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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]
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.
In the citing paper
“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
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 Lee et al., 2012
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“Recent evidence has demonstrated that MGCs are actively providing metabolic supports to meet the energy needs of axons (Funfschilling et al., 2012; Lee et al., 2012; Morrison et al., 2013; Simons & Nave, 2015).”
BackgroundInfluentialErythropoietin: A potential drug in the management of diabetic neuropathy
Suárez-Méndez, S., Tovilla‐Zárate, C. A., Juárez‐Rojop, I. E., & Bermudez‐Ocaña, D. Y. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.06.068 · Cited by 16
ALS, a cellular whodunit on motor neuron degeneration
Karagiannis, P., & Inoue, H. (2020) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2020.103524 · Cited by 16
Bayne, M. A., Alvarsson, A., Devarakonda, K., Li, R., Jiménez-González, M., Garibay, D., Conner, K., Varghese, M., Serasinghe, M. N., Chipuk, J. E., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.133488 · Cited by 16
Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination
Pruvost, M., & Moyon, S. (2021) · Life · doi:10.3390/life11010062 · Cited by 18
“…a reciprocal relationship between neurons and OLs, with OLs providing metabolic support to axons, which is crucial to their survival [3,188,189], and neurons being able to regulate OPC proliferation and differentiation [14,22,23,128,131,190–192], as well as myelin formation, repair, and…”
BackgroundThe role of aquaporin-4 in optic nerve head astrocytes in experimental glaucoma
Kimball, E. C., Schaub, J. A., Quillen, S. E., Keuthan, C. J., Pease, M. E., Korneva, A., & Quigley, H. A. (2021) · PLoS ONE · doi:10.1371/journal.pone.0244123 · Cited by 15
Clinical Applications of Myelin Plasticity for Remyelinating Therapies in Multiple Sclerosis
Pan, S., & Chan, J. R. (2021) · Annals of Neurology · doi:10.1002/ana.26196 · Cited by 17
“As there is a growing body of evidence that OLs provide metabolic support to the underlying axon via transfer of short carbon chain metabolites such as pyruvate and lactate through monocarboxylate transporters, myelination may also help to maintain neuronal energy homeostasis and prevent degeneration in the setting of…”
BackgroundAquaporin 4 is not present in normal porcine and human lamina cribrosa
Kimball, E. C., Quillen, S. E., Pease, M. E., Keuthan, C. J., Nagalingam, A., Zack, D. J., Johnson, T. V., & Quigley, H. A. (2022) · PLoS ONE · doi:10.1371/journal.pone.0268541 · Cited by 16
“Both nutrient delivery and extracellular fluid content and flow are managed by brain astrocytes using transmembrane channels, including monocarboxylate transporters [8], glucose transporters [9], and aquaporin (AQP) channels [10].”
BackgroundLoPresti, P. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1707-x · Cited by 16
Normal lactate concentration range in the neonatal brain
Tomiyasu, M., Aida, N., Shibasaki, J., Tachibana, Y., Endo, M., Nozawa, K., Shimizu, E., Tsuji, H., & Obata, T. (2016) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2016.07.006 · Cited by 16
Ideno, M., Kobayashi, M., Sasaki, S., Futagi, Y., Narumi, K., Furugen, A., & Iseki, K. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.10.022 · Cited by 17
Joseph, S., Vingill, S., Jahn, O., Fledrich, R., Werner, H. B., Katona, I., Möbius, W., Mitkovski, M., Huang, Y., Weis, J., et al. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.3094-18.2019 · Cited by 15
“Lee et al. (2012) showed evidence that the monocarboxylate transporter MCT1, which is predominantly expressed by oligodendrocytes and responsible for lactate transport, may provide the metabolic connection as Mct1 / mice display axonopathy without loss of myelin.”
BackgroundProgressive axonopathy when oligodendrocytes lack the myelin protein CMTM5
Buscham, T. J., Eichel-Vogel, M. A., Steyer, A. M., Jahn, O., Strenzke, N., Dardawal, R., Memhave, T. R., Siems, S. B., Müller, C., Meschkat, M., et al. (2022) · eLife · doi:10.7554/elife.75523 · Cited by 18
“Oligodendroglial support of axons involves several mechanisms, including supplying energy- rich substrates via monocarboxylate transporters (Fünfschilling et al., 2012; Lee et al., 2012; Philips et al., 2021; Trevisiol et al., 2020), allocating antioxidative proteins and other enzymes via extracellular vesicles (Chamb…”
BackgroundCircadian neurogenetics and its implications in neurophysiology, behavior, and chronomedicine
Naveed, M., Chao, O. Y.-H., Hill, J. W., Yang, Y., Huston, J. P., & Cao, R. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105523 · Cited by 16
Shim, G., Romero-Morales, A. I., Sripathy, S. R., & Maher, B. J. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1322813 · Cited by 16
He, Z., Chen, Q., Wang, K., Lin, J., Peng, Y., Zhang, J., Yan, X., & Yan, J. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16242 · Cited by 18
“Similarly, myelin dysfunction and UPR are also observed in neurodegenerative diseases (Lee et al., 2012; Zhu et al., 2021), prompting scientists to discover strategies targeting myelination and restoring normal protein synthesis (Chen et al., 2021; Smith & Mallucci, 2016).”
