title: Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity.
abstract: Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.
authors.affiliation: Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Strasse 3, D-37075 Göttingen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Fünfschilling
authors.forename: Lotti M
authors.initials: LM
authors.lastname: Supplie
authors.forename: Don
authors.initials: D
authors.lastname: Mahad
authors.forename: Susann
authors.initials: S
authors.lastname: Boretius
authors.forename: Aiman S
authors.initials: AS
authors.lastname: Saab
authors.forename: Julia
authors.initials: J
authors.lastname: Edgar
authors.forename: Bastian G
authors.initials: BG
authors.lastname: Brinkmann
authors.forename: Celia M
authors.initials: CM
authors.lastname: Kassmann
authors.forename: Iva D
authors.initials: ID
authors.lastname: Tzvetanova
authors.forename: Wiebke
authors.initials: W
authors.lastname: Möbius
authors.forename: Francisca
authors.initials: F
authors.lastname: Diaz
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Bernd
authors.initials: B
authors.lastname: Hamprecht
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
authors.forename: Jens
authors.initials: J
authors.lastname: Frahm
authors.forename: Sandra
authors.initials: S
authors.lastname: Goebbels
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
mesh_terms: D000200:Action Potentials; D019883:Alkyl and Aryl Transferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D019069:Cell Respiration; D002470:Cell Survival; D003711:Demyelinating Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011522:Protons; D012583:Schwann Cells / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors
chemical_list: D008565:Membrane Proteins; D050505:Mutant Proteins; D011522:Protons; D019344:Lactic Acid; D003576:Electron Transport Complex IV; D019883:Alkyl and Aryl Transferases; C512252:COX10 protein, mouse