Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Griffiths, I. et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998)

    Article  ADS  CAS  Google Scholar 

  2. Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nature Genet. 33, 366–374 (2003)

    Article  CAS  Google Scholar 

  3. Kassmann, C. M. et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nature Genet. 39, 969–976 (2007)

    Article  CAS  Google Scholar 

  4. Nave, K. A. Myelination and the trophic support of long axons. Nature Rev. Neurosci. 11, 275–283 (2010)

    Article  CAS  Google Scholar 

  5. Ziabreva, I. et al. Injury and differentiation following inhibition of mitochondrial respiratory chain complex IV in rat oligodendrocytes. Glia 58, 1827–1837 (2010)

    Article  Google Scholar 

  6. Tekkök, S. B., Brown, A. M., Westenbroek, R., Pellerin, L. & Ransom, B. R. Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity. J. Neurosci. Res. 81, 644–652 (2005)

    Article  Google Scholar 

  7. Diaz, F., Thomas, C. K., Garcia, S., Hernandez, D. & Moraes, C. T. Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency. Hum. Mol. Genet. 14, 2737–2748 (2005)

    Article  CAS  Google Scholar 

  8. Antonicka, H. et al. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum. Mol. Genet. 12, 2693–2702 (2003)

    Article  CAS  Google Scholar 

  9. Diaz, F. et al. Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies. Gut 57, 232–242 (2008)

    Article  CAS  Google Scholar 

  10. Fukui, H., Diaz, F., Garcia, S. & Moraes, C. T. Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 104, 14163–14168 (2007)

    Article  ADS  CAS  Google Scholar 

  11. Goebbels, S. et al. Elevated phosphatidylinositol 3,4,5-trisphosphate in glia triggers cell-autonomous membrane wrapping and myelination. J. Neurosci. 30, 8953–8964 (2010)

    Article  CAS  Google Scholar 

  12. Genoud, S. et al. Notch1 control of oligodendrocyte differentiation in the spinal cord. J. Cell Biol. 158, 709–718 (2002)

    Article  CAS  Google Scholar 

  13. Miller, R. H., David, S., Patel, R., Abney, E. R. & Raff, M. C. A quantitative immunohistochemical study of macroglial cell development in the rat optic nerve: in vivo evidence for two distinct astrocyte lineages. Dev. Biol. 111, 35–41 (1985)

    Article  CAS  Google Scholar 

  14. Beattie, D. S., Basford, R. E. & Koritz, S. B. The turnover of the protein components of mitochondria from rat liver, kidney, and brain. J. Biol. Chem. 242, 4584–4586 (1967)

    CAS  PubMed  Google Scholar 

  15. Menzies, R. A. & Gold, P. H. The turnover of mitochondria in a variety of tissues of young adult and aged rats. J. Biol. Chem. 246, 2425–2429 (1971)

    CAS  PubMed  Google Scholar 

  16. Viader, A. et al. Schwann cell mitochondrial metabolism supports long-term axonal survival and peripheral nerve function. J. Neurosci. 31, 10128–10140 (2011)

    Article  CAS  Google Scholar 

  17. Garlid, K. D. & Paucek, P. Mitochondrial potassium transport: the K+ cycle. Biochim. Biophys. Acta 1606, 23–41 (2003)

    Article  CAS  Google Scholar 

  18. Dubois-Dalcq, M., Ffrench-Constant, C. & Franklin, R. J. Enhancing central nervous system remyelination in multiple sclerosis. Neuron 48, 9–12 (2005)

    Article  CAS  Google Scholar 

  19. Diaz, F., Fukui, H., Garcia, S. & Moraes, C. T. Cytochrome c oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts. Mol. Cell. Biol. 26, 4872–4881 (2006)

    Article  CAS  Google Scholar 

  20. Moreland, C., Henjum, S., Iversen, E. G., Skredde, K. K. & Hassel, B. Evidence for a higher glycolytic than oxidative metabolic activity in white matter of rat brain. Neurochem. Int. 50, 703–709 (1990)

    Article  Google Scholar 

  21. Brown, A. M., Wender, R. & Ransom, B. R. Metabolic substrates other than glucose support axon function in central white matter. J. Neurosci. Res. 66, 839–843 (2001)

    Article  CAS  Google Scholar 

  22. Gandhi, G. K., Cruz, N. F., Ball, K. K. & Dienel, G. A. Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J. Neurochem. 111, 522–536 (2009)

    Article  CAS  Google Scholar 

  23. Vannucci, S. J. & Simpson, I. A. Developmental switch in brain nutrient transporter expression in the rat. Am. J. Physiol. Endocrinol. Metab. 285, E1127–E1134 (2003)

    Article  CAS  Google Scholar 

  24. Rinholm, J. E. et al. Regulation of oligodendrocyte development and myelination by glucose and lactate. J. Neurosci. 31, 538–548 (2011)

    Article  CAS  Google Scholar 

  25. Leveille, P. J., McGinnis, J. F., Maxwell, D. S. & de Vellis, J. Immunocytochemical localization of glycerol-3-phosphate dehydrogenase in rat oligodendrocytes. Brain Res. 196, 287–305 (1980)

    Article  CAS  Google Scholar 

  26. Jalil, M. A. et al. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. J. Biol. Chem. 280, 31333–31339 (2005)

    Article  CAS  Google Scholar 

  27. Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 91, 10625–10629 (1994)

    Article  ADS  CAS  Google Scholar 

  28. Suzuki, A. et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011)

    Article  CAS  Google Scholar 

  29. Jaegle, M. et al. The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development. Genes Dev. 17, 1380–1391 (2003)

    Article  CAS  Google Scholar 

  30. Leone, D. P. et al. Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells. Mol. Cell. Neurosci. 22, 430–440 (2003)

    Article  CAS  Google Scholar 

  31. Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999)

    Article  CAS  Google Scholar 

  32. Michaelis, T., Boretius, S. & Frahm, J. Localized proton MRS of animal brain in vivo: Models of human disorders. Prog. Nucl. Magn. Reson. Spectrosc. 55, 1–34 (2009)

    Article  CAS  Google Scholar 

  33. Provencher, S. W. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn. Reson. Med. 30, 672–679 (1993)

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12. (PDF 2073 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11007

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing