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Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity

Nature volume 485, pages 517–521 (2012)Cite this article

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Abstract

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity1,2,3. However, the underlying support mechanisms are not understood4. 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 inhibitors5, 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-deprived6, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function.

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Figure 1: Genetic targeting of the mitochondrial COX complex in myelinating glial cells.
Figure 2: Peripheral neuropathy caused by Cox10 mutant Schwann cells.
Figure 3: Oligodendroglial survival, myelin preservation and white matter integrity in Cnp1 Cre/+ *Cox10 flox/flox mice.
Figure 4: Rapid use of lactate shown by proton MRS.

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Acknowledgements

We thank C. Stiles for the OLIG2 antibodies, A. Fahrenholz, U. Bode, T. Ruhwedel, and R. Tammer for technical support, and members of the Nave laboratory for discussions. We acknowledge grant support from the BMBF (Leukonet), DFG (CMPB), EU-FP7 programs (NGIDD, Leukotreat) and Oliver’s Army. U.S. is supported by the Swiss National Science Foundation and the National Center ‘Neural Plasticity and Repair’. U.F. was supported by fellowships from the EU-FP7 (Marie-Curie), the Swiss National Science Foundation (PAOOA-117479/1) and the European Leukodystrophy Association. K.-A.N. holds an ERC Advanced Grant.

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Author notes

  1. Don Mahad, Aiman S. Saab, Bastian G. Brinkmann & Wiebke Möbius

    Present address: Present addresses: Center for Neuroregeneration, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK (D.M.); Department of Molecular Physiology, Institute of Physiology, University of Saarland, D-66421 Homburg, Germany (A.S.S.); Department of Neurosurgery, Charité-University Medicine Berlin, Charitéplatz 1, D-10117 Berlin, Germany (B.G.B.); Department of Diagnostic Radiology, Am Botanischen Garten 14, University of Kiel, D-24118 Kiel, Germany.,

  2. Ursula Fünfschilling, Lotti M. Supplie, Don Mahad and Susann Boretius: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, D-37075 Göttingen, Germany,

    Ursula Fünfschilling, Lotti M. Supplie, Aiman S. Saab, Julia Edgar, Bastian G. Brinkmann, Celia M. Kassmann, Iva D. Tzvetanova, Wiebke Möbius, Bernd Hamprecht, Michael W. Sereda, Sandra Goebbels & Klaus-Armin Nave

  2. Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK ,

    Don Mahad

  3. Biomedizinische NMR Forschungs GmbH am Max Planck Institute of Biophysical Chemistry, D-37070 Göttingen, Germany ,

    Susann Boretius & Jens Frahm

  4. Department of Neurology and Cell Biology & Anatomy, University of Miami, Miller School of Medicine, 1095 NW 14th Terrace, Miami, Florida 33136, USA,

    Francisca Diaz & Carlos T. Moraes

  5. Department of Cell Biology, Erasmus MC, 3000 CA Rotterdam, Netherlands,

    Dies Meijer

  6. Department of Biology, Institute of Cell Biology, ETH Hönggerberg, Schafmattstrasse 18, 8093 Zürich, Switzerland,

    Ueli Suter

  7. Department of Clinical Neurophysiology, University of Göttingen (UMG), Robert-Koch-Strasse 40, D-37075 Göttingen, Germany,

    Michael W. Sereda

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Contributions

U.F., L.M.S., C.M.K. and I.D.T. performed mouse breeding experiments, histology and light microscopy; D.Ma. carried out immunohistochemistry; S.B .performed magnetic resonance imaging and spectroscopy; A.S.S. and J.E. carried out ex vivo experiments; B.G.B. and M.W.S. performed electrophysiology; W.M. performed electron microscopy; F.D. and C.T.M. provided floxed mice; D.Mi. and U.S. provided Cre-transgenic lines. B.H., J.F. and S.G. supervised parts of the work or contributed essential ideas. K.-A.N. designed experiments, analysed data and wrote the manuscript.

Corresponding author

Correspondence to Klaus-Armin Nave.

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Fünfschilling, U., Supplie, L., Mahad, D. et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517–521 (2012). https://doi.org/10.1038/nature11007

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