Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 53, Issue 2, Pages 383-394Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.05.002
Keywords
Uncoupling protein; UCP4; Mitochondria; Mitochondrial dysfunction; Nuclear factor-kappa B; c-Rel; Oxidative stress; UCP; Parkinson's disease; Free radicals
Funding
- Henry G. Leong Professorship in Neurology
- Donation Fund for Neurology Research
- Seed Funding for Basic Research, Committee on Research and Conference Grants [HKU200901159008]
- University of Hong Kong
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Mitochondrial uncoupling protein-4 (UCP4) enhances neuronal survival in 1-methyl-4-phenylpyridinium (MPP+) toxicity by suppressing oxidative stress and preserving intracellular ATP and mitochondrial membrane potential (MMP). NF-kappa B regulates neuronal viability via its complexes, p65 mediating cell death and c-Rel promoting cell survival. We reported previously that NF-kappa B mediates UCP4 neuroprotection against MPP+ toxicity. Here, we investigated its link with the NF-kappa B c-Rel prosurvival pathway in alleviating mitochondrial dysfunction and oxidative stress. We overexpressed a c-Rel-encoding plasmid in SH-SY5Y cells and showed that c-Rel overexpression induced NF-kappa B activity without affecting p65 level. Overexpression of c-Rel increased UCP4 promoter activity and protein expression. Electrophoretic mobility shift assay showed that H2O2 increased NF-kappa B binding to the UCP4 promoter and that NF-kappa B complexes were composed of p50/p50 and p50/c-Rel dimers. Under H2O2-induced oxidative stress. UCP4 knockdown significantly increased superoxide levels, decreased reduced glutathione (GSH) levels, and increased oxidized glutathione levels, compared to controls. UCP4 expression induced by c-Rel overexpression significantly decreased superoxide levels and preserved GSH levels and MMP under similar stress. These protective effects of c-Rel overexpression in H2O2-induced oxidative stress were significantly reduced after UCP4 knockdown, indicating that UCP4 is a target effector gene of the NF-kappa B c-Rel prosurvival pathway to mitigate the effects of oxidative stress. (C) 2012 Elsevier Inc. All rights reserved.
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