Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway.
Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway.
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DOI：
10.1038/ncomms10640
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发表时间：
2016-02-16
影响因子：
16.6
通讯作者：
Lutsenko S
中科院分区：
文献类型：
--
作者：
Hatori Y;Yan Y;Schmidt K;Furukawa E;Hasan NM;Yang N;Liu CN;Sockanathan S;Lutsenko S
大脑发育需要一个微调铜稳态。铜缺乏或过量导致严重的神经病理学。我们证明，神经元分化后，细胞对铜的需求增加，特别是在分泌途径。通过转录和代谢调节促进铜流向该隔室。定量实时成像显示，神经元分化后细胞质谷胱甘肽的氧化态发生逐渐变化。从一个广泛的氧化还原状态的过渡到一个统一的还原胞质溶胶促进铜伴侣Atox1的还原，释放其金属结合位点。与此同时，Atox1及其伴侣，铜转运蛋白ATP 7A的表达上调。这些事件通过分泌途径产生更高的铜通量，所述分泌途径平衡胞质溶胶中的铜并增加辅因子向铜依赖性酶的供应，所述铜依赖性酶的表达在分化的神经元中升高。谷胱甘肽氧化和铜区室化之间的直接联系允许对正常神经元功能至关重要的快速代谢调节。 分化的神经元比其前体细胞对铜的需求增加，但改变铜稳态的机制尚不清楚。在这里，Hatori等人表明，神经元分化伴随着通过分泌途径的铜流量增加，增加了对铜依赖性酶的供应。
Brain development requires a fine-tuned copper homoeostasis. Copper deficiency or excess results in severe neuro-pathologies. We demonstrate that upon neuronal differentiation, cellular demand for copper increases, especially within the secretory pathway. Copper flow to this compartment is facilitated through transcriptional and metabolic regulation. Quantitative real-time imaging revealed a gradual change in the oxidation state of cytosolic glutathione upon neuronal differentiation. Transition from a broad range of redox states to a uniformly reducing cytosol facilitates reduction of the copper chaperone Atox1, liberating its metal-binding site. Concomitantly, expression of Atox1 and its partner, a copper transporter ATP7A, is upregulated. These events produce a higher flux of copper through the secretory pathway that balances copper in the cytosol and increases supply of the cofactor to copper-dependent enzymes, expression of which is elevated in differentiated neurons. Direct link between glutathione oxidation and copper compartmentalization allows for rapid metabolic adjustments essential for normal neuronal function. Differentiating neurons have an increased requirement for copper than their precursors, but the mechanism of altered copper homoeostasis is not known. Here, Hatori et al. show that neuronal differentiation is accompanied by an increased flux of copper through the secretory pathway, increasing supply to copper-dependent enzymes.
影响因子：
2.7
作者：
Periz G;Yan Y;Bitzer ZT;Sockanathan S
通讯作者：
Sockanathan S