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.
- Calkins, MJ; Jakel, RJ; Johnson, DA; Chan, K; Kan, YW; Johnson, JA
- January 4, 2005
Volume / Issue
- 102 / 1
Start / End Page
- 244 - 249
Pubmed Central ID
International Standard Serial Number (ISSN)
Digital Object Identifier (DOI)
- United States