In vivo evidence for a lactate gradient from astrocytes to neurons
Open accessAbstract
Investigating lactate dynamics in brain tissue is challenging, partly because in vivo data at cellular resolution are not available. We monitored lactate in cortical astrocytes and neurons of mice using the genetically encoded FRET sensor Laconic in combination with two-photon microscopy. An intravenous lactate injection rapidly increased the Laconic signal in both astrocytes and neurons, demonstrating high lactate permeability across tissue. The signal increase was significantly smaller in astrocytes, pointing to higher basal lactate levels in these cells, confirmed by a one-point calibration protocol. Trans-acceleration of the monocarboxylate transporter with pyruvate was able to reduce intracellular lactate in astrocytes but not in neurons. Collectively, these data provide in vivo evidence for a lactate gradient from astrocytes to neurons. This gradient is a prerequisite for a carrier-mediated lactate flux from astrocytes to neurons and thus supports the astrocyte-neuron lactate shuttle model, in which astrocyte-derived lactate acts as an energy substrate for neurons.
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The original ANLS has been controversially discussed but has also gained considerable experimental support by in vitro and in vivo studies.
“While the original ANLS has been controversially discussed (Albanese et al., 2016;Bosoi & Rose, 2014;Dienel, 2017;Liguori et al., 2015;Yellen, 2018), it has also gained considerable experimental support by in vitro (Bouzier-Sore et al., 2003;Karagiannis et al., 2021) and in vivo studies (Mächler et al., 2016;Suzuki et al., 2011;Wyss et al., 2011;Zuend et al., 2020).”
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 Mächler et al., 2016
Inhibition of astrocyte-specific glycolysis or astrocyte-neuron lactate shuttles impairs long-term memory formation in mice.
“Inhibition of astrocyte-specific glycolysis or astrocyte-neuron lactate shuttles was shown to impair long-term memory formation in mice.37”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [37]
In resting brain or quiescent brain slice, astrocytes appear to be more glycolytic than neurons.
“Consistent with most of the cultured cell studies, in resting brain or in quiescent brain slice astrocytes appear to be more glycolytic than neurons, with higher resting cytosolic NADH/NAD+ (NADHCYT) ratios (Mongeon et al., 2016) that predispose them to higher resting lactate/pyruvate ratios and higher resting lactate levels (Mächler et al., 2016).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Mächler et al., 2016
Higher resting NADHCYT predisposes astrocytes to higher resting lactate/pyruvate ratios and higher resting lactate levels.
“Consistent with most of the cultured cell studies, in resting brain or in quiescent brain slice astrocytes appear to be more glycolytic than neurons, with higher resting cytosolic NADH/NAD+ (NADHCYT) ratios (Mongeon et al., 2016) that predispose them to higher resting lactate/pyruvate ratios and higher resting lactate levels (Mächler et al., 2016).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Mächler et al., 2016
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Non-Canonical Control of Neuronal Energy Status by the Na+ Pump
Baeza-Lehnert, F., Saab, A. S., Gutiérrez, R., Larenas, V., Díaz, E., Horn, M., Vargas, M., Hösli, L., Stobart, J., Hirrlinger, J., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.11.005 · Cited by 126 · see citing works
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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases
Yang, S., Park, J. H., & Lu, H.-C. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00634-3 · Cited by 94 · see citing works
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Glucose metabolism, neural cell senescence and Alzheimer's disease
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Physiological significance of elevated levels of lactate by exercise training in the brain and body
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Insulin action on astrocytes: From energy homeostasis to behaviour
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Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
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Imaging Approaches for the Study of Metabolism in Real Time Using Genetically Encoded Reporters
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Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy
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- Authors
- Mächler, P., Wyss, M. T., Elsayed, M., Stobart, J., Gutierrez, R., von Faber-Castell, A., Kaelin, V., Zuend, M., San Martín, A., Romero-Gómez, I., Baeza-Lehnert, F., Lengacher, S., Schneider, B. L., Aebischer, P., Magistretti, P. J., Barros, L. F., & Weber, B.
- Affiliations
- University of Zurich (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Centro de Estudios Científicos (CL)
- Corresponding author
- Weber, Bruno
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 23
- Issue
- 1
- Pages
- 94-102
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2202641067
- Cited by
- 571
- References
- 71
- Citations by year
- 2026: 43 · 2025: 53 · 2024: 58 · 2023: 55 · 2022: 58 · 2021: 66 · 2020: 58 · 2019: 44 · 2018: 65 · 2017: 47 · 2016: 22 · 2015: 1 · 2014: 1
- FWCI
- 20.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 377 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, other-oa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica (1130095)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Comisión Nacional de Investigación Científica y Tecnológica
- Hartmann Müller-Stiftung für Medizinische Forschung
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- astrocytes, neurons, astrocyte-neuron lactate shuttle, lactate transport, monocarboxylate transporters, pyruvate, cortical tissue, brain energy metabolism, intracellular lactate
- MeSH terms
- Animals, Astrocytes, Brain, Energy Metabolism, Female, Mice, Inbred C57BL, Neurons, Microscopy, Confocal, Lactic Acid
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