Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription.
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.
Calkins
Marcus J
MJ
School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
Jakel
Rebekah J
RJ
Johnson
Delinda A
DA
Chan
Kaimin
K
Kan
Yuet Wai
YW
Johnson
Jeffrey A
JA
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*
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