Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Calkins, MJ; Jakel, RJ; Johnson, DA; Chan, K; Kan, YW; Johnson, JA

Published Date

  • January 4, 2005

Published In

Volume / Issue

  • 102 / 1

Start / End Page

  • 244 - 249

PubMed ID

  • 15611470

Pubmed Central ID

  • PMC538748

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0408487101


  • eng

Conference Location

  • United States