitro models confirmed PQ2+- induced O₂•⁻ formation (Krall et al. 1988; Tampo et al. 1999; Tsukamoto et al. 2002). Consistent with the accumulation of PQ2+ in mitochondria, multiple studies support a predominant role of the organelle, particularly the mitochondrial matrix, in ROS production (Castello et al. 2007; Pinho et al. 2019; Robb et al. 2015; Cocheme et al. 2008; Drechsel et al. 2009; Filograna et al. 2016). More detailed analyses demonstrated that PQ2+ predominantly enhances ROS formation in the mitochondrial matrix, with only minor cytosolic effects (Rodriguez-Rocha et al. 2013). This is in line with the spatial organization of complex I in the inner mitochondrial membrane, where electron transfer to redox cyclers via the N1a cluster occurs primarily on the matrix side (St-Pierre et al. 2002; Han et al. 2001; Muller et al. 2004). Because membranes are impermeable to charged species such as O₂•⁻, the localization of ROS formation largely dictates the site of oxidative stress. Accordingly, PQ2+ accumulation within the mitochondrial matrix, together with the impermeability of O₂•⁻, explains the preferential induction of ROS in this compartment.

Uncoupling of mitochondria with FCCP prevented PQ2+ uptake and abolished PQ2+ induced ROS formation, indicating that the presence of redox cyclers in the matrix is a prerequisite for ROS generation (Castello et al. 2007). Notably, MnSOD overexpression did not prevent PQ2+ induced mitochondrial membrane potential collapse (Rodriguez-Rocha et al. 2013).

To enhance mitochondrial targeting, MitoParaquat (MitoPQ2+) was developed by conjugating PQ2+ with a lipophilic cation. This modification enabled membrane potential-dependent accumulation and selective O₂•⁻ generation within the mitochondrial matrix, resulting in markedly higher toxicity compared to unmodified PQ2+. These findings further support the central role of intra-mitochondrial ROS in redox cycler toxicity (Robb et al. 2015). Additional indirect evidence includes PQ2+ induced oxidative damage to mitochondrial DNA and inactivation of matrix-localized aconitase (Cochemé et al. 2008; Cochemé et al. 2009).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

In vitro studies:

Incubation of rat primary mesencephalic cells or a dopaminergic cell line, N27, with PQ 0.250–1 mM for 3 or 4 h resulted in a dose-dependent reduction of aconitase activity significant for all the tested doses (Cantu et al., 2009, 2011). Aconitase is uniquely sensitive to O₂•⁻ mediated oxidative inactivation thus being an indirect marker of O₂•⁻ production. O₂•⁻ formation was coupled to a dose dependent H2O2 production after 2–6 h exposure of both cell type to PQ. The effect was significant only for PQ 1mM at 2 h, 0.5 and 1 mM at 4 h and 0.25–1 mM at 6 h (Cantu et al., 2009, 2011). Cell death occurred only 18 h after PQ exposure (i.e. after 4–6 h) (Cantu et al., 2009, 2011). Mitochondrial aconitase has also been shown to be a source of °OH, probably Via Fenton chemistry initiated by the co-released Fe2+ and H2O2 (Vasquez-Vivar et al., 2000). 60–70% reduction of mitochondrial aconitase expression in N27 cells resulted in a decreased H2O2 production, attenuation of respiratory capacity deficiency and death after PQ exposure (Cantu et al., 2011). On the contrary, overexpression of m-aconitase resulted in exacerbation of H2O2 production and increased primary mesencepahlic neuron death (Cantu et al., 2009). Aconitase inhibition by PQ (0.1 and 1 mM) has been reported also in yeast and bovine heart mitochondrial within minutes from the exposure (Cochemé and Murphy, 2008). This effect is coupled as well to a dose dependent (PQ 0.1, 0.5 and 1 mM) mitochondrial H2O2 formation and is a consequence of a mitochondrial membrane potential-dependent uptake of PQ dication (Cochemé and Murphy, 2008).
In another study performed on primary mesencephalic neurons (Cantu et al., 2009) exposure to PQ 0.25 and 0.5 mM reduced aconitase activity of 43% and 58% respectively. A dose– and time–response increase in H2O2
Exposure of human neuroblastoma SK-N-SH cells to PQ dose (0.2–1 mM) and time (6–72 h) dependently increases the production of O₂•⁻, as measured by mitosox and electron paramagnetic resonance. PQ (0.5 mM)-induced O₂•⁻ production up to 48 h was due to mitochondria, being prevented by MnSOD (located in the mitochondrial matrix) but not by CuZnSOD (primarily localised in the cytosol). In addition, PQ dose-dependently increases oxidative stress in the mitochondrial matrix at 24 h and both in mitochondrial matrix and cytosol at 48 h. A mitochondrial restricted ROS production after SH-SY5Y cell exposure to PQ 0.5 mM for 6 and 12 h was also observed in another study (Filograna et al., 2016). MnSOD pretreatment significantly reduced mitochondrial oxidative stress and neuronal cell death induced by PQ 0.5 mM at 48 h, while CuZnSOD had no effect (Rodriguez-Rocha et al., 2013). Similar results were obtained by Filograna et al. (2016) in SH-SY5Y after 24 h exposure to PQ. All together these data shows that PQ induces an early increase in oxidative stress in the mitochondrial matrix associated with O₂•⁻ production, which is followed by subsequent oxidative stress in the cytosol and is a trigger to neural cell death (Rodriguez-Rocha et al., 2013).

