Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

Kira M. Holmström, Liam Baird, Ying Zhang, Iain Hargreaves, Annapurna Chalasani, John M. Land, Lee Stanyer, Masayuki Yamamoto, Albena T. Dinkova-Kostova (Lead / Corresponding author), Andrey Y. Abramov (Lead / Corresponding author)

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    Abstract

    Transcription factor Nrf2 and its repressor Keap1 regulate a network of cytoprotective genes involving more than 1% of the genome, their best known targets being drug-metabolizing and antioxidant genes. Here we demonstrate a novel role for this pathway in directly regulating mitochondrial bioenergetics in murine neurons and embryonic fibroblasts. Loss of Nrf2 leads to mitochondrial depolarisation, decreased ATP levels and impaired respiration, whereas genetic activation of Nrf2 increases the mitochondrial membrane potential and ATP levels, the rate of respiration and the efficiency of oxidative phosphorylation. We further show that Nrf2-deficient cells have increased production of ATP in glycolysis, which is then used by the F1Fo-ATPase for maintenance of the mitochondrial membrane potential. While the levels and in vitro activities of the respiratory complexes are unaffected by Nrf2 deletion, their activities in isolated mitochondria and intact live cells are substantially impaired. In addition, the rate of regeneration of NADH after inhibition of respiration is much slower in Nrf2-knockout cells than in their wild-type counterparts. Taken together, these results show that Nrf2 directly regulates cellular energy metabolism through modulating the availability of substrates for mitochondrial respiration. Our findings highlight the importance of efficient energy metabolism in Nrf2-mediated cytoprotection.
    Original languageEnglish
    Pages (from-to)761-770
    Number of pages10
    JournalOpen Biology
    Volume2
    Issue number8
    Early online date25 Jun 2013
    DOIs
    Publication statusPublished - 15 Aug 2013

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    Keywords

    • NRF2
    • Keap1
    • Energy metabolism
    • oxidative phosphorylation
    • Mitochondria

    Cite this

    Holmström, K. M., Baird, L., Zhang, Y., Hargreaves, I., Chalasani, A., Land, J. M., Stanyer, L., Yamamoto, M., Dinkova-Kostova, A. T., & Abramov, A. Y. (2013). Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Open Biology, 2(8), 761-770. https://doi.org/10.1242/bio.20134853