多巴胺信号损害人神经祖细胞中线粒体己糖激酶对 ROS 的调节

Dopamine signaling impairs ROS modulation by mitochondrial hexokinase in human neural progenitor cells

Keywords：ROS; dopamine; mitochondria; mt-HK; neurodevelopment.

关键词：活性氧； 多巴胺； 线粒体； mt-香港; 神经发育

哺乳动物：人类
作者：urihata T, Maekawa S, Takada S, Kakutani N, Nambu H, Shirakawa R, Yokota T, Kinugawa S
出版期刊：《BIOSCIENCE REPORTS》（2021）

Abstract：

Dopamine signaling has numerous roles during brain development. In addition, alterations in dopamine signaling may be also involved in the pathophysiology of psychiatric disorders. Neurodevelopment is modulated in multiple steps by reactive oxygen species (ROS),
byproducts of oxidative metabolism that are signaling factors involved in proliferation, differentiation, and migration. Hexokinase (HK), when associated with the mitochondria (mt-HK),is a potent modulator of the generation of mitochondrial ROS in the brain. In the present study, we investigated whether dopamine could affect both the activity and redox function of mt-HK in human neural progenitor cells (NPCs). We found that dopamine signaling via D1R decreases mt-HK activity and impairs ROS modulation, which is followed by an
expressive release of H2O2 and impairment in calcium handling by the mitochondria. Nevertheless, mitochondrial respiration is not affected, suggesting specificity for dopamine on mt-HK function. In neural stem cells (NSCs) derived from induced-pluripotent stem cells (iPSCs) of schizophrenia patients, mt-HK is unable to decrease mitochondrial ROS, in contrast with NSCs derived from healthy individuals. Our data point to mitochondrial hexokinase as a novel target of dopaminergic signaling, as well as a redox modulator in human neural progenitor cells, which may be relevant to the pathophysiology of neurodevelopmental disorders such as schizophrenia.

文章摘要：

多巴胺信号传导在大脑发育过程中具有多种作用。此外，多巴胺信号的改变也可能与精神疾病的病理生理学有关。神经发育受到活性氧 (ROS) 的多个步骤的调节，活性氧是氧化代谢的副产物，是参与增殖、分化和迁移的信号因子。当与线粒体 (mt-HK) 结合时，己糖激酶 (HK) 是大脑中线粒体 ROS 生成的有效调节剂。在本研究中，我们研究了多巴胺是否会影响人类神经祖细胞 (NPC) 中 mt-HK 的活性和氧化还原功能。我们发现通过 D1R 的多巴胺信号传导会降低 mt-HK 活性并损害 ROS 调节，然后是 H2O2 的表达性释放和线粒体对钙处理的损害。然而，线粒体呼吸不受影响，表明多巴胺对 mt-HK 功能的特异性。在源自精神分裂症患者的诱导多能干细胞 (iPSCs) 的神经干细胞 (NSCs) 中，与源自健康个体的 NSCs 相比，mt-HK 无法减少线粒体 ROS。我们的数据表明线粒体己糖激酶是多巴胺能信号传导的新靶点，也是人类神经祖细胞中的氧化还原调节剂，这可能与精神分裂症等神经发育障碍的病理生理学有关。

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