NF-E2-related Factor-2 Mediates Neuroprotection against Mitochondrial Complex I Inhibitors and Increased Concentrations of Intracellular Calcium in Primary Cortical Neurons
Open accessAbstract
NF-E2-related factor-2 (Nrf2) regulates the gene expression of phase II detoxification enzymes and antioxidant proteins through an enhancer sequence referred to as the antioxidant-responsive element (ARE). In this study, we demonstrate that Nrf2 protects neurons in mixed primary neuronal cultures containing both astrocytes ( approximately 10%) and neurons ( approximately 90%) through coordinate up-regulation of ARE-driven genes. Nrf2-/- neurons in this mixed culture system were more sensitive to mitochondrial toxin (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine or rotenone)-induced apoptosis compared with Nrf2+/+ neurons. To understand the underlying mechanism of this observed differential sensitivity, we compared the gene expression profiles using oligonucleotide microarrays. Microarray data showed that Nrf2+/+neuronal cultures had higher expression levels of genes encoding detoxification enzymes, antioxidant proteins, calcium homeostasis proteins, growth factors, neuron-specific proteins, and signaling molecules compared with Nrf2-/- neuronal cultures. As predicted from the microarray data, Nrf2-/- neurons were indeed more vulnerable to the cytotoxic effects of ionomycin- and 2,5-di-(t-butyl)-1,4-hydroquinone-induced increases in intracellular calcium. Finally, adenoviral vector-mediated overexpression of Nrf2 recovered ARE-driven gene expression in Nrf2-/- neuronal cultures and rescued Nrf2-/- neurons from rotenone- or ionomycin-induced cell death. Taken together, these findings suggest that Nrf2 plays an important role in protecting neurons from toxic insult.
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Neuronal cultures derived from Nrf2 knockout mice show increased susceptibility to oxidative stress, as well as damage produced by mitochondrial electron transport chain complex inhibitors such as MPP+ and rotenone.
“Neuronal cultures derived from the Nrf2 knockout mice show increased susceptibility to oxidative stress, as well as damage produced by mitochondrial electron transport chain complex inhibitors such as MPP+ and rotenone184.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [184]
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- Authors
- Lee, J.-M., Shih, A. Y., Murphy, T. H., & Johnson, J. A.
- Affiliations
- University of Wisconsin–Madison (US)
- University of British Columbia (CA)
- Corresponding author
- Johnson, Jeffrey A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 278
- Issue
- 39
- Pages
- 37948-37956
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2065397424
- Cited by
- 308
- References
- 45
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 10 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 6 · 2018: 13 · 2017: 18 · 2016: 16 · 2015: 19 · 2014: 16 · 2013: 26 · 2012: 20
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Heart and Stroke Foundation of British Columbia and Yukon
- National Institutes of Health (5p30es009090-04, ES08089)
- National Institute of Environmental Health Sciences (ES-09090, ES10042, R01ES010042, ES08089)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Nrf2, neuroprotection, mitochondrial complex I inhibitors, rotenone, intracellular calcium, ionomycin, antioxidant response element, antioxidant enzymes, apoptosis, cortical neurons, astrocytes, gene expression profiling, adenoviral overexpression
- MeSH terms
- Animals, Antioxidants, Calcium, Cells, Cultured, Cerebral Cortex, DNA-Binding Proteins, Homeostasis, Rotenone, Trans-Activators, 1-Methyl-4-phenylpyridinium, Oxidative Stress, Neuroprotective Agents, Reverse Transcriptase Polymerase Chain Reaction, Response Elements, Electron Transport Complex I, NF-E2-Related Factor 2, Mice
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