The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1
| Autor: | Carolina Maestre, Juan P. Bolaños, Salvador Moncada, Emilio Fernández, Angeles Almeida, Angel Herrero-Mendez |
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| Rok vydání: | 2009 |
| Předmět: |
Antioxidant
Bioenergetics Phosphofructokinase-2 medicine.medical_treatment Molecular Sequence Data Pentose phosphate pathway Nitric Oxide Anaphase-Promoting Complex-Cyclosome Antioxidants Pentose Phosphate Pathway chemistry.chemical_compound Downregulation and upregulation medicine Animals Humans Glycolysis Amino Acid Sequence RNA Small Interfering Rats Wistar Cerebral Cortex Neurons biology Activator (genetics) Ubiquitin-Protein Ligase Complexes Cell Biology Glutathione Rats Cell biology Ubiquitin ligase Isoenzymes Glucose Biochemistry chemistry Mutagenesis Site-Directed biology.protein RNA Interference Energy Metabolism Reactive Oxygen Species Oxidation-Reduction Sequence Alignment |
| Zdroj: | Nature Cell Biology. 11:747-752 |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/ncb1881 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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