Mitochondrial Hexokinase II Promotes Neuronal Survival and Acts Downstream of Glycogen Synthase Kinase-3
Mitochondrial Hexokinase II Promotes Neuronal Survival and Acts Downstream of Glycogen Synthase Kinase-3
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DOI：
10.1074/jbc.m808698200
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发表时间：
2009-01-30
影响因子：
4.8
通讯作者：
Diaz-Nido, Javier
中科院分区：
文献类型：
--
作者：
Gimenez-Cassina, Alfredo;Lim, Filip;Diaz-Nido, Javier
线粒体改变在大多数神经退行性疾病中都可检测到，并可能导致神经细胞的功能障碍和死亡。由于糖原合成酶-3(GSK-3)被认为是调节神经细胞存活和死亡的关键因素，我们研究了线粒体抑制剂鱼藤酮对培养神经元GSK-3活性的调节作用。有趣的是，长期抑制GSK-3对鱼藤酮诱导培养的神经细胞的凋亡具有保护作用。为了阐明这种神经保护的分子机制，我们证明了慢性抑制GSK-3重新编程神经细胞的新陈代谢，导致糖酵解的增强。伴随这一作用的是线粒体中己糖激酶II(HKII)的诱导和积聚。干扰线粒体结合的HKII或HKII的表达显著减弱了GSK-3抑制所引起的神经保护，更重要的是，HKII的过度表达足以对抗鱼藤酮诱导的细胞死亡。因此，线粒体HKII是GSK-3调控下神经元存活的启动子。此外，HKII的神经保护作用可能与以葡萄糖代谢不足和线粒体功能障碍为显著特征的神经退行性疾病有关。
Mitochondrial alterations are detected in most neurodegenerative disorders and may contribute to the dysfunction and demise of neuronal cells. Because glycogen synthase kinase-3 (GSK-3) is considered to be a critical factor in regulating neuronal cell survival and death, we studied the effects of modulating GSK-3 activity in cultured neurons treated with the mitochondrial inhibitor, rotenone. Interestingly, chronic inhibition of GSK-3 protects against rotenone-induced apoptosis in cultured neuronal cells. In an attempt to elucidate the molecular mechanisms underlying this neuroprotection, we demonstrated that chronic inhibition of GSK-3 reprograms the metabolism of neuronal cells, leading to an enhancement of glycolysis. This effect was accompanied by the induction and accumulation of hexokinase II (HKII) in the mitochondria. Interfering with either the mitochondrial binding of HKII or HKII expression significantly diminished the neuroprotection evoked by GSK-3 inhibition, and importantly, HKII overexpression is sufficient to protect against rotenone-induced cell death. Thus, mitochondrial HKII is a promoter of neuronal survival under the regulation of GSK-3. Furthermore, the neuroprotective effect of HKII may be relevant to neurodegenerative diseases in which glucose hypometabolism and mitochondrial dysfunction are prominent features.