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Cited by 247Genomics, phytochemicals, and oxidative stressGenetic Neurodegenerative DiseasesNuclear Receptors and Signaling

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

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Calkins, Marcus J., Jakel, Rebekah J., Johnson, Delinda A., Chan, Kaimin, Kan, Yuet Wai, Johnson, Jeffrey A.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0408487101PMC PMC538748
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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.

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  • Nrf2-/- mice show profound susceptibility to striatal lesions produced by the mitochondrial complex-II inhibitor malonate.

    “Further, Nrf2-/- mice also show profound susceptibility to striatal lesions produced by the mitochondrial complex-II inhibitor malonate186.”

    From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [186]

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Authors
Calkins, M. J., Jakel, R. J., Johnson, D. A., Chan, K., Kan, Y. W., & Johnson, J. A.
Affiliations
University of Wisconsin–Madison (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-12-20
Volume
102
Issue
1
Pages
244-249
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0408487101
PMC
PMC538748
OpenAlex
W1986070505
Cited by
247
References
68
Citations by year
2026: 1 · 2025: 6 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 9 · 2019: 9 · 2018: 12 · 2017: 10 · 2016: 15 · 2015: 12 · 2014: 21 · 2013: 12 · 2012: 21
FWCI
2.96
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK16666, R01DK016666, R37DK016666)
  • National Institute of Environmental Health Sciences (ES-07015, ES10042, R01ES010042, ES08089, R01ES008089, R29ES008089, T32ES007015)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Nrf2, mitochondrial complex II inhibition, 3-nitropropionic acid, malonate, Huntington's disease, oxidative stress, antioxidant response element, astrocytes, striatal neurotoxicity, Nrf2 knockout mice, neuroprotection, neurodegenerative disease treatment
MeSH terms
Animals, Astrocytes, DNA-Binding Proteins, Humans, Malonates, Nitro Compounds, Propionates, Succinate Dehydrogenase, Transcription, Genetic, Trans-Activators, Genes, Reporter, NF-E2-Related Factor 2, Mice

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