Publication Date:
2012-05-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613737/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613737/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Funfschilling, Ursula -- Supplie, Lotti M -- Mahad, Don -- Boretius, Susann -- Saab, Aiman S -- Edgar, Julia -- Brinkmann, Bastian G -- Kassmann, Celia M -- Tzvetanova, Iva D -- Mobius, Wiebke -- Diaz, Francisca -- Meijer, Dies -- Suter, Ueli -- Hamprecht, Bernd -- Sereda, Michael W -- Moraes, Carlos T -- Frahm, Jens -- Goebbels, Sandra -- Nave, Klaus-Armin -- 078415/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Apr 29;485(7399):517-21. doi: 10.1038/nature11007.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Strasse 3, D-37075 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622581" target="_blank"〉PubMed〈/a〉
Keywords:
Action Potentials
;
Alkyl and Aryl Transferases/deficiency/genetics/metabolism
;
Animals
;
Axons/*physiology
;
Brain/cytology/metabolism
;
Cell Respiration
;
Cell Survival
;
Demyelinating Diseases/enzymology/genetics/metabolism/pathology
;
Electron Transport Complex IV/antagonists & inhibitors/genetics/metabolism
;
*Glycolysis
;
Lactic Acid/metabolism
;
Magnetic Resonance Spectroscopy
;
Membrane Proteins/deficiency/genetics/metabolism
;
Mice
;
Mitochondria/enzymology/genetics/metabolism/pathology
;
Mutant Proteins/genetics/metabolism
;
Myelin Sheath/*metabolism
;
Oligodendroglia/cytology/drug effects/enzymology/*metabolism
;
Protons
;
Schwann Cells/enzymology/metabolism
;
Time Factors
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