BackgroundWang, H. V., Xiang, J., Yuan, C., Veire, A. M., Gendron, T. F., Murray, M. E., Tansey, M. G., Hu, J., Gearing, M., Glass, J. D., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2419818122 · Cited by 15
Modeling the C9ORF72 repeat expansion mutation using human induced pluripotent stem cells
Selvaraj, B. T., Livesey, M. R., & Chandran, S. (2017) · Brain Pathology · doi:10.1111/bpa.12520 · Cited by 14
Lee, S. W., Park, J. B., Kim, H. J., Kim, H. Y., Lee, S. Y., Chung, W. T., Shin, Y. K., Park, H. T., Rho, J. H., & Yoo, Y. H. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.07.034 · Cited by 15
Efficacy of exogenous pyruvate in TremblerJ mouse model of Charcot‐Marie‐Tooth neuropathy
Sahenk, Z., YALVAÇ, M. E., Amornvit, J., Arnold, W. D., Chen, L., Shontz, K. M., & Lewis, S. (2018) · Brain and Behavior · doi:10.1002/brb3.1118 · Cited by 14
Kim, H., Lee, D., Kim, E., Jeong, I., Kim, S., Kim, B.-J., & Park, H. (2020) · Experimental Neurobiology · doi:10.5607/en20050 · Cited by 15
“Oligodendrocytes also play a crucial role in promoting neuronal survival by providing metabolic support, including the supply of lactate to neurons [1].”
BackgroundBergaglio, T., Luchicchi, A., & Schenk, G. J. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.610295 · Cited by 16
SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection
Crawford, C. L., Antoniou, C., Komarek, L., Schultz, V., Donald, C. L., Montague, P., Barnett, S. C., Linington, C., Willison, H. J., Kohl, A., et al. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.860410 · Cited by 15
“These cells provide energy metabolites to neurons (Pellerin et al., 1998; Fünfschilling et al., 2012; Lee et al., 2012), although energy insufficiency due to failed energy substrate provision is unlikely in this context because neuronal processes are suffused in a glucoserich media in vitro.”
BackgroundTu, N. H., Katano, T., Matsumura, S., Funatsu, N., Pham, V. M., Fujisawa, J., & Ito, S. (2017) · European Journal of Neuroscience · doi:10.1111/ejn.13647 · Cited by 15
“Lactate shuttling between glia and neurons has been recently revived as being an energy source and intercellular messenger of neural functions such as oligodendrocyte myelination and memory formation (Gladden, 2004; Suzuki et al., 2011; Lee et al., 2012; Barros, 2013).”
Kinney, H. C., & Volpe, J. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-42876-7.00014-4 · Cited by 16
Tackling mitochondrial diversity in brain function: from animal models to human brain organoids
Menacho, C., & Prigione, A. (2020) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2020.105760 · Cited by 15
Gotoh, H., Nomura, T., & Ono, K. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16665380 · Cited by 15
Identification of genome-wide targets of Olig2 in the adult mouse spinal cord using ChIP-Seq
Darr, A. J., Danzi, M. C., Brady, L., Emig-Agius, D., Hackett, A., Golshani, R., Warner, N., Lee, J., Lemmon, V. P., & Tsoulfas, P. (2017) · PLOS ONE · doi:10.1371/journal.pone.0186091 · Cited by 14
Lactylation and Central Nervous System Diseases
Chen, Y., Xiao, D., & Li, X. (2025) · Brain Sciences · doi:10.3390/brainsci15030294 · Cited by 15
“Astrocytes mainly express MCT1 and MCT4 with low affinity, and neurons express MCT2 [28,29].”
Huang, H., Jing, B., Zhu, F., Jiang, W., Tang, P., Shi, L., Chen, H., Ren, G., Xia, S., Wang, L., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112801 · Cited by 15
“2,3 Therefore, the formation of mature oligodendrocytes and subsequent myelination of axons during postnatal brain development are critically important for maintaining brain function.”
Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs
Zhu, Y., Burg, T., Neyrinck, K., Vervliet, T., Nami, F., Vervoort, E., Ahuja, K., Sassano, M. L., Chai, Y. C., Tharkeshwar, A. K., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-023-02666-x · Cited by 14
“Specifically, oligodendrocyte precursor cells (OPCs) showed increased proliferation and differentiation, and the newly generated oligodendrocytes appeared dysfunctional, resulting in impaired MN insulation and decreased metabolic support [48].”
BackgroundNuclear receptor PPARγ targets GPNMB to promote oligodendrocyte development and remyelination
Han, B., Bao, M.-Y., Sun, Q., Wang, R., Deng, X., Xing, K., Yu, F.-L., Zhang, Y., Li, X., Li, X.-Q., et al. (2024) · Brain · doi:10.1093/brain/awae378 · Cited by 14
The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes
König, H., Coughlan, K. S., Kinsella, S. M., Breen, B. A., & Prehn, J. H. M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.06.008 · Cited by 14
Cystatin C Triggers Neuronal Degeneration in a Model of Multiple System Atrophy
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Recruitment of endogenous CNS stem cells for regeneration in demyelinating disease
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Oligodendrocyte differentiation
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White-Matter Repair as a Novel Therapeutic Target for Early Adversity
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Involvement of GPR17 in Neuronal Fibre Outgrowth
Braune, M., Scherf, N., Heine, C., Sygnecka, K., Pillaiyar, T., Parravicini, C., Heimrich, B., Abbracchio, M. P., Müller, C. E., & Franke, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111683 · Cited by 14
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Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
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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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