Ex vivo:

Mitochondria isolated from the striatum of Sprague Dawley rats 24 h after exposure to PQ 25 mg/kg produce a signi!cant higher amount of H2O2 compared to controls (+150%) and display decreased complex I and IV activity (-37 and -21%), increased mitochondrial membrane potential, increased lipid peroxidation (+42%) and increased cardiolipin oxidation/ depletion (+12%). No changes were observed in cortical mitochondria from PQ treated animals. (Czerniczyniec et al., 2015). Increased O₂•⁻ production (50% and 20% for cortical and striatal mitochondria respectively), decreased aconitase activity (30% Cx, 50% Str), increased lipid peroxidation (20% Cx, 30% Str) and release of cytochrome c and AIF were also observed in mitochondria isolated from the cortex and the striatum of Sprague Dawley exposed to PQ (10 mg/kg) over 4 weeks (one injection weekly) (Czerniczyniec et al., 2013). These results show that both acute and prolonged in vivo exposure to PQ promotes mitochondrial O₂•⁻ and ROS production coupled to mitochondrial dysfunction with the striatum more sensitive than the cortex

In vivo:

Paraquat (10 mg/kg i.p.) once a week for 3 weeks causes loss of dopaminergic neurons (TH+) after 2 weeks in mice in vivo. In parallel, 4-hydroxynonenal (4-HNE, time course) and nitrotyrosine proteins (single time point) (as markers of PQ-induced oxidative stress) were measured in TH+ cells of these animals. Lipid peroxidation at TH+ neurons is already significant after the 1st PQ injection (+200%) and increases up to 600% on the 2nd PQ injection (McCormack et al., 2005).
Mice exposed to PQ (5, 10, 20, 40, 80 mg/kg, twice a week for 4 weeks, i.p.) displayed a dose-dependent increase in superoxide, catalase and glutathione s-transferase activity as measured in homogenate obtained from substantia nigra, (SN) frontal cortex and the hippocampus. ROS-scavenging activity dose dependently increased in all the three areas both at sublethal (PQ 5–10 mg/kg) and lethal doses (PQ 20–80 mg/kg) (Mitra et al., 2011).

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

Besides mitochondria, NADPH-oxidase 1 (NOX1) (Cristovao et al., 2012) and plasma membrane microglia NOX (Rappold et al., 2011) also contribute to PQ-induced ROS production. Furthermore, in vitro data suggest that for time points of exposure longer than 48 h oxidative stress occurs both at mitochondria and cytosol in dependence to the dose. Thus, it is difficult to discriminate the source of PQ-induced ROS and the early involvement of mitochondria in vivo due to the extensive treatments and to the indirect detection of oxidative stress mainly by mean of lipoperoxidation, protein oxidation. Mitochondrial involvement is suggested by ex-vivo studies (Czerniczyniec et al., 2013, 2015).

