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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]
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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“It is well known that protection of the naked axons is necessary to prevent axonal transection and persistent neurological dysfunction (7, 8).”
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“Importantly, lactate increase was also observed in DS and Nacc and may reflect upregulation of the activity of the astrocyte-neuron lactate shuttle (37, 38), known to play a major role in central nervous system homeostasis and energy metabolism (39, 40), especially in energy production.”
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“Additional work found that oligodendroglia are the primary cell type that expresses MCT1 in the brain and that oligodendroglial precursor cells (OPCs) specifically exhibit reduced expression of MCT1 in SOD1G93A mice compared to wild type animals [116].”
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“In addition to ensuring saltatory conduction, oligodendrocytes secrete via myelin metabolic and trophic factors that maintain the integrity and survival of axons [10,11].”
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“Also, myelin provides metabolic support to the axon by supplying energy molecules (Lee et al., 2012; Micheva et al., 2016).”
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BackgroundInfluentialGlial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome
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“Furthermore, they supply axons with glycolysis products, such as L-lactate, to offer metabolic support ( Fünfschilling et al., 2012 ; Lee et al., 2012 ).”
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“Interestingly, there have been no reports of the influence of oligodendroglia and Schwann cells on the endurance of ALS MNs of humans, even though during development, these cells play a crucial role in MN differentiation and functional integration (Lee et al. 2012; Horner et al. 2021).”
BackgroundRadiation-Induced Brain Injury: Mechanistic Insights and the Promise of Gut–Brain Axis Therapies
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“These cells have been shown in several studies to support axonal metabolism [89,90] and regulate the behavior of neural networks [91,92].”
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“The loss of adult myelination and the accompanying metabolic support it would provide (Hirrlinger & Nave, 2014; Lee et al., 2012; Meyer et al., 2018), may account for the increase in average axon diameter that we detected, that was not accompanied by any change in myelin thickness.”
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“The axonal energy metabolism is highly complex: axons are dependent of at least two different energy sources—direct local supply of ATP by axonal mitochondria as well as lactate supply via monocarboxylate transporters in the OLs (Fünfschilling et al., 2012; Lee et al., 2012; Saab et al., 2013).”
BackgroundNeuron‐glia (mis)interactions in brain energy metabolism during aging
Mayorga-Weber, G. A., Rivera, F. J., & Castro, M. A. (2022) · Journal of Neuroscience Research · doi:10.1002/jnr.25015 · Cited by 27
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“During the process of myelin formation, oligodendrocytes require substantial nutritional and metabolic support; therefore, they must establish close connections with neurovascular structures (Lee et al., 2012).”
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“While oligodendrocytes are important to the metabolic support of central axons by offering substrates that are glycolysis-derived, but not originated from mitochondrial respiration [70,71], Schwann cells participate in the metabolic support of peripheral axons in a mitochondrial dependent pathway [72].”
BackgroundOligodendroglial Response in the Spinal Cord in TDP-43 Proteinopathy with Motor Neuron Involvement
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“Though presumed to express MCT2 like other CNS neurons [74], this has not yet been confirmed in publications.”
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Lin, T.-J., Cheng, K.-C., Wu, L.-Y., Lai, W.-Y., Ling, T., Kuo, Y., & Huang, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.851613 · Cited by 26
“Lactate is transported abundantly through monocarboxylate transporter-1 (MCT1), which is highly expressed in oligodendrocytes (Lee et al., 2012), In the disease model of sporadic ALS, MCT1 expression is reduced, causing the death of MNs consequently through two pathways: the deleterious effect on…”
BackgroundType‐1 cannabinoid receptors and their ever‐expanding roles in brain energy processes
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“Furthermore, as the oligodendrocyte lactate production has been proposed to be necessary for axonal health (Fünfschilling et al., 2012; Lee et al., 2012; Simons & Nave, 2015), a potential oligodendrocyte metabolic malfunction alongside a demyelination insult might accelerate axonal death, and loss…”
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Shengui Sansheng San Ameliorates Cerebral Energy Deficiency via Citrate Cycle After Ischemic Stroke
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“If CS silences, citrate synthesis will decrease, which induces the disorder of cellular respiratory and inefficient production of ATP (Nelson and Cox, 2008; Lin et al., 2012).”
BackgroundSenescence in aging and disorders of the central nervous system
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“Oligodendrocytes—the glial cells that myelinate axons—have also been shown to metabolically support the axons they ensheath 55,56 .”
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“Moreover, these astrocytes release inflammatory mediators, including prostaglandin E2 and nitric oxide, which exacerbate neuronal vulnerability and contribute to synaptic dysfunction [81].”
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“Myelin enables saltatory conduction of action potentials along axons (1, 2), provides axonal metabolic support via metabolite delivery (3, 4) and is required for efficient motor skill learning (5, 6).”
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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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