Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes

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.

Automated summary

The transcription factor Nrf2 and its repressor Keap1 play a crucial role in cell stress adaptation by regulating gene expression related to cellular detoxification, antioxidant defense, and energy metabolism. This study investigated the impact of Nrf2 on glucose distribution and the connection between NADH production in energy metabolism and NADPH homeostasis using glio-neuronal cultures. The findings showed that Nrf2 activation enhances glucose uptake in neurons and astrocytes, with prioritized consumption for mitochondria-related energy production rather than NADPH synthesis in the pentose phosphate pathway.