University of Oulu

Noemí Esteras, Thomas S. Blacker, Evgeny A. Zherebtsov, Olga A. Stelmashuk, Ying Zhang, W. Christian Wigley, Michael R. Duchen, Albena T. Dinkova-Kostova, Andrey Y. Abramov, Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes, Redox Biology, Volume 62, 2023, 102672, ISSN 2213-2317,

Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes

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Author: Esteras, Noemí1; Blacker, Thomas S.2; Zherebtsov, Evgeny A.3;
Organizations: 1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
2Research Department of Cell & Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK
3Optoelectronics and Measurement Techniques, University of Oulu, Oulu, Finland
4Laboratory of Cell Physiology and Pathology, Orel State University, Orel, Russia
5Jacqui Wood Cancer, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, UK
6Reata Pharmaceuticals, 2801 Gateway Dr, Suite 150, Irving, TX, 75063, USA
7Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 16.2 MB)
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Language: English
Published: Elsevier, 2023
Publish Date: 2023-04-05


The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence and energy metabolism. Energy production and antioxidant defence employ NADH and NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways of glucose metabolism, and both pathways are enhanced by Nrf2 activation. Here, we examined the role of Nrf2 on glucose distribution and the interrelation between NADH production in energy metabolism and NADPH homeostasis using glio-neuronal cultures isolated from wild-type, Nrf2-knockout and Keap1-knockdown mice. Employing advanced microscopy imaging of single live cells, including multiphoton fluorescence lifetime imaging microscopy (FLIM) to discriminate between NADH and NADPH, we found that Nrf2 activation increases glucose uptake into neurons and astrocytes. Glucose consumption is prioritized in brain cells for mitochondrial NADH and energy production, with a smaller contribution to NADPH synthesis in the pentose phosphate pathway for redox reactions. As Nrf2 is suppressed during neuronal development, this strategy leaves neurons reliant on astrocytic Nrf2 to maintain redox balance and energy homeostasis.

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Series: Redox biology
ISSN: 2213-2317
ISSN-E: 2213-2317
ISSN-L: 2213-2317
Volume: 62
Article number: 102672
DOI: 10.1016/j.redox.2023.102672
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: We thank Cancer Research UK (C20953/A18644) for funding. OS was supported by FEBS Travel Fellowship. NE is funded by a Ramon y Cajal Fellowship (RYC2021-034267-I) from the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 and the European Union “NextGenerationEU”/PRTR.
Copyright information: © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (