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, Andrey Y. Abramov

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)761-770
Number of pages10
JournalBiology Open
Volume2
Issue number8
DOIs
StatePublished - Aug 15 2013

Fingerprint

cell respiration
energy metabolism
Energy Metabolism
Respiration
Genes
Adenosine Triphosphate
Mitochondrial Membrane Potential
Availability
membrane potential
Substrates
Membranes
Mitochondria
Cytoprotection
oxidative phosphorylation
Gene Regulatory Networks
Oxidative Phosphorylation
Depolarization
glycolysis
Glycolysis
cells

Keywords

  • Energy metabolism
  • Keap1
  • Mitochondria
  • Nrf2
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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

Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. / Holmström, Kira M.; Baird, Liam; Zhang, Ying; Hargreaves, Iain; Chalasani, Annapurna; Land, John M.; Stanyer, Lee; Yamamoto, Masayuki; Dinkova-Kostova, Albena T.; Abramov, Andrey Y.

In: Biology Open, Vol. 2, No. 8, 15.08.2013, p. 761-770.

Research output: Contribution to journalArticle

Holmström, KM, Baird, L, Zhang, Y, Hargreaves, I, Chalasani, A, Land, JM, Stanyer, L, Yamamoto, M, Dinkova-Kostova, AT & Abramov, AY 2013, 'Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration', Biology Open, vol. 2, no. 8, pp. 761-770. https://doi.org/10.1242/bio.20134853
Holmström KM, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land JM et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biology Open. 2013 Aug 15;2(8):761-770. https://doi.org/10.1242/bio.20134853
Holmström, Kira M. ; Baird, Liam ; Zhang, Ying ; Hargreaves, Iain ; Chalasani, Annapurna ; Land, John M. ; Stanyer, Lee ; Yamamoto, Masayuki ; Dinkova-Kostova, Albena T. ; Abramov, Andrey Y. / Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. In: Biology Open. 2013 ; Vol. 2, No. 8. pp. 761-770.
@article{5b54a451d1784d6b8ff32585f5c8189b,
title = "Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration",
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.",
keywords = "Energy metabolism, Keap1, Mitochondria, Nrf2, Oxidative phosphorylation",
author = "Holmstr{\"o}m, {Kira M.} and Liam Baird and Ying Zhang and Iain Hargreaves and Annapurna Chalasani and Land, {John M.} and Lee Stanyer and Masayuki Yamamoto and Dinkova-Kostova, {Albena T.} and Abramov, {Andrey Y.}",
year = "2013",
month = "8",
day = "15",
doi = "10.1242/bio.20134853",
language = "English (US)",
volume = "2",
pages = "761--770",
journal = "Biology Open",
issn = "2046-6390",
publisher = "Company of Biologists Ltd",
number = "8",

}

TY - JOUR

T1 - Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

AU - Holmström, Kira M.

AU - Baird, Liam

AU - Zhang, Ying

AU - Hargreaves, Iain

AU - Chalasani, Annapurna

AU - Land, John M.

AU - Stanyer, Lee

AU - Yamamoto, Masayuki

AU - Dinkova-Kostova, Albena T.

AU - Abramov, Andrey Y.

PY - 2013/8/15

Y1 - 2013/8/15

N2 - 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.

AB - 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.

KW - Energy metabolism

KW - Keap1

KW - Mitochondria

KW - Nrf2

KW - Oxidative phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=84964999321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964999321&partnerID=8YFLogxK

U2 - 10.1242/bio.20134853

DO - 10.1242/bio.20134853

M3 - Article

VL - 2

SP - 761

EP - 770

JO - Biology Open

JF - Biology Open

SN - 2046-6390

IS - 8

ER -