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Antioxidant factors	1: manganese-dependent superoxide dismutase (MnSOD), CuZnSOD (SOD1); 2: glutathione peroxidase (GPX1 and GPX4) and peroxiredoxin (Prx) 3: Coenzyme Q	1: dismutated the released superoxide; 2: metabolize most of the H₂O₂ _3:carries electrons from complex I and II to complex III of the mitochondrial respiratory chain. It also functions as a fat-soluble antioxidant	Napolitano et al., 2021

Modulating Factor (MF)

MF Specification

Effect(s) on the KER

Reference(s)

Antioxidant factors

1: manganese-dependent superoxide dismutase (MnSOD), CuZnSOD (SOD1);

2: glutathione peroxidase (GPX1 and GPX4) and peroxiredoxin (Prx)

3: Coenzyme Q

1: dismutated the released superoxide;

2: metabolize most of the H₂O₂

_3:carries electrons from complex I and II to complex III of the mitochondrial respiratory chain. It also functions as a fat-soluble antioxidant

Napolitano et al., 2021

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

PQ ability to trigger mitochondrial ROS production (O₂•⁻ and correlated species) by redox cycling has been demonstrated in vitro, both in isolated mitochondria, mitochondrial brain homogenates and cells and ex-vivo from brain mitochondria isolated from PQ-treated rats. In vivo evidence of oxidative stress, as a consequence of PQ exposure, is mainly supported by the occurrence of lipoperoxidation, accumulation of oxidised protein or by mean of sodium salicylate molecular trap. PQ (0.1–1 mM) induces ROS production within minutes in isolated mitochondria and mitochondrial brain fraction (Castello et al., 2007; Cochemé and Murphy, 2008), while in cells this process is detectable after 2–6 h from the exposure in dependence on the dose (Cantu et al., 2011, Dranka et al., 2012; Huang et al., 2012; Rodriguez-Rocha et al., 2013). Based on the work of Cantu et al. (2009), which compare O2 and H2O2 production by PQ (0.25–0.5 mM) along different time points, O2 formation slightly precedes H2O2 production at the lowest PQ concentrations. In addition, at these time points no death is usually detected in cells exposed to PQ up to 1 mM, pointing at ROS production as an early event preceding cell death.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Treatment	PQ redox cycling with superoxide formation	ROS formation (KE1)
Rat primary mesencephalic cell culture PQ at 0.25–1 mM	Inhibition of aconitase after 3: 43% at 0.25 mM; 58% at 0.5 mM	Increase in H2O2: At 2 h 17% at 1 mM; At 4 h 28% at 0.5 mM and 64% at 1 mM; At 6 h 31% at 0.25 mM, 59% at 0.5 mM and 119% at 1 mM
N27 cell culture, PQ at 0.3–1 mM	Inhibition of aconitase, 80% at 0.5 mM, 98% at 1 mM at 4 h	Increase in H2O2 at 4–6 h; 25% at 0.3 mM and 33% at 1 mM
SK-N-SH human neuroblastoma cells treated with PQ 0.2 mM up to 1 mM. 6–62 h sampling	Dose and time related increase of O2 by electro paramagnetic resonance spectroscopy. 50% at 0.2 mM, 80% at 0.5 mM and 150% at 1 mM at 24 h	Increase in DHE ROS production 800% at 0.5 mM at 48 h
SD rat treated at 25 mg/kg and observed 24 h later		H2O2 increase of 150% in isolated mitochondria from SN neurons corresponding to 42% mitochondrial lipid peroxidation. Decrease in Complex I 33% and Complex IV 21%. Increase mitochondrial membrane potential
SD rat treated at 10 mg/kg weekly for 4 weeks	Increase in O2 production in isolated mitochondrial of 20% Decrease in aconitase activity in mitochondrial of 50% in striatum	Increase in lipid peroxidation in isolated mitochondria of 30%
C57BL/6 mice treated with 10 mg/kg PQ i.p. once a week for 3 weeks		Increased neuronal lipid peroxidation measured 1 day after weekly injection each: 10 mg kg i.p.; 200% increase in lipid peroxidation at 2 and 4 days post-inj; 500–600% in lipid peroxidation after 2nd injection 2/4 days after; After third injection limited response due to significant neuronal cell loss
Swiss albino mice i.p. at 5 and 10 mg kg twice a week for 4 weeks	SOD activity ex vivo: At 5 mg/kg increase of 42%; At 10 mg/kg increase of 75%	Glutatathione s transferase activity ex vivo: At 5 mg/kg increase of 25%; At 10 mg/kg increase of 75%; Catalase activity ex vivo; At 5 increase of 17%; At 10 increase of 50%

Time-scale

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

Following PQ exposure in vitro, significant ROS formation occurs within a few hours. Signs of oxidative damage, such as lipid peroxidation and increased antioxidant activity, become evident in vivo only after several weeks of repeated PQ exposure.

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

Taxonomic - Isolated mitochondria, cultured cells and whole organisms like yeast, worms, flies, rodents and plants generate O₂•⁻ in the presence of redox chemicals like Paraquat mostly increasing mitochondrial oxidative damage (Mason, 1990; Vafleteren, 1993, Sturz and Culotta, 2002; Van Remmen et al., 2004; Bonila et al., 2006).

