Review
Glycolysis: a bioenergetic or a survival pathway?

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Following inhibition of mitochondrial respiration neurons die rapidly, whereas astrocytes utilize glycolytically-generated ATP to increase their mitochondrial membrane potential, thus becoming more resistant to pro-apoptotic stimuli. Neurons are unable to increase glycolysis due to the lack of activity of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase, isoform 3 (PFKFB3). In neurons, PFKFB3 is degraded constantly via the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)– CDH1. Glucose metabolism in neurons is directed mainly to the pentose phosphate pathway, leading to regeneration of reduced glutathione. In addition to their relevance to brain physiology and pathophysiology, these observations suggest that APC/C–CDH1 might link activation of glycolysis and cell proliferation as it is also involved in the regulation of cell cycle proteins.

Section snippets

Glucose metabolism in the brain

The way in which the brain meets its considerable metabolic needs has long remained unclear, and has been the subject of controversy 1, 2, 3, 4. Neurons and astrocytes, the two major types of brain cells, are largely responsible for its massive consumption of O2 and glucose; indeed, the brain represents only ∼2% of the total body weight, yet it accounts for more than 20% of the total consumption of both of these substrates. Under resting conditions, astrocytes release ∼85% of the glucose they

Control of PFKFB stability: a key regulatory step in glycolysis

PFKFB is a homodimeric bifunctional enzyme that can both catalyze the conversion of fructose-6-phosphate into F2,6P2 and act as a phosphatase to convert F2,6P2 back into fructose-6-phosphate. There are four isoforms of PFKFB, each encoded by a separate gene [27]. Each isoform displays markedly different regulatory and kinetic properties and this, in turn, determines the ratio of kinase:phosphatase activity, and therefore the concentration of F2,6P2 in different tissues (see [28]). Isoform 3

What is the role of glucose in neurons?

As upregulation of glycolysis and utilization of glycolytic ATP to maintain the Δψm in astrocytes is responsible for their effective defence against inhibition of respiration [17], we tested the hypothesis that transfection of the full-length Pfkfb3 cDNA into neurons would render them more resistant to inhibition of respiration by NO. Indeed, these experiments showed that activation of glycolysis did occur in neurons after such transfection and that this procedure could partially protect

Concluding remarks and future perspectives

Regulation of PFKFB3 activity by the APC/C–CDH1 proteasome system is critical for the understanding of glucose metabolism, bioenergetic supply and, possibly, the response to stress in the functioning brain. Indeed, in astrocytes, the low activity of this regulatory pathway is responsible for the presence of PFKFB3, thus allowing the AMPK-dependent activation of glycolysis in these cells. It remains to be investigated whether changes in APC/C–CDH1 activity occur in astrocytes and account for

Acknowledgements

The authors are grateful to Annie Higgs for help in the preparation of this manuscript. J.P.B. is supported by the Ministerio de Ciencia e Innovación (SAF2007-61492 and Consolider-Ingenio CSD2007-00020, Spain) and by the Junta de Castilla y León (SA046A10-2, GR206 and Red de Terapia Celular y Medicina Regenerativa). A.A. is supported by the Instituto de Salud Carlos III (PS09/00366 and Renevas) and by the Junta de Castilla y León. J.P.B and A.A are recipients of “Salvador de Madariaga” grants

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