AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival.
AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival.
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DOI：
10.1016/j.celrep.2020.108092
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发表时间：
2020-09-01
期刊：
影响因子：
8.8
通讯作者：
Dasgupta B
中科院分区：
文献类型：
--
作者：
Muraleedharan R;Gawali MV;Tiwari D;Sukumaran A;Oatman N;Anderson J;Nardini D;Bhuiyan MAN;Tkáč I;Ward AL;Kundu M;Waclaw R;Chow LM;Gross C;Rao R;Schirmeier S;Dasgupta B
乳酸盐被生产细胞用作能量来源或穿梭到邻近的细胞和组织。葡萄糖和乳酸满足神经元的生物能量需求，后者从星形胶质细胞输入。星形胶质细胞乳酸对神经元生物能量学的贡献和星形胶质细胞乳酸产生的机制尚不完全清楚。通过在体内1H磁共振波谱，13 C葡萄糖质谱，脑电图和分子研究，在这里，我们表明，能量传感器AMP激活的蛋白激酶（AMPK）调节神经元的生存在一个非细胞自主的方式。Ampk基因敲除小鼠缺乏脑乳酸，易于癫痫发作。Ampk在星形胶质细胞中的缺失，而不是神经元中的缺失，导致哺乳动物和苍蝇大脑中的神经元损失。从机制上讲，星形胶质细胞AMPK磷酸化和不稳定的硫氧还蛋白相互作用蛋白（TXNIP），使表达和表面转运的葡萄糖转运蛋白GLUT 1，葡萄糖摄取和乳酸的生产。星形胶质细胞中的Ampk缺失导致TXNIP超稳定性、GLUT 1失调、葡萄糖代谢不足和神经元缺失。Muraleedharan等人证明，AMPK是星形胶质细胞糖酵解、乳酸盐产生和乳酸盐穿梭作为神经元的能量来源所必需的，使得神经胶质中的AMPK损失导致哺乳动物和苍蝇脑中的非细胞自主神经元损失。
Lactate is used as an energy source by producer cells or shuttled to neighboring cells and tissues. Both glucose and lactate fulfill the bioenergetic demand of neurons, the latter imported from astrocytes. The contribution of astrocytic lactate to neuronal bioenergetics and the mechanisms of astrocytic lactate production are incompletely understood. Through in vivo 1H magnetic resonance spectroscopy, 13C glucose mass spectroscopy, and electroencephalographic and molecular studies, here we show that the energy sensor AMP activated protein kinase (AMPK) regulates neuronal survival in a non-cell-autonomous manner. Ampk-null mice are deficient in brain lactate and are seizure prone. Ampk deletion in astroglia, but not neurons, causes neuronal loss in both mammalian and fly brains. Mechanistically, astrocytic AMPK phosphorylated and destabilized thioredoxin-interacting protein (TXNIP), enabling expression and surface translocation of the glucose transporter GLUT1, glucose uptake, and lactate production. Ampk loss in astrocytes causes TXNIP hyperstability, GLUT1 misregulation, inadequate glucose metabolism, and neuronal loss. Muraleedharan et al. demonstrate that AMPK is required for astrocytic glycolysis, lactate production, and lactate shuttle as an energy source to neurons such that AMPK loss in glia causes non-cell-autonomous neuronal loss in the mammalian and fly brain.
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影响因子：
8.9
作者：
Hardie DG
通讯作者：
Hardie DG
影响因子：
6.2
作者：
Halim, Nader D.;Mcfate, Thomas;Mohyeldin, Armed;Okagaki, Peter;Korotchkina, Lioubov G.;Patel, Mulchand S.;Jeoung, Nam Ho;Harris, Robert A.;Schell, Michael J.;Verma, Ajay
通讯作者：
Verma, Ajay
影响因子：
29
作者：
Díaz-García CM;Mongeon R;Lahmann C;Koveal D;Zucker H;Yellen G
通讯作者：
Yellen G
DOI：
10.1016/s0305-0491(98)00025-x
发表时间：
1998-05-01
影响因子：
2.2
作者：
Brooks, GA
通讯作者：
Brooks, GA
影响因子：
3.5
作者：
Anderl, Stefanie;Freeland, Megan;Goto, June
通讯作者：
Goto, June