In vivo, evidence about the effects of paraquat on ROS generation was reported for different species: yeast and bovine (Cochemé and Murphy, 2008), Rat (Cantu et al., 2009), Drosophila (Mockett et al. 2003) and Mice (Kirby et al., 2002).

Sex/Life stages - This KER is plausibly applicable to both sexes and any life stage.

References

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

Bonila E, Medina-Leendertz S, Villalobos V, Molero L, Bohorquez A, 2006. Paraquat-induced oxidative stress in Drosophila melanogaster: effects of melatonin, glutathione, serotonin, minocycline, lipoic acid and ascorbic acid. Neurochemical Research, 31, 1425–1432.

Breckenridge CB, Sturgess NC, Butt M, Wolf JC, Zadory D, Beck M, Mathews JM, Tisdel MO, Minnema D, Travis KZ, Cook AR, Botham PA, Smith LL, 2013. Pharmacokinetic, neurochemical, stereological and neuropathological studies on the potential effects of paraquat in the substantia nigra pars compacta and striatum of male C57BL/6J mice. Neurotoxicology, 37, 1–14. doi: 10.1016/j.neuro.2013.03.005

Cantu D, Schaack J, Patel M, 2009. Oxidative inactivation of mitochondrial aconitase results in iron and H2O2- mediated neurotoxicity in rat primary mesencephalic cultures. Public Library of Science (PLoS ONE), 4, e7095.

Cantu D, Fulton RE, Drechsel DA, Patel M, 2011. Mitochondrial aconitase knockdown attenuates paraquat-induced dopaminergic cell death via decreased cellular metabolism and release of iron and H2O2. Journal of Neurochemistry, 118, 79–92.

Castello PR, Drechsel DA, Patel M, 2007. Mitochondria are a major source of paraquat-induced reactive oxygenspecies production in the brain. Journal of Biological Chemistry, 282, 14186–14193

Cochemé HM, Murphy MP, 2008. Complex I is the major site of mitochondrial superoxide production by paraquat. Journal of Biological Chemistry, 283, 1786–1798.

Cochemé HM, Murphy MP, 2009. Chapter 22 The uptake and interactions of the redox cycler paraquat with mitochondria. Methods in Enzymology, 456, 395–417. doi: 10.1016/S0076-6879(08)04422-4

Cristovao AC, Guhathakurta S, Bok E, Je G, Yoo SD, Choi DH, Kim YS, 2012. NADPH oxidase 1 mediates asynucleinopathy in Parkinson’s disease. Journal of Neuroscience, 32, 14465–14477

Czerniczyniec A, Lores-Arnaiz S, Bustamante J, 2013. Mitochondrial susceptibility in a model of paraquat neurotoxicity. Free Radical Research, 47, 614–623.

Czerniczyniec A, Lanza EM, Karadayian AG, Bustamante J, Lores-Arnaiz S, 2015. Impairment of striatal mitochondrial function by acute paraquat poisoning. Journal of Bioenergetics and Biomembranes, 47, 395–408.

Day BJ, Shawen S, Liochev SI, Crapo JD. A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced endothelial cell injury, in vitro. J Pharmacol Exp Ther. 1995 Dec;275(3):1227-32. PMID: 8531085.

Dranka BP, Zielonka J, Kanthasamy AG, Kalyanaraman B, 2012. Alterations in bioenergetic function induced by Parkinson’s disease mimetic compounds: lack of correlation with superoxide generation. Journal of Neurochemistry, 122, 941–951.

Drechsel DA, Patel M. Differential contribution of the mitochondrial respiratory chain complexes to reactive oxygen species production by redox cycling agents implicated in parkinsonism. Toxicol Sci. 2009 Dec;112(2):427-34. doi: 10.1093/toxsci/kfp223. Epub 2009 Sep 18. PMID: 19767442; PMCID: PMC2777080.

Filograna R, Godena VK, Sanchez-Martinez A, Ferrari E, Casella L, Beltramini M, Bubacco L, Whitworth AJ, Bisaglia M, 2016. SOD-mimetic M40403 is protective in cell and "y models of paraquat toxicity: implications for Parkinson disease. Journal of Biological Chemistry, pii: jbc.M115.708057.

Fukushima T, Tawara T, Isobe A, Hojo N, Shiwaku K, Yamane Y. Radical formation site of cerebral complex I and Parkinson's disease. J Neurosci Res. 1995 Oct 15;42(3):385-90. doi: 10.1002/jnr.490420313. PMID: 8583507.

