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Oligodendroglia metabolically support axons and contribute to neurodegeneration
Open accessAbstract
Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.
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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 [4]
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“It is finally in agreement with axonal degeneration observed in mice lacking the monocarboxylate transporter MCT1 in oligodendrocytes lineage cells (Lee et al., 2012;Philips et al., 2021).”
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 Lee et al., 2012
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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 Lee 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 [6]
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“Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters.”
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 Lee 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 Lee et al., 2012
In the citing paper
“an essential lactate transporter in the CNS whose expression is regulated by autophagy [458].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [458]
In the citing paper
“and lower levels of SLC16A1/MCT1 (solute carrier family 16 member 1), an essential lactate transporter in the CNS whose expression is regulated by autophagy [458].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [458]
In the citing paper
“blocking neuronal oxidative utilization of lactate affects neuronal survival and even memory formation (Suzuki et al., 2011; Lee et al., 2012).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Lee et al., 2012
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“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 Lee et al., 2012
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Manukjan, N., Ahmed, Z., Fulton, D. J., Blankesteijn, W. M., & Foulquier, S. (2020) · Cells · doi:10.3390/cells9061545 · Cited by 35
Where and Why Modeling Amyotrophic Lateral Sclerosis
Liguori, F., Amadio, S., & Volonté, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083977 · Cited by 36
“Of note, these pathological features confirm those previously described in ALS rodent models and in patients [206,246,247].”
Know How to Regrow—Axon Regeneration in the Zebrafish Spinal Cord
Tsata, V., & Wehner, D. (2021) · Cells · doi:10.3390/cells10061404 · Cited by 37
The Glial Cells Respond to Spinal Cord Injury
Wang, R., Zhou, R., Chen, Z., Gao, S., & Zhou, F. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.844497 · Cited by 35
“OLs can express a large number of MCT1, which can mediate metabolic support to neurons by co-transporting lactate and pyruvate (66).”
BackgroundFunctional Expression of Drug Transporters in Glial Cells
Ashraf, T., Kao, A. C.-C., & Bendayan, R. (2014) · Advances in pharmacology · doi:10.1016/bs.apha.2014.06.010 · Cited by 38
Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia
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Li, T., Giaume, C., & Xiao, L. (2014) · Molecular Neurobiology · doi:10.1007/s12035-013-8625-1 · Cited by 38
The environment rules: spatiotemporal regulation of oligodendrocyte differentiation
Mayoral, S. R., & Chan, J. R. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2016.04.002 · Cited by 36
The intellectual disability protein PAK3 regulates oligodendrocyte precursor cell differentiation
Renkilaraj, M. R. L. M., Baudouin, L., Wells, C. M., Doulazmi, M., Wehrlé, R., Cannaya, V., Bachelin, C., Barnier, J., Jia, Z., Nait‐Oumesmar, B., et al. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.12.004 · Cited by 33
Approaches to Remyelination Therapies in Multiple Sclerosis
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Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?
Zhang, X., Huang, N., Xiao, L., Wang, F., & Li, T. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.760200 · Cited by 32
Age and Alzheimer’s Disease-Related Oligodendrocyte Changes in Hippocampal Subregions
DeFlitch, L., González‐Fernández, E., Crawley, I., & Kang, S. H. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.847097 · Cited by 34
Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives
Chang, C., Wu, C.-W., & Chern, Y. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106672 · Cited by 37
“6) (Lee et al., 2012).”
Neural Metabolic Networks: Key Elements of Healthy Brain Function
Madrer, N., Perera, N. D., Uccelli, N. A., Abbondanza, A., Andersen, J. V., Carsana, E. V., Demmings, M. D., Fernandez, R. F., de Fragas, M. G., Gbadamosi, I., et al. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70084 · Cited by 37
“Of note, metabolic support of axons via release of lactate by oligodendrocytes has also been proposed (Nave et al. 2023; Lee, Morrison, et al. 2012).”
Baldassarro, V. A., Marchesini, A., Giardino, L., & Calzà, L. (2019) · Glia · doi:10.1002/glia.23750 · Cited by 34
“…or repair the myelin sheaths is severely impaired during pathological conditions characterized by HI and severe inflammation both in development and F IGURE 7 Legend on next page. adulthood, OPCs and OLs being the most vulnerable cells in the CNS (Bradl & Lassmann, 2010; Y. Lee et al., 2012).”
