Journal Article

Differential Contribution of the Mitochondrial Respiratory Chain Complexes to Reactive Oxygen Species Production by Redox Cycling Agents Implicated in Parkinsonism

Derek A. Drechsel and Manisha Patel

in Toxicological Sciences

Volume 112, issue 2, pages 427-434
Published in print December 2009 | ISSN: 1096-6080
Published online September 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp223
Differential Contribution of the Mitochondrial Respiratory Chain Complexes to Reactive Oxygen Species Production by Redox Cycling Agents Implicated in Parkinsonism

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Exposure to environmental pesticides can cause significant brain damage and has been linked with an increased risk of developing neurodegenerative disorders, including Parkinson's disease. Bipyridyl herbicides, such as paraquat (PQ), diquat (DQ), and benzyl viologen (BV), are redox cycling agents known to exert cellular damage through the production of reactive oxygen species (ROS). We examined the involvement of the mitochondrial respiratory chain in ROS production by bipyridyl herbicides. In isolated rat brain mitochondria, H2O2 production occurred with the following order of potency: BV > DQ > PQ in accordance with their measured ability to redox cycle. H2O2 production was significantly attenuated in all cases by antimycin A, an inhibitor of complex III. Interestingly, at micromolar (≤ 300μM) concentrations, PQ-induced H2O2 production was unaffected by complex I inhibition via rotenone, whereas DQ-induced H2O2 production was equally attenuated by inhibition of complex I or III. Moreover, complex I inhibition decreased BV-induced H2O2 production to a greater extent than with PQ or DQ. These data suggest that multiple sites within the respiratory chain contribute to H2O2 production by redox cycling bipyridyl herbicides. In primary midbrain cultures, H2O2 differed slightly with the following order of potency: DQ > BV > PQ. In this model, inhibition of complex III resulted in roughly equivalent inhibition of H2O2 production with all three compounds. These data identify a novel role for complex III dependence of mitochondrial ROS production by redox cycling herbicides, while emphasizing the importance of identifying mitochondrial mechanisms by which environmental agents generate oxidative stress contributing to parkinsonism.

Keywords: paraquat; redox cycling; mitochondria; Parkinson's disease

Journal Article.  4934 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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