Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes.
Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes.
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DOI：
10.1016/j.redox.2023.102672
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发表时间：
2023-06
期刊：
影响因子：
11.4
通讯作者：
Abramov, Andrey Y.
中科院分区：
文献类型：
--
作者：
Esteras, Noemi;Blacker, Thomas S.;Zherebtsov, Evgeny A.;Stelmashuk, Olga A.;Zhang, Ying;Wigley, W. Christian;Duchen, Michael R.;Dinkova-Kostova, Albena T.;Abramov, Andrey Y.
转录因子Nrf2及其抑制子Keap1通过诱导调节细胞解毒、抗氧化防御和能量代谢的基因表达，介导细胞应激适应。能量产生和抗氧化防御分别利用NADH和NADPH作为必需的代谢辅助因子；两者都是在不同的葡萄糖代谢途径中产生的，并且这两个途径都被Nrf2激活所增强。在这里，我们通过从野生型、Nrf2基因敲除和Keap1基因敲除的小鼠分离的神经胶质细胞培养，研究了Nrf2在葡萄糖分布中的作用以及NADH产生在能量代谢和NADPH动态平衡中的相互关系。使用先进的单个活细胞的显微成像，包括多光子荧光寿命成像显微镜(FLIM)来区分NADH和NADPH，我们发现Nrf2的激活增加了神经元和星形胶质细胞对葡萄糖的摄取。葡萄糖消耗在脑细胞中优先用于线粒体NADH和能量产生，而在氧化还原反应的戊糖磷酸途径中对NADPH合成的贡献较小。由于Nrf2在神经元发育过程中受到抑制，这一策略使神经元依赖于星形细胞Nrf2来维持氧化还原平衡和能量平衡。NRF2增加了神经元和星形胶质细胞对葡萄糖的摄取。在基础条件下，NRF2的激活可提高NADH和NADPH胞浆水平。当葡萄糖供应减少时，NRF2有利于星形胶质细胞产生能量。葡萄糖是大脑中线粒体NADH和能量产生的优先考虑因素。
The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence and energy metabolism. Energy production and antioxidant defence employ NADH and NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways of glucose metabolism, and both pathways are enhanced by Nrf2 activation. Here, we examined the role of Nrf2 on glucose distribution and the interrelation between NADH production in energy metabolism and NADPH homeostasis using glio-neuronal cultures isolated from wild-type, Nrf2-knockout and Keap1-knockdown mice. Employing advanced microscopy imaging of single live cells, including multiphoton fluorescence lifetime imaging microscopy (FLIM) to discriminate between NADH and NADPH, we found that Nrf2 activation increases glucose uptake into neurons and astrocytes. Glucose consumption is prioritized in brain cells for mitochondrial NADH and energy production, with a smaller contribution to NADPH synthesis in the pentose phosphate pathway for redox reactions. As Nrf2 is suppressed during neuronal development, this strategy leaves neurons reliant on astrocytic Nrf2 to maintain redox balance and energy homeostasis. Nrf2 increases glucose uptake in neurons and astrocytes. Nrf2 activation enhances both NADH and NADPH cytoplasmic levels in basal conditions. Nrf2 favours energy production in astrocytes when glucose availability is reduced. Glucose is prioritized in brain for mitochondrial NADH and energy production.
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影响因子：
3.9
作者：
Dinkova-Kostova AT;Baird L;Holmström KM;Meyer CJ;Abramov AY
通讯作者：
Abramov AY
影响因子：
11.4
作者：
Heiss, Elke H.;Schachner, Daniel;Zimmermann, Kristin;Dirsch, Verena M.
通讯作者：
Dirsch, Verena M.
影响因子：
7.4
作者：
Blacker, Thomas S.;Duchen, Michael R.
通讯作者：
Duchen, Michael R.
影响因子：
4.6
作者：
Bartolome F;Esteras N;Martin-Requero A;Boutoleau-Bretonniere C;Vercelletto M;Gabelle A;Le Ber I;Honda T;Dinkova-Kostova AT;Hardy J;Carro E;Abramov AY
通讯作者：
Abramov AY
影响因子：
5.8
作者：
Knatko EV;Tatham MH;Zhang Y;Castro C;Higgins M;Dayalan Naidu S;Leonardi C;de la Vega L;Honda T;Griffin JL;Hay RT;Dinkova-Kostova AT
通讯作者：
Dinkova-Kostova AT