pubmed.ncbi.nlm.nih.gov

The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1 - PubMed

doi: 10.1038/ncb1881. Epub 2009 May 17.

Affiliations

The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1

Angel Herrero-Mendez et al. Nat Cell Biol. 2009 Jun.

Abstract

Neurons are known to have a lower glycolytic rate than astrocytes and when stressed they are unable to upregulate glycolysis because of low Pfkfb3 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3) activity. This enzyme generates fructose-2,6-bisphosphate (F2,6P(2)), the most potent activator of 6-phosphofructo-1-kinase (Pfk1; ref. 4), a master regulator of glycolysis. 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 ligase, 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 glutathione) 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.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Biochem J. 1987 Jul 15;245(2):313-24 - PubMed
    1. J Neurosci. 1996 Feb 1;16(3):877-85 - PubMed
    1. Arch Biochem Biophys. 1979 Dec;198(2):478-92 - PubMed
    1. Nat Biotechnol. 2004 Mar;22(3):326-30 - PubMed
    1. Biochem J. 2004 Dec 15;384(Pt 3):629-36 - PubMed

Publication types

MeSH terms

Substances