Departamento de Bioquimica y Biologia Molecular, Instituto de Neurociencias de Castilla y Leon, Universidad de Salamanca, 37007 Salamanca, Spain.
IUBMB Life. 2010 Jan;62(1):14-8. doi: 10.1002/iub.280.
Neurons are thought to be particularly vulnerable cells against reactive oxygen and nitrogen species (RONS) damage (nitrosative stress), due in part to their weak antioxidant defense and low ability to compensate energy homeostasis. Intriguingly, nitrosative stress efficiently stimulates the rate of the antioxidant pentose-phosphate pathway (PPP), which generates NADPH a necessary cofactor for the reduction of glutathione disulfide. In fact, inhibition of PPP sensitizes cultured neurons to glutathione oxidation and apoptotic death, whereas its stimulation confers resistance to nitrosative stress. Furthermore, we recently described that neurons can preferentially use glucose through the PPP by inhibiting glycolysis, which is achieved by continuously degrading the glycolytic positive-effector protein, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (Pfkfb3) by the action of the E3 ubiquitine ligase anaphase-promoting complex/cyclosome (APC/C)(Cdh1). These results suggest that the antioxidant fragility of neurons may be compensated by the PPP at the expense of inhibiting bioenergetic glycolysis.
神经元被认为是特别容易受到活性氧和氮物种 (RONS) 损伤（硝化应激）的细胞，部分原因是它们的抗氧化防御能力较弱，能量稳态的补偿能力较低。有趣的是，硝化应激能有效地刺激抗氧化戊糖磷酸途径 (PPP) 的速率，该途径产生 NADPH，是还原谷胱甘肽二硫化物所必需的辅助因子。事实上，抑制 PPP 会使培养的神经元对谷胱甘肽氧化和细胞凋亡死亡敏感，而刺激 PPP 则会赋予神经元对硝化应激的抗性。此外，我们最近描述了神经元可以通过抑制糖酵解，通过 PPP 优先利用葡萄糖，这是通过持续降解糖酵解正效应蛋白 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶-3 (Pfkfb3) 来实现的，该蛋白通过有丝分裂促进复合物/环体 (APC/C)(Cdh1) 的 E3 泛素连接酶的作用。这些结果表明，神经元的抗氧化脆弱性可以通过 PPP 来补偿，代价是抑制生物能量糖酵解。
