title: Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription.
abstract: Complex II inhibitors 3-nitropropionic acid (3NP) and malonate cause striatal damage reminiscent of Huntington's disease and have been shown to involve oxidative stress in their pathogenesis. Because nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent transcriptional activation by means of the antioxidant response element is known to coordinate the up-regulation of cytoprotective genes involved in combating oxidative stress, we investigated the significance of Nrf2 in complex II-induced toxicity. We found that Nrf2-deficient cells and Nrf2 knockout mice are significantly more vulnerable to malonate and 3NP and demonstrate increased antioxidant response element (ARE)-regulated transcription mediated by astrocytes. Furthermore, ARE preactivation by means of intrastriatal transplantation of Nrf2-overexpressing astrocytes before lesioning conferred dramatic protection against complex II inhibition. These observations implicate Nrf2 as an essential inducible factor in the protection against complex II inhibitor-mediated neurotoxicity. These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease.
authors.affiliation: School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Calkins
authors.forename: Rebekah J
authors.initials: RJ
authors.lastname: Jakel
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Kaimin
authors.initials: K
authors.lastname: Chan
authors.forename: Yuet Wai
authors.initials: YW
authors.lastname: Kan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000637:transplantation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D008314:Malonates / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D008314:Malonates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D009574:Nitro Compounds; D011422:Propionates; D015534:Trans-Activators; C030290:malonic acid; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid