Neurons are known to have a lower glycolytic rate than astrocytes and when stressed they are unable to upregulate glycolysis1 because of low Pfkfb3 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3) activity2. This enzyme generates fructose-2,6-bisphosphate (F2,6P2)3, the most potent activator of 6-phosphofructo-1-kinase (Pfk1; ref. 4), a master regulator of glycolysis5. Here, we show that Pfkfb3 is absent from neurons in the brain cortex and that Pfkfb3 in neurons is constantly subject to proteasomal degradation by the action of the E3 ubiquitin ligase6, anaphase-promoting complex/cyclosome (APC/C)–Cdh1. By contrast, astrocytes have low APC/C–Cdh1 activity and therefore Pfkfb3 is present in these cells. Upregulation of Pfkfb3 by either inhibition of Cdh1 or overexpression of Pfkfb3 in neurons resulted in the activation of glycolysis. This, however, was accompanied by a marked decrease in the oxidation of glucose through the pentose phosphate pathway (a metabolic route involved in the regeneration of reduced glutathione7) resulting in oxidative stress and apoptotic death. Thus, by actively downregulating glycolysis by APC/C–Cdh1, neurons use glucose to maintain their antioxidant status at the expense of its utilization for bioenergetic purposes.
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This work was supported by Ministerio de Ciencia e Innovación (SAF2007-61492 and Consolider-Ingenio CSD2007-00020, Spain), Instituto de Salud Carlos-III (FIS06/0794 and Renevas), and Junta de Castilla y León (SA066A07 and Red de Terapia Celular y Medicina Regenerativa). We would like to thank H. Yamano for valuable help with the APC/C–Cdh1 activity assays, Carmela Gómez-Rodríguez for immunohistochemistry experiments, M. Resch for technical assistance and A. Higgs for critical evaluation of this paper.
The authors declare no competing financial interests.
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Herrero-Mendez, A., Almeida, A., Fernández, E. et al. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1. Nat Cell Biol 11, 747–752 (2009). https://doi.org/10.1038/ncb1881
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