AMP-activated protein kinase (AMPK) regulates astrocyte oxidative metabolism by balancing TCA cycle dynamics
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AMP-activated protein kinase (AMPK) regulates astrocyte oxidative metabolism by balancing TCA cycle dynamics. / Voss, Caroline M; Andersen, Jens V; Jakobsen, Emil; Siamka, Olga; Karaca, Melis; Maechler, Pierre; Waagepetersen, Helle S.
In: Glia, Vol. 68, No. 9, 2020, p. 1824-1839.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - AMP-activated protein kinase (AMPK) regulates astrocyte oxidative metabolism by balancing TCA cycle dynamics
AU - Voss, Caroline M
AU - Andersen, Jens V
AU - Jakobsen, Emil
AU - Siamka, Olga
AU - Karaca, Melis
AU - Maechler, Pierre
AU - Waagepetersen, Helle S
N1 - © 2020 Wiley Periodicals, Inc.
PY - 2020
Y1 - 2020
N2 - 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 13 C-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.
AB - 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 13 C-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.
U2 - 10.1002/glia.23808
DO - 10.1002/glia.23808
M3 - Journal article
C2 - 32092215
VL - 68
SP - 1824
EP - 1839
JO - GLIA
JF - GLIA
SN - 0894-1491
IS - 9
ER -
ID: 236555362