BackgroundTrevisiol, A., Kusch, K., Steyer, A. M., Gregor, I., Nardis, C., Winkler, U., Köhler, S., Restrepo, A., Möbius, W., Werner, H. B., et al. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000943 · Cited by 35
“Considering that oligodendrocytes have been suggested to contribute to axonal energy metabolism by providing lactate to the axon [4,5], we hypothesized that axonal degeneration in Plp mice is associated with an early subclinical perturbation of axonal energy metabolism.”
BackgroundDefective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis
Traiffort, É., Morisset‐Lopez, S., Moussaed, M., & Zahaf, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073426 · Cited by 36
“MCT1 decrease was also observed in rodent and canine models of the disease [67,86].”
BackgroundResultInfluentialNutraceutical and therapeutic potential of Phycocyanobilin for treating Alzheimer’s disease
Piniella‐Matamoros, B., Marín‐Prida, J., & Pentón‐Rol, G. (2021) · Journal of Biosciences · doi:10.1007/s12038-021-00161-7 · Cited by 34
Oligodendrocytes and myelin: Active players in neurodegenerative brains?
Chen, J., Wang, F., Huang, N., Xiao, L., & Mei, F. (2022) · Developmental Neurobiology · doi:10.1002/dneu.22867 · Cited by 37
Oligodendrocytes in neurodegenerative diseases
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Self-citationLC3, an autophagosome marker, is expressed on oligodendrocytes in Nasu-Hakola disease brains
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“Yet, evidence that remyelination protects axons in humans is still needed in spite of good experimental evidence.(10-12)”
BackgroundRegulation of the E/I-balance by the neural matrisome
Mueller-Buehl, C., Wegrzyn, D., Bauch, J., & Faissner, A. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1102334 · Cited by 35
“Acute lesions in the CNS are generally characterized by the demyelination of axons, inflammation and gliosis, which in the end leads to axonal degeneration and death (Franklin and Ffrench-Constant, 2008; Hagemeier et al., 2012; Lee et al., 2012; Motavaf et al., 2017).”
BackgroundLi, Z., Qi, Y., Sun, L., Li, Z., Chen, S., Zhang, Y., Ma, Y., Han, J., Wang, Z., Zhang, Y., et al. (2023) · Theranostics · doi:10.7150/thno.87288 · Cited by 33
“Luxol fast blue (LFB) and hematoxylin and eosin (H&E) staining showed that the 3D NS + NSC group exhibited the highest myelin regeneration capacity and tissue preservation (Figure 6C, 6H, and Figure S14B), which can aid in the support of metabolism and integrity in axons [33].”
BackgroundThe Role of Glial Cells in the Pathophysiology of Epilepsy
Onat, F., Andersson, M., & Çarçak, N. (2025) · Cells · doi:10.3390/cells14020094 · Cited by 35
“This is crucial for sustaining repetitive action potential firing [166] and preserving axonal health [167].”
Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b
Marshall-Phelps, K. L., Kegel, L., Baraban, M., Ruhwedel, T., Almeida, R., Rubio-Brotons, M., Klingseisen, A., Benito-Kwiecinski, S. K., Early, J. J., Bin, J. M., et al. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.201909022 · Cited by 33
“, 2018), neuronal health (Schirmer et al., 2018; Saab et al., 2016; Lee et al., 2012; Jha et al., 2020), and potentially also neurodevelopmental, neuropsychiatric, and neurodegenerative disorders (Micu et al.”
BackgroundChao, F., Zhang, Y., Zhang, L., Jiang, L. H., Zhou, C., Tang, J., Liang, X., Fan, J., Dou, X., & Tang, Y. C. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.627362 · Cited by 34
“Oligodendrocyte injury and demyelination disrupt brain function (Lee et al., 2012).”
BackgroundInfluentialEide, P. K., & Hansson, H. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.900057 · Cited by 34
“Impairment of the glial cells that support the function of the optic nerve axons leads to axonal and eventually nerve cell body degeneration (Lee et al., 2012).”
