Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes
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
Affiliations
Noemí Esteras
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK; Corresponding author.
Thomas S. Blacker
Research Department of Cell & Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK
Evgeny A. Zherebtsov
Optoelectronics and Measurement Techniques, University of Oulu, Oulu, Finland
Olga A. Stelmashuk
Laboratory of Cell Physiology and Pathology, Orel State University, Orel, Russia
Ying Zhang
Jacqui Wood Cancer, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, UK
W. Christian Wigley
Reata Pharmaceuticals, 2801 Gateway Dr, Suite 150, Irving, TX, 75063, USA
Michael R. Duchen
Research Department of Cell & Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK
Albena T. Dinkova-Kostova
Jacqui Wood Cancer, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, UK; Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
Andrey Y. Abramov
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK; Corresponding author.
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.
