Impairment of mitochondrial electron transport by tetrachloroethylene

Miyazaki, Y.; Takano, Takehito

doi:10.1016/0378-4274(83)90088-7

Cited by 6 publications

(4 citation statements)

References 6 publications

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“…Similarly, PERC (165.83 g/mol) appears to decrease electron flow at the inner mitochondrial membrane 19 , and paraquat (257.16 g/mol) is characterized as an inducer of redox cycling resulting in toxic ROS production and permeability of the inner mitochondrial membrane 6,59,60 . Thus, despite differences in precise mechanism, each toxicant associated with PD risk causes direct or indirect mitochondrial dysfunction 13,19,25,47,49,60 , which likely acts as a common mechanism associated with parkinsonian neurotoxicity. This was consistent with our findings that each toxicant, when used at subtoxic doses in cell treatments, caused a similar degree of ROS generation over a spectrum of time; early/immediate for rotenone and paraquat and delayed for TCE and PERC, consistent with the data suggesting a metabolite of the solvents ultimately causes mitochondrial toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…While different from neurons, HEK cells are extensively characterized in the LRRK2 literature 25,26,44,80,81 , have been used as a model system to study the effects of LRRK2 mutations and display similar energetic demands of neurons that rely heavily on mitochondrial function [82][83][84] . We also strategically chose to evaluate toxicants linked to PD risk with structural dissimilarities but associated with mitochondrial dysfunction 13,19,47,[56][57][58][59][60]85 . However, we could not feasibly compare each in an in vivo model.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, TCE is a small (131.4 g/mol) chlorinated solvent that is reported to inhibit mitochondria at high doses 47,58 , possibly through its metabolites such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC) 15 . Similarly, PERC (165.83 g/mol) appears to decrease electron flow at the inner mitochondrial membrane 19 , and paraquat (257.16 g/mol) is characterized as an inducer of redox cycling resulting in toxic ROS production and permeability of the inner mitochondrial membrane 6,59,60 . Thus, despite differences in precise mechanism, each toxicant associated with PD risk causes direct or indirect mitochondrial dysfunction 13,19,25,47,49,60 , which likely acts as a common mechanism associated with parkinsonian neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Environmental contaminants such as the pesticides rotenone [1][2][3][4][5] and paraquat 1,4,6,7 , as well as the commonly used organic solvent trichloroethylene (TCE) [8][9][10][11][12] increase Parkinson's disease (PD) risk by approximately 0.7 -2.5-fold 4,8,9 . Given the similar risk for neurodegeneration from structurally distinct environmental toxicants, convergent mechanisms on cellular pathways such as mitochondrial damage and subsequent oxidative stress are implicated in the pathogenesis of idiopathic PD [13][14][15][16][17][18][19] . We and others have previously shown that systemic exposure to environmental mitochondrial toxicants, such as rotenone, paraquat, and TCE, cause the selective degeneration of nigrostriatal dopaminergic neurons [20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

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LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Ilieva,

Hoffman,

Ghalib

et al. 2024

Preprint

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Idiopathic Parkinson′s disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk — rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant–induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Ilieva,

Hoffman,

Ghalib

et al. 2024

Preprint

View full text Add to dashboard Cite

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Parkinson's Disease

Goldman¹

2013

Effects of Persistent and Bioactive Organic Pollutants on Human Health

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Solvent exposures and parkinson disease risk in twins

Goldman

Quinlan

Ross

et al. 2011

Annals of Neurology

149

108

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Objective Several case reports have linked solvent exposure to Parkinson’s disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design. Methods 99 twin pairs discordant for PD ascertained from the National Academy of Science/National Research Council (NAS/NRC) World War II Veteran Twins Cohort were interviewed regarding lifetime occupations and hobbies using detailed job-task-specific questionnaires. Exposures to 6 specific solvents selected a priori were estimated by expert raters unaware of case status. Results Ever exposure to trichloroethylene (TCE) was associated with significantly increased risk of PD (OR 6.1, 95%CI 1.2 – 33; p = 0.034), and exposure to perchloroethylene (PERC) and carbon tetrachloride (CCl4) tended toward significance (respectively: OR 10.5, 95%CI 0.97-113, p = 0.053; OR 2.3, 95%CI 0.9-6.1, p = 0.088). Results were similar for estimates of exposure duration and cumulative lifetime exposure. Interpretation Exposure to specific solvents may increase risk of PD. TCE is the most common organic contaminant in groundwater, and PERC and CCl4 are also ubiquitous in the environment. Our findings require replication in other populations with well-characterized exposures, but the potential public health implications are substantial.

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Impairment of mitochondrial electron transport by tetrachloroethylene

Cited by 6 publications

References 6 publications

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

LRRK2 kinase inhibition protects against Parkinson’s disease-associated environmental toxicants

Parkinson's Disease

Solvent exposures and parkinson disease risk in twins

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