title: Nrf2 affects the efficiency of mitochondrial fatty acid oxidation.
abstract: Transcription factor Nrf2 (NF-E2 p45-related factor 2) regulates the cellular redox homoeostasis and cytoprotective responses, allowing adaptation and survival under conditions of stress. The significance of Nrf2 in intermediary metabolism is also beginning to be recognized. Thus this transcription factor negatively affects fatty acid synthesis. However, the effect of Nrf2 on fatty acid oxidation is currently unknown. In the present paper, we report that the mitochondrial oxidation of long-chain (palmitic) and short-chain (hexanoic) fatty acids is depressed in the absence of Nrf2 and accelerated when Nrf2 is constitutively active. Addition of fatty acids stimulates respiration in heart and liver mitochondria isolated from wild-type mice. This effect is significantly weaker when Nrf2 is deleted, whereas it is stronger when Nrf2 activity is constitutively high. In the absence of glucose, addition of fatty acids differentially affects the production of ATP in mouse embryonic fibroblasts from wild-type, Nrf2-knockout and Keap1 (Kelch-like ECH-associated protein 1)-knockout mice. In acute tissue slices, the rate of regeneration of FADH2 is reduced when Nrf2 is absent. This metabolic role of Nrf2 on fatty acid oxidation has implications for chronic disease conditions including cancer, metabolic syndrome and neurodegeneration.
authors.affiliation: *Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, U.K.
authors.forename: Marthe H R
authors.initials: MH
authors.lastname: Ludtmann
authors.affiliation: *Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, U.K.
authors.forename: Plamena R
authors.initials: PR
authors.lastname: Angelova
authors.affiliation: †Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, U.K.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: *Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, U.K.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002208:Caproates / Q000378:metabolism; D019069:Cell Respiration; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D019308:Palmitic Acid / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002208:Caproates; D003598:Cytoskeletal Proteins; D005230:Fatty Acids, Nonesterified; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D005182:Flavin-Adenine Dinucleotide; C037652:hexanoic acid; D019308:Palmitic Acid; D000255:Adenosine Triphosphate