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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.
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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]
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“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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Berthet, C., Castillo, X., Magistretti, P. J., & Hirt, L. (2012) · Cerebrovascular Diseases · doi:10.1159/000343657 · Cited by 155
Self-citationBarros, L. F., & Weber, B. (2018) · The Journal of Physiology · doi:10.1113/jp274944 · Cited by 154
“However several studies have reported perturbation of neuronal function and viability in response to pharmacological or genetic disruption of MCTs in astrocytes, oligodendrocytes or neurons (Newman et al. 2011; Suzuki et al. 2011; Funfschilling et al. 2012; Lee et al. 2012; Mazuel et al. 2017).”
BackgroundMitochondrial dysfunction in glial cells: Implications for neuronal homeostasis and survival
Rose, J., Brian, C., Woods, J., Pappa, A., Panayiotidis, M. I., Powers, R., & Franco, R. (2017) · Toxicology · doi:10.1016/j.tox.2017.06.011 · Cited by 156
Respiration-Deficient Astrocytes Survive As Glycolytic Cells In Vivo
Supplie, L. M., Düking, T., Campbell, G., Diaz, F., Moraes, C. T., Götz, M., Hamprecht, B., Boretius, S., Mahad, D., & Nave, K.-A. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.0756-16.2017 · Cited by 153
Demyelination as a rational therapeutic target for ischemic or traumatic brain injury
Shi, H., Hu, X., Leak, R. K., Shi, Y., An, C., Suenaga, J., Chen, J., & Gao, Y. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.03.017 · Cited by 159
Intrinsic and adaptive myelination—A sequential mechanism for smart wiring in the brain
Bechler, M. E., Swire, M., & ffrench‐Constant, C. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22518 · Cited by 157
“Seminal progress has been the recent development of neuron-free, electrospun microfiber cultures, demonstrating the capacity for oligodendrocytes to generate compact, multilamellar myelin membranes ensheathing microfibers (Lee et al., 2012a, 2013; Bechler et al., 2015).”
InfluentialHypomyelinating leukodystrophies: Translational research progress and prospects
Pouwels, P. J. W., Vanderver, A. L., Bernard, G., Wolf, N. I., Dreha‐Kulaczewski, S. F., Deoni, S., Bertini, E., Kohlschütter, A., Richardson, W. D., ffrench‐Constant, C., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24194 · Cited by 153
Kougioumtzidou, E., Shimizu, T., Hamilton, N. B., Tohyama, K., Sprengel, R., Monyer, H., Attwell, D., & Richardson, W. D. (2017) · eLife · doi:10.7554/elife.28080 · Cited by 154
Andersen, J. V., & Schousboe, A. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15811 · Cited by 161
“…PDH: pyruvate dehydrogenase. be noted that metabolic impairments, not only of astrocytes but also of microglia (Aldana, 2019; Paolicelli et al., 2022) and oligodendrocytes (Lee et al., 2012; Philips & Rothstein, 2017) may play significant roles in the development of multiple cerebral diseases.”
BackgroundMonitoring ATP dynamics in electrically active white matter tracts
Trevisiol, A., Saab, A. S., Winkler, U., Marx, G., Imamura, H., Möbius, W., Kusch, K., Nave, K.-A., & Hirrlinger, J. (2017) · eLife · doi:10.7554/elife.24241 · Cited by 151
The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA
Ackerman, S. D., Garcia, C. M., Piao, X., Gutmann, D. H., & Monk, K. R. (2015) · Nature Communications · doi:10.1038/ncomms7122 · Cited by 149
The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration
Tu, D., Gao, Y., Yang, R., Guan, T., Hong, J., & Gao, H. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1659-1 · Cited by 150
Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis
Mohassel, P., Donkervoort, S. C., Lone, M. A., Nalls, M., Gable, K. S., Gupta, S. D., Foley, A. R., Hu, Y., Saute, J. A. M., Moreira, A. L., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01346-1 · Cited by 149
Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD
Pineda, S. S., Lee, H., Fitzwalter, B. E., Mohammadi, S., Pregent, L., Gardashli, M., Mantero, J. C., Engelberg-Cook, E., DeJesus‐Hernandez, M., van Blitterswijk, M., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.031 · Cited by 158
“47 Negative enrichment of GO terms associated with oligodendrocyte development and differentiation was most pronounced in ALS (Figure S2H).”
BackgroundSOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS
Hayashi, Y., Homma, K., & Ichijo, H. (2015) · Advances in Biological Regulation · doi:10.1016/j.jbior.2015.10.006 · Cited by 161
Making myelin basic protein -from mRNA transport to localized translation
Müller, C., Bauer, N., Schäfer, I., & White, R. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00169 · Cited by 154
Oligodendrocytes in the Mouse Corpus Callosum Maintain Axonal Function by Delivery of Glucose
Meyer, N., Richter, N., Fan, Z., Siemonsmeier, G., Pivneva, T., Jordan, P., Steinhäuser, C., Semtner, M., Nolte, C., & Kettenmann, H. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.022 · Cited by 145
Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers
Vahsen, B. F., Gray, E., Thompson, A. G., Ansorge, O., Anthony, D. C., Cowley, S. A., Talbot, K., & Turner, M. R. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00487-8 · Cited by 147
Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS
Taes, I., Timmers, M., Hersmus, N., Bento‐Abreu, A., Bosch, L. V. D., Damme, P. V., Auwerx, J. H., & Robberecht, W. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt028 · Cited by 142
Novel pathogenic pathways in diabetic neuropathy
Zenker, J., Ziegler, D., & Chrast, R. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.04.008 · Cited by 148
The central role of mitochondria in axonal degeneration in multiple sclerosis
Campbell, G. R., Worrall, J. T., & Mahad, D. (2014) · Multiple Sclerosis · doi:10.1177/1352458514544537 · Cited by 137
Diverse cellular and molecular modes of axon degeneration
Neukomm, L. J., & Freeman, M. R. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.04.003 · Cited by 144
Scekic‐Zahirovic, J., Oussini, H. E., Mersmann, S., Drenner, K., Wagner, M., Sun, Y., Allmeroth, K., Dieterle, S., Sinniger, J., Dirrig‐Grosch, S., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1687-9 · Cited by 135
Yao, S., Xu, M.-D., Wang, Y., Zhao, S., Wang, J., Chen, G.-F., Chen, W., Liu, J., Huang, G., Sun, W.-J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36209-5 · Cited by 144
Amyotrophic lateral sclerosis: Problems and prospects
Sreedharan, J., & Brown, R. H. (2013) · Annals of Neurology · doi:10.1002/ana.24012 · Cited by 143
Regulation of myelination by microglia
Santos, E. N., & Fields, R. D. (2021) · Science Advances · doi:10.1126/sciadv.abk1131 · Cited by 137
Complex interactions between hypoxia‐ischemia and inflammation in preterm brain injury
Galinsky, R., Lear, C. A., Dean, J. M., Wassink, G., Dhillon, S. K., Fraser, M., Davidson, J. O., Bennet, L., & Gunn, A. J. (2017) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.13629 · Cited by 136
Kaushik, D. K., Bhattacharya, A., Mirzaei, R., Rawji, K. S., Ahn, Y., Rho, J. M., & Yong, V. W. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124012 · Cited by 136
“Our results Monocarboxylate transporters (MCTs) play a crucial role in the sustained production of lactate by transporting excess lactate across cell membranes; MCTs such as MCT-1 and MCT-4, which have a low affinity for lactate, are enriched in cells with high rates of glycolysis (17, 18).”
BackgroundAstrocyte metabolism and signaling pathways in the CNS
Zhang, Y.-M., Qi, Y., Gao, Y.-N., Chen, W.-G., Zhou, T., Zang, Y., & Li, J. X. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1217451 · Cited by 152
“One way for the brain to obtain KBs is from the BBB through monocarboxylate transporter 1 (MCT1) in endothelial cells, oligodendrocytes, and astrocytes.”
Rone, M. B., Cui, Q., Fang, J. Q., Wang, L., Zhang, J., Khan, D., Bedard, M., Almazán, G., Ludwin, S. K., Jones, R., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4077-15.2016 · Cited by 136
Joutel, A., & Chabriat, H. (2017) · Clinical Science · doi:10.1042/cs20160380 · Cited by 141
Neurotransmitter signaling in white matter
Butt, A. M., Fern, R. F., & Matute, C. (2014) · Glia · doi:10.1002/glia.22674 · Cited by 133
Thakur, A., Qiu, G., Xu, C., Han, X., Yang, T., Ng, S., Chan, K. W. Y., Wu, C. L., & Lee, Y. (2020) · Science Advances · doi:10.1126/sciadv.aaz6119 · Cited by 134
Self-citationRedistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress
Cooper, M., Pasini, S., Lambert, W. S., D’Alessandro, K. B., Yao, V., Risner, M. L., & Calkins, D. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009425117 · Cited by 132
“Similar metabolic transfer occurs in corpus callosum, with astrocytes and oligodendrocytes coupling in response to glucose deprivation to maintain action potential generation (56, 57).”
BackgroundGriemsmann, S., Höft, S. P., Bedner, P., Zhang, J., von Staden, E., Beinhauer, A., Degen, J., Dublin, P., Cope, D. W., Richter, N., et al. (2015) · Cerebral Cortex · doi:10.1093/cercor/bhu157 · Cited by 132
White matter aging and its impact on brain function
Groh, J., & Simons, M. (2025) · Neuron · doi:10.1016/j.neuron.2024.10.019 · Cited by 124
The Diameter of Cortical Axons Depends Both on the Area of Origin and Target
Innocenti, G. M., Vercelli, A., & Caminiti, R. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht070 · Cited by 138
Retinal energy metabolism in health and glaucoma
Casson, R. J., Chidlow, G., Crowston, J. G., Williams, P. A., & Wood, J. P. M. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100881 · Cited by 132
“(Funfschilling et al., 2012; Harun-Or-Rashid et al., 2018; Lee et al., 2012) MCT1 is highly enriched within oligodendroglia and its disruption causes neurodegeneration in animal and cell culture models.”
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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