Respiration-Deficient Astrocytes Survive As Glycolytic CellsIn Vivo.
Neurons and glial cells exchange energy-rich metabolites and it has been suggested, originally based onin vitrodata, that astrocytes provide lactate to glutamatergic synapses ("lactate shuttle"). Here, we have studied astrocytes that lack mitochondrial respirationin vitroandin vivoA novel mouse mutant (GLASTCreERT2::Cox10flox/flox) was generated, in which the administration of tamoxifen causes mutant astrocytes to fail in the assembly of mitochondrial cytochromecoxidase (COX). Focusing on cerebellar Bergmann glia (BG) cells, which exhibit the highest rate of Cre-mediated recombination, we found a normal density of viable astrocytes even 1 year after tamoxifen-inducedCox10gene targeting. Our data show that BG cells, and presumably all astrocytes, can survive by aerobic glycolysis for an extended period of time in the absence of glial pathology or unspecific signs of neurodegeneration.SIGNIFICANCE STATEMENTWhen astrocytes are placed into culture, they import glucose and release lactate, an energy-rich metabolite readily metabolized by neurons. This observation led to the "glia-to-neuron lactate shuttle hypothesis," butin vivoevidence for this hypothesis is weak. To study astroglial energy metabolism and the directionality of lactate flux, we generated conditionalCox10mouse mutants lacking mitochondrial respiration in astrocytes, which forces these cells to survive by aerobic glycolysis. Here, we report that these mice are fully viable in the absence of any signs of glial or neuronal loss, suggesting that astrocytes are naturally glycolytic cells.
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, D-37075 Göttingen, Germany.
Lotti M
0000-0003-4098-1424
LM
Supplie
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, D-37075 Göttingen, Germany.
Tim
0000-0002-4347-7648
T
Düking
Centre for Neuroregeneration, Chancellor's Building, Edinburgh EH16 4SB, United Kingdom.
Graham
G
Campbell
Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida 33136.
Francisca
0000-0002-1252-0594
F
Diaz
Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida 33136.
Carlos T
0000-0002-8077-7092
CT
Moraes
Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764 Neuherberg, Germany, and.
Magdalena
M
Götz
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, D-37075 Göttingen, Germany.
Bernd
B
Hamprecht
German Primate Research Center, D-37077 Goettingen, Germany.
Susann
0000-0003-2792-7423
S
Boretius
Centre for Neuroregeneration, Chancellor's Building, Edinburgh EH16 4SB, United Kingdom.
Don
0000-0002-6093-4185
D
Mahad
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, D-37075 Göttingen, Germany, nave@em.mpg.de.
Klaus-Armin
0000-0001-8724-9666
KA
Nave
D019883:Alkyl and Aryl Transferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D019069:Cell Respiration; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D019344:Lactic Acid / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D008565:Membrane Proteins; D019344:Lactic Acid; D019883:Alkyl and Aryl Transferases; C512252:COX10 protein, mouse; D005947:Glucose
astrocytes; brain energy metabolism; glycolysis; lactate shuttle; mitochondria