BackgroundSignaling mechanisms regulating myelination in the central nervous system
Ahrendsen, J. T., & Macklin, W. B. (2013) · Neuroscience Bulletin · doi:10.1007/s12264-013-1322-2 · Cited by 38
Verden, D. R., & Macklin, W. B. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23923 · Cited by 33
Stroke in CNS white matter: Models and mechanisms
Marin, M. A., & Carmichael, S. T. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.07.039 · Cited by 34
X‐linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron
Hodgkinson, V. L., Dale, J. M., Garcia, M. L., Weisman, G. A., Lee, J., Gitlin, J. D., & Petris, M. J. (2015) · The Journal of Pathology · doi:10.1002/path.4511 · Cited by 32
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Macroglial diversity: white and grey areas and relevance to remyelination
Werkman, I. L., Lentferink, D. H., & Baron, W. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03586-9 · Cited by 33
Brain energy metabolism and multiple sclerosis: progress and prospects
Park, S. J., & Choi, J. W. (2020) · Archives of Pharmacal Research · doi:10.1007/s12272-020-01278-3 · Cited by 32
“Monocarboxylate transporter 1 (MCT1) was identified as the specific lactate transporter in oligodendrocytes, and its expression is highly affected by the state and development of CNS diseases including MS, ischemia, and ALS (Lee et al.”
BackgroundInfluentialGluA2 overexpression in oligodendrocyte progenitors promotes postinjury oligodendrocyte regeneration
Khawaja, R. R., Agarwal, A., Fukaya, M., Jeong, H., Gross, S., González‐Fernández, E., Soboloff, J., Bergles, D. E., & Kang, S. H. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109147 · Cited by 31
“suggests that they also provide metabolic support to axons (Fünfschilling et al., 2012; Lee et al., 2012) and control extracellular potassium ion homeostasis (Larson et al.”
BackgroundKöhler, S., Winkler, U., Junge, T., Lippmann, K., Eilers, J., & Hirrlinger, J. (2022) · Glia · doi:10.1002/glia.24268 · Cited by 33
“Furthermore, in WM also oligodendrocytes contribute to metabolic support and ion homeostasis (Fünfschilling et al., 2012; Hirrlinger & Nave, 2014; Lee et al., 2012; Nave, 2010a, 2010b; Rash, 2010) and glutamate released from axons regulates metabolic support from oligodendrocytes to axons via…”
Background
Metadata
- Authors
- Lee, Y., Morrison, B. M., Li, Y., Lengacher, S., Farah, M. H., Hoffman, P. N., Liu, Y., Tsingalia, A., Jin, L., Zhang, P.-W., Pellerin, L., Magistretti, P. J., & Rothstein, J. D.
- Affiliations
- Johns Hopkins University (US)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
- Corresponding author
- Rothstein, Jeffrey D.
- ORCID
- Venue
- Nature
- Published
- 2012-07
- Volume
- 487
- Issue
- 7408
- Pages
- 443-448
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3408792
- OpenAlex
- W2038811384
- Cited by
- 1,664
- References
- 49
- Citations by year
- 2026: 110 · 2025: 107 · 2024: 130 · 2023: 118 · 2022: 133 · 2021: 150 · 2020: 141 · 2019: 107 · 2018: 110 · 2017: 133 · 2016: 107 · 2015: 106 · 2014: 98 · 2013: 97 · 2012: 13
- FWCI
- 72.44
- 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)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation
- Muscular Dystrophy Association
- Johns Hopkins University
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A, 108336, 125063)
- Fonds De La Recherche Scientifique - FNRS
- National Institutes of Health
- National Institute on Aging (P50AG005146, P50AG05146)
- National Institute of Neurological Disorders and Stroke (P01NS016375, NS 33958, P01 NS16375, R01NS033958)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- oligodendroglia, MCT1, lactate transport, axonal degeneration, neurodegeneration, amyotrophic lateral sclerosis, oligodendrocytes, neuronal loss, lactate export
- MeSH terms
- Superoxide Dismutase-1, Monocarboxylate Transport Protein 1, Amyotrophic Lateral Sclerosis, Animals, Axons, Cell Line, Cell Survival, Disease Models, Animal, Heterozygote, Humans, Mice, Transgenic, Motor Neurons, Myelin Sheath, Nerve Degeneration, Oligodendroglia, Superoxide Dismutase, Down-Regulation, Lactic Acid, Protein Transport, Monocarboxylic Acid Transporters, Symporters, RNA, Small Interfering, Mice
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