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Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity
Open accessAbstract
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.
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“However, there is so far no experimental approach to the question of whether oligodendrocytes release lactate or pyruvate (Fünfschilling et al., 2012) for the support of axonal energy metabolism.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Fünfschilling et al., 2012
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“Remyelination is a crucial regenerative process in demyelinating diseases, limiting persisting damage to the CNS. It restores saltatory nerve conduction and ensures trophic support of axons.”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [3]
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In the citing paper
“Oligodendrocytes with impaired oxidative phosphorylation instead boost aerobic glycolysis, as indicated by increased lactate levels [127].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [127]
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“This shift of normal myelin turnover to lipid-based ATP generation allows OLs to share more glucose-derived pyruvate/lactate with the axons to support ATP generation and prevent axon degeneration [278,280].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [280]
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“This led to a working model of glycolytic oligodendrocytes providing direct metabolic support to axons via non-compacted cytoplasmic channels in myelin and monocarboxylate transporters, which preserves functional integrity and axon survival (Amaral et al., 2013;Fünfschilling et al., 2012;Lee et al., 2012).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Fünfschilling et al., 2012
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“This is compatible with the idea that adult oligodendrocytes become predominantly glycolytic with a reduced rate of oxidative phosphorylation (OXPHOS) (Fünfschilling et al., 2012).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Fünfschilling et al., 2012
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“Our data are thus compatible with a revised working model of Fünfschilling et al. (2012), in which lactate is preferentially produced in astrocytes close to their gap junctions with neighboring cells, and in which myelinic channels funnel astroglial lactate and oligodendroglial pyruvate to the periaxonal space of myelinated internodes.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Fünfschilling et al., 2012
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“As oligodendrocytes support axonal energy metabolism and neuronal health4–7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [5]
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“Oligodendrocyte-specific deletion of Cox10, which encodes a crucial component for cyt c oxidase assembly and is necessary for oxidative phosphorylation, failed to cause demyelination or neurodegeneration even at 14-months of age.”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [127]
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In the citing paper
“For example, impaired mitochondrial metabolism alone does not induce oligodendrocyte death in vivo [127].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [127]
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“we found that mature oligodendrocytes survive well in Cox10 (protoheme IX farnesyltransferase)-deficient mice, in which oligodendrocytes lack an assembly factor of stable mitochondrial cytochrome c oxidase (COX, mitochondrial complex IV).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Fünfschilling et al., 2012
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“This opens the possibility that glycolytic oligodendrocytes, which are suggested to support electrically active axons with an excess of glycolysis products (Fünfschilling et al., 2012;Lee et al., 2012;Saab et al., 2016;Trevisiol et al., 2017) do so primarily by self-made pyruvate.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Fünfschilling et al., 2012
In the citing paper
“This confirms that axons readily use lactate for ATP generation”
From Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism (2016) · cites this paper as Fünfschilling et al., 2012
In the citing paper
“Myelin modulates the speed of neural impulse conduction (Smith and Koles, 1970; Waxman, 1980), provides metabolic support to axons (Fünfschilling et al., 2012), and exhibits adaptive plasticity (Gibson et al., 2014);”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Fünfschilling et al., 2012
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Metadata
- Authors
- Fünfschilling, U., Supplie, L. M., Mahad, D., Boretius, S., Saab, A. S., Edgar, J., Brinkmann, B. G., Kassmann, C. M., Tzvetanova, I. D., Möbius, W., Diaz, F., Meijer, D., Suter, U., Hamprecht, B., Sereda, M. W., Moraes, C. T., Frahm, J., Goebbels, S., & Nave, K.-A.
- Affiliations
- Max Planck Institute of Experimental Medicine (DE)
- Max Planck Society (DE)
- Newcastle University (GB)
- Erasmus MC (NL)
- ETH Zurich (CH)
- University of Miami (US)
- Corresponding author
- Nave, Klaus-Armin
- ORCID
- Venue
- Nature
- Published
- 2012-04-29
- Volume
- 485
- Issue
- 7399
- Pages
- 517-521
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3613737
- OpenAlex
- W2085029391
- Cited by
- 1,523
- References
- 33
- Citations by year
- 2026: 121 · 2025: 120 · 2024: 127 · 2023: 107 · 2022: 125 · 2021: 142 · 2020: 121 · 2019: 107 · 2018: 91 · 2017: 128 · 2016: 95 · 2015: 93 · 2014: 64 · 2013: 65 · 2012: 13
- FWCI
- 25.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- GRO (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust (078415)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- oligodendrocytes, myelination, aerobic glycolysis, lactate, mitochondrial cytochrome c oxidase, COX10, axonal integrity, demyelination, Schwann cells, white matter, brain lactate, mitochondrial respiration
- MeSH terms
- Action Potentials, Animals, Axons, Brain, Cell Survival, Electron Transport Complex IV, Demyelinating Diseases, Glycolysis, Membrane Proteins, Mitochondria, Myelin Sheath, Magnetic Resonance Spectroscopy, Oligodendroglia, Protons, Schwann Cells, Time Factors, Cell Respiration, Lactic Acid, Alkyl and Aryl Transferases, Mutant Proteins, Mice
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