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      The emerging role of Nrf2 in mitochondrial function

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          Abstract

          The transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) allows adaptation and survival under conditions of stress by regulating the gene expression of diverse networks of cytoprotective proteins, including antioxidant, anti-inflammatory, and detoxification enzymes as well as proteins that assist in the repair or removal of damaged macromolecules. Nrf2 has a crucial role in the maintenance of cellular redox homeostasis by regulating the biosynthesis, utilization, and regeneration of glutathione, thioredoxin, and NADPH and by controlling the production of reactive oxygen species by mitochondria and NADPH oxidase. Under homeostatic conditions, Nrf2 affects the mitochondrial membrane potential, fatty acid oxidation, availability of substrates (NADH and FADH 2/succinate) for respiration, and ATP synthesis. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria via transcriptional upregulation of uncoupling protein 3 and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α, as well as by promoting purine nucleotide biosynthesis. Pharmacological Nrf2 activators, such as the naturally occurring isothiocyanate sulforaphane, inhibit oxidant-mediated opening of the mitochondrial permeability transition pore and mitochondrial swelling. Curiously, a synthetic 1,4-diphenyl-1,2,3-triazole compound, originally designed as an Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis. Thus, Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress.

          Highlights

          • Nrf2 has a crucial role in maintaining cellular redox homeostasis.

          • Nrf2 affects the mitochondrial membrane potential and ATP synthesis.

          • Nrf2 influences mitochondrial fatty acid oxidation.

          • Nrf2 supports the structural and functional integrity of the mitochondria.

          • Nrf2 activators have beneficial effects when mitochondrial function is compromised.

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          Most cited references72

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          Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network.

          The PGC-1 family of regulated coactivators, consisting of PGC-1α, PGC-1β and PRC, plays a central role in a regulatory network governing the transcriptional control of mitochondrial biogenesis and respiratory function. These coactivators target multiple transcription factors including NRF-1, NRF-2 and the orphan nuclear hormone receptor, ERRα, among others. In addition, they themselves are the targets of coactivator and co-repressor complexes that regulate gene expression through chromatin remodeling. The expression of PGC-1 family members is modulated by extracellular signals controlling metabolism, differentiation or cell growth and in some cases their activities are known to be regulated by post-translational modification by the energy sensors, AMPK and SIRT1. Recent gene knockout and silencing studies of many members of the PGC-1 network have revealed phenotypes of wide ranging severity suggestive of complex compensatory interactions or broadly integrative functions that are not exclusive to mitochondrial biogenesis. The results point to a central role for the PGC-1 family in integrating mitochondrial biogenesis and energy production with many diverse cellular functions. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. Copyright © 2010 Elsevier B.V. All rights reserved.
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            PGC-1 coactivators: inducible regulators of energy metabolism in health and disease.

            Members of the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.
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              DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.

              DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.
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                Author and article information

                Contributors
                Journal
                Free Radic Biol Med
                Free Radic. Biol. Med
                Free Radical Biology & Medicine
                Elsevier Science
                0891-5849
                1873-4596
                1 November 2015
                November 2015
                : 88
                : Pt B
                : 179-188
                Affiliations
                [a ]Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, UK
                [b ]Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
                [c ]Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BG, UK
                Author notes
                [* ]Corresponding author at: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, UK. a.dinkovakostova@ 123456dundee.ac.uk
                [** ]Corresponding author at: Department of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UK. a.abramov@ 123456ucl.ac.uk
                Article
                S0891-5849(15)00212-9
                10.1016/j.freeradbiomed.2015.04.036
                4726722
                25975984
                3acaf58c-909f-41be-81f4-51e90b02ac69
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 13 March 2015
                : 28 April 2015
                : 30 April 2015
                Categories
                Article

                Molecular biology
                bioenergetics,cytoprotection,keap1,mitochondria,nrf2,free radicals
                Molecular biology
                bioenergetics, cytoprotection, keap1, mitochondria, nrf2, free radicals

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