Respiration-Deficient Astrocytes Survive As Glycolytic Cells In Vivo
Open accessAbstract
Neurons and glial cells exchange energy-rich metabolites and it has been suggested, originally based on in vitro data, that astrocytes provide lactate to glutamatergic synapses (“lactate shuttle”). Here, we have studied astrocytes that lack mitochondrial respiration in vitro and in vivo . A novel mouse mutant ( GLAST CreERT2 :: Cox10 flox/flox ) was generated, in which the administration of tamoxifen causes mutant astrocytes to fail in the assembly of mitochondrial cytochrome c oxidase (COX). Focusing on cerebellar Bergmann glia (BG) cells, which exhibit the highest rate of Cre-mediated recombination, we found a normal density of viable astrocytes even 1 year after tamoxifen-induced Cox10 gene targeting. Our data show that BG cells, and presumably all astrocytes, can survive by aerobic glycolysis for an extended period of time in the absence of glial pathology or unspecific signs of neurodegeneration. SIGNIFICANCE STATEMENT When astrocytes are placed into culture, they import glucose and release lactate, an energy-rich metabolite readily metabolized by neurons. This observation led to the “glia-to-neuron lactate shuttle hypothesis,” but in vivo evidence for this hypothesis is weak. To study astroglial energy metabolism and the directionality of lactate flux, we generated conditional Cox10 mouse mutants lacking mitochondrial respiration in astrocytes, which forces these cells to survive by aerobic glycolysis. Here, we report that these mice are fully viable in the absence of any signs of glial or neuronal loss, suggesting that astrocytes are naturally glycolytic cells.
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Mature astrocytes are naturally glycolytic cells that can survive by aerobic glycolysis for an extended period without functional impairments.
“Previous studies have shown that mature astrocytes are naturally glycolytic cells that can survive by aerobic glycolysis for an extended period without functional impairments [18].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [18]
The Abstract reports that respiration-deficient cerebellar Bergmann glia survived for a year by aerobic glycolysis without glial pathology or nonspecific signs of neurodegeneration; it extends this to other astrocytes only as a presumption. The Discussion describes adult steady-state Bergmann glia without signs of cerebellar dysfunction and calls natural glycolysis a supported model. The claim presents survival without functional impairments as established for mature astrocytes generally, beyond what the study