Nrf2 affects the efficiency of mitochondrial fatty acid oxidation

Marthe H R Ludtmann, Plamena R. Angelova, Ying Zhang, Andrey Y. Abramov, Albena T. Dinkova-Kostova

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

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 livermitochondria 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.

Original languageEnglish (US)
Pages (from-to)415-424
Number of pages10
JournalBiochemical Journal
Volume457
Issue number3
DOIs
StatePublished - Feb 1 2014

Keywords

  • ATP
  • FAD
  • Fatty acid oxidation
  • Kelch-like ECH-associated protein 1 (Keap1)
  • Live-cell imaging
  • Tissue slice

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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