The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1
The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1
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DOI：
10.1038/ncb1881
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发表时间：
2009-06-01
影响因子：
21.3
通讯作者：
Bolanos, Juan P.
中科院分区：
文献类型：
--
作者：
Herrero-Mendez, Angel;Almeida, Angeles;Bolanos, Juan P.
已知神经元具有比星形胶质细胞更低的糖酵解速率，并且当受到应激时，它们不能上调糖酵解（1），因为Pfkfb 3（6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶-3）活性低（2）。这种酶产生果糖-2，6-二磷酸（F2，6P（2））（3），是6-磷酸果糖-1-激酶（Pfk 1;参考文献4）最有效的激活剂，是糖酵解的主要调节剂（5）。在这里，我们发现脑皮质神经元中没有Pfkfb 3，并且神经元中的Pfkfb 3通过E3泛素连接酶（6），后期促进复合物/环体（APC/C）-Cdh 1的作用不断受到蛋白酶体降解。相比之下，星形胶质细胞具有低APC/C-Cdh 1活性，因此Pfkfb 3存在于这些细胞中。通过抑制Cdh 1或过度表达Pfkfb 3在神经元中上调Pfkfb 3导致糖酵解的激活。然而，这伴随着通过戊糖磷酸途径（参与还原型谷胱甘肽再生的代谢途径（7））的葡萄糖氧化显著减少，导致氧化应激和凋亡性死亡。因此，通过APC/C-Cdh 1主动下调糖酵解，神经元使用葡萄糖来维持其抗氧化状态，而代价是其用于生物能量目的。
Neurons are known to have a lower glycolytic rate than astrocytes and when stressed they are unable to upregulate glycolysis(1) because of low Pfkfb3 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3) activity(2). This enzyme generates fructose-2,6- bisphosphate (F2,6P(2))(3), the most potent activator of 6-phosphofructo-1-kinase (Pfk1; ref. 4), a master regulator of glycolysis(5). 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(6), 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(7))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.