AMP-activated protein kinase (AMPK) regulates astrocyte oxidative metabolism by balancing TCA cycle dynamics.,Glia

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AMP-activated protein kinase (AMPK) regulates astrocyte oxidative metabolism by balancing TCA cycle dynamics.
Glia ( IF 5.4 ) Pub Date : 2020-02-24 , DOI: 10.1002/glia.23808
Caroline M Voss ₁ , Jens V Andersen ₁ , Emil Jakobsen ₁ , Olga Siamka ₁ , Melis Karaca ₂ , Pierre Maechler ₂ , Helle S Waagepetersen ₁

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AMP‐activated protein kinase (AMPK) is an important energy sensor located in cells throughout the human body. From the periphery, AMPK is known to be a metabolic master switch controlling the use of energy fuels. The energy sensor is activated when the energy status of the cell is low, initiating energy‐producing pathways and deactivating energy‐consuming pathways. All brain cells are crucially dependent on energy production for survival, and the availability of energy substrates must be closely regulated. Intriguingly, the role of AMPK in the regulation of brain cell metabolism has been sparsely investigated, particularly in astrocytes. By investigating metabolism of ¹³C‐labeled energy substrates in acutely isolated hippocampal slices and cultured astrocytes, with subsequent mass spectrometry analysis, we here show that activation of AMPK increases glycolysis as well as the capacity of the TCA cycle, that is, anaplerosis, through the activity of pyruvate carboxylase (PC) in astrocytes. In addition, we demonstrate that AMPK activation leads to augmented astrocytic glutamate oxidation via pyruvate recycling (i.e., cataplerosis). This regulatory mechanism induced by AMPK activation is mediated via glutamate dehydrogenase (GDH) shown in a CNS‐specific GDH knockout mouse. Collectively, these findings demonstrate that AMPK regulates TCA cycle dynamics in astrocytes via PC and GDH activity. AMPK functionality has been shown to be hampered in Alzheimer's and Parkinson's disease and our findings may therefore add to the toolbox for discovery of new metabolic drug targets.

中文翻译：

AMP 活化蛋白激酶 (AMPK) 通过平衡 TCA 循环动力学来调节星形胶质细胞的氧化代谢。

AMP 活化蛋白激酶 (AMPK) 是一种重要的能量传感器，位于整个人体的细胞中。从外围来看，AMPK 是控制能量燃料使用的代谢主开关。当细胞的能量状态低时，能量传感器被激活，启动能量产生途径并停用能量消耗途径。所有脑细胞都至关重要地依赖于能量产生以维持生存，并且必须密切调节能量底物的可用性。有趣的是，对 AMPK 在调节脑细胞代谢中的作用的研究很少，特别是在星形胶质细胞中。通过研究¹³急性分离的海马切片和培养的星形胶质细胞中的 C 标记能量底物，随后进行质谱分析，我们在这里表明，AMPK 的激活通过丙酮酸羧化酶的活性增加糖酵解以及 TCA 循环的能力，即回补(PC) 在星形胶质细胞中。此外，我们证明 AMPK 激活导致通过丙酮酸再循环（即cataplerosis）增强星形胶质细胞谷氨酸氧化。这种由 AMPK 激活诱导的调节机制是通过 CNS 特异性 GDH 敲除小鼠中显示的谷氨酸脱氢酶 (GDH) 介导的。总的来说，这些发现表明 AMPK 通过 PC 和 GDH 活性调节星形胶质细胞中的 TCA 循环动态。AMPK 功能已被证明在阿尔茨海默氏症和帕金森氏症中受到阻碍

更新日期：2020-02-24

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