AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival

Ranjithmenon Muraleedharan; Mruniya V. Gawali; Durgesh Tiwari; Abitha Sukumaran; Nicole Oatman; Jane Anderson; Diana Nardini; Mohammad Alfrad Nobel Bhuiyan; Ivan Tkáč; Amber Lynne Ward; Mondira Kundu; Ronald Waclaw; Lionel M. Chow; Christina Gross; Raghavendra Rao; Stefanie Schirmeier; Biplab Dasgupta

doi:10.1016/j.celrep.2020.108092

AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival

Ranjithmenon Muraleedharan, Mruniya V. Gawali, Durgesh Tiwari, Abitha Sukumaran, Nicole Oatman, Jane Anderson, Diana Nardini, Mohammad Alfrad Nobel Bhuiyan, Ivan Tkáč, Amber Lynne Ward, Mondira Kundu, Ronald Waclaw, Lionel M. Chow, Christina Gross, Raghavendra Rao, Stefanie Schirmeier, Biplab Dasgupta

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Abstract

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.

Original language	English (US)
Article number	108092
Journal	Cell reports
Volume	32
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2020.108092
State	Published - Sep 1 2020

Bibliographical note

Funding Information:
We would like to thank Shabnam Pooya and Janvi Gandhi for assisting with western blots, Oluwadamilola Omojola for performing genotyping PCR, and Ashwini Hinge for assistance with fluorescence-activated cell sorting (FACS) analysis. We thank Matthew Kofron of CCHMC Microscopy Core for assistance with imaging. This work was supported by National Institutes of Health (NIH) grants R01 NS075291 and R01 NS099162 (to B.D.), R01 MH115058 (to M.K.), and R01 NS092705 (to C.G.). The Center for Magnetic Resonance Research at the University of Minnesota is supported by NIH grants P41 EB015894 and P30 NS076408 .

Publisher Copyright:
© 2020 The Author(s)

Keywords

AMP kinase
GLUT1
TXNIP
astrocyte-neuron lactate shuttle
brain metabolism
glucose flux
glycolysis
proton spectroscopy

Center for Magnetic Resonance Research (CMRR) tags

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10.1016/j.celrep.2020.108092

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Muraleedharan, R., Gawali, M. V., Tiwari, D., Sukumaran, A., Oatman, N., Anderson, J., Nardini, D., Bhuiyan, M. A. N., Tkáč, I., Ward, A. L., Kundu, M., Waclaw, R., Chow, L. M., Gross, C., Rao, R., Schirmeier, S., & Dasgupta, B. (2020). AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival. Cell reports, 32(9), Article 108092. https://doi.org/10.1016/j.celrep.2020.108092

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 2020, 'AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival', Cell reports, vol. 32, no. 9, 108092. https://doi.org/10.1016/j.celrep.2020.108092

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abstract = "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.",

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AU - Muraleedharan, Ranjithmenon

AU - Gawali, Mruniya V.

AU - Tiwari, Durgesh

AU - Sukumaran, Abitha

AU - Oatman, Nicole

AU - Anderson, Jane

AU - Nardini, Diana

AU - Bhuiyan, Mohammad Alfrad Nobel

AU - Tkáč, Ivan

AU - Ward, Amber Lynne

AU - Kundu, Mondira

AU - Waclaw, Ronald

AU - Chow, Lionel M.

AU - Gross, Christina

AU - Rao, Raghavendra

AU - Schirmeier, Stefanie

AU - Dasgupta, Biplab

N1 - Funding Information: We would like to thank Shabnam Pooya and Janvi Gandhi for assisting with western blots, Oluwadamilola Omojola for performing genotyping PCR, and Ashwini Hinge for assistance with fluorescence-activated cell sorting (FACS) analysis. We thank Matthew Kofron of CCHMC Microscopy Core for assistance with imaging. This work was supported by National Institutes of Health (NIH) grants R01 NS075291 and R01 NS099162 (to B.D.), R01 MH115058 (to M.K.), and R01 NS092705 (to C.G.). The Center for Magnetic Resonance Research at the University of Minnesota is supported by NIH grants P41 EB015894 and P30 NS076408 . Publisher Copyright: © 2020 The Author(s)

PY - 2020/9/1

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N2 - 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.

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AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival

Abstract

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Keywords

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