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Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

Holmström, KM; Baird, L; Zhang, Y; Hargreaves, I; Chalasani, A; Land, JM; Stanyer, L; ... Abramov, AY; + view all (2013) Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biology Open , 2 761 - 770. 10.1242/bio.20134853. Green open access

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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.

Type: Article
Title: Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/bio.20134853
Publisher version: http://dx.doi.org/10.1242/bio.20134853
Language: English
Additional information: © 2013. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. PMCID: PMC3744067
Keywords: Energy metabolism, Keap1, Mitochondria, Nrf2, Oxidative phosphorylation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1404742
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