Han D, Williams E, Cadenas E. Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem J. 2001 Jan 15;353(Pt 2):411-6. doi: 10.1042/0264-6021:3530411. PMID: 11139407; PMCID: PMC1221585.

Huang CL, Lee YC, Yang YC, Kuo TY, Huang NK, 2012. Minocycline prevents paraquat-induced cell death through attenuating endoplasmic reticulum stress and mitochondrial dysfunction. Toxicology Letters, 209, 203–210.

James AM, Cochemé HM, Smith RA, Murphy MP. Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem. 2005 Jun 3;280(22):21295-312. doi: 10.1074/jbc.M501527200. Epub 2005 Mar 23. PMID: 15788391.

Kappus H, 1986. Overview of enzyme systems involved in bio-reduction of drugs and in redox cycling. Biochemical Pharmacology, 35, 1–6.

Kirby K, Hu J, Hilliker AJ, Phillips JP. RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16162-7. doi: 10.1073/pnas.252342899. Epub 2002 Nov 27. PMID: 12456885; PMCID: PMC138582.

Krall J, Bagley AC, Mullenbach GT, Hallewell RA, Lynch RE. Superoxide mediates the toxicity of paraquat for cultured mammalian cells. J Biol Chem. 1988 Feb 5;263(4):1910-4. PMID: 2828357.

Liang LP, Kavanagh TJ, Patel M, 2013. Glutathione de!ciency in Gclm null mice results in complex I inhibition and dopamine depletion following paraquat administration Toxicological Sciences, 134, 366–373. doi: 10.1093/ toxsci/kft112

Mason RP, 1990. Redox cycling of radical anion metabolites of toxic chemicals and drugs and the Marcus theory of electron transfer. Environmental Health Perspectives, 87, 237–243.

McCarthy S, Somayajulu M, Sikorska M, Borowy-Borowski H, Pandey S. Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10. Toxicol Appl Pharmacol. 2004 Nov 15;201(1):21-31. doi: 10.1016/j.taap.2004.04.019. PMID: 15519605.

Mitra S, Chakrabarti N, Bhattacharyya A, 2011. Differential regional expression patterns ofa-synuclein, TNF-a, and IL-1b; and variable status of dopaminergic neurotoxicity in mouse brain after Paraquat treatment. Journal of Neuroinflammation, 8, 163.

Mockett RJ, Bayne AC, Kwong LK, Orr WC, Sohal RS. Ectopic expression of catalase in Drosophila mitochondria increases stress resistance but not longevity. Free Radic Biol Med. 2003 Jan 15;34(2):207-17. doi: 10.1016/s0891-5849(02)01190-5. PMID: 12521602.

Mohammadi-Bardbori A, Ghazi-Khansari M. Alternative electron acceptors: Proposed mechanism of paraquat mitochondrial toxicity. Environ Toxicol Pharmacol. 2008 Jul;26(1):1-5. doi: 10.1016/j.etap.2008.02.009. Epub 2008 Feb 29. PMID: 21783880.

Mollace V, Iannone M, Muscoli C, Palma E, Granato T, Rispoli V, Nisticò R, Rotiroti D, Salvemini D. The role of oxidative stress in paraquat-induced neurotoxicity in rats: protection by non peptidyl superoxide dismutase mimetic. Neurosci Lett. 2003 Jan 2;335(3):163-6. doi: 10.1016/s0304-3940(02)01168-0. PMID: 12531458.

Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 2004 Nov 19;279(47):49064-73. doi: 10.1074/jbc.M407715200. Epub 2004 Aug 17. PMID: 15317809.

Murakami K, Yoshino M. Inactivation of aconitase in yeast exposed to oxidative stress. Biochem Mol Biol Int. 1997 Mar;41(3):481-6. doi: 10.1080/15216549700201501. PMID: 9090455.

Napolitano G, Fasciolo G, Venditti P. Mitochondrial Management of Reactive Oxygen Species. Antioxidants (Basel). 2021 Nov 17;10(11):1824. doi: 10.3390/antiox10111824. PMID: 34829696; PMCID: PMC8614740.

Peixoto F, Vicente J, Madeira VM. A comparative study of plant and animal mitochondria exposed to paraquat reveals that hydrogen peroxide is not related to the observed toxicity. Toxicol In Vitro. 2004 Dec;18(6):733-9. doi: 10.1016/j.tiv.2004.02.009. PMID: 15465637.

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