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

Autor:	Muraleedharan R; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Gawali MV; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Tiwari D; Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Sukumaran A; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Oatman N; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Anderson J; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Nardini D; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Bhuiyan MAN; Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Tkáč I; Center for Magnetic Resonance Research, University of Minnesota, 2450 Riverside Ave., Minneapolis, MN 55455, USA., Ward AL; Pathology and Cell and Molecular Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA., Kundu M; Pathology and Cell and Molecular Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA., Waclaw R; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Chow LM; Hematology/Oncology, Dayton Children's Hospital, 1 Childrens Plaza, Dayton, OH 45404, USA., Gross C; Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Rao R; Pediatrics, University of Minnesota, 2450 Riverside Ave., Minneapolis, MN 55455, USA., Schirmeier S; Institute for Neuro-and Behavioral Biology, University of Münster, Badestrasse 9, 48149 Münster, Germany., Dasgupta B; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: biplab.dasgupta@cchmc.org.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Sep 01; Vol. 32 (9), pp. 108092.
DOI:	10.1016/j.celrep.2020.108092
Abstrakt:	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 1 H magnetic resonance spectroscopy, 13 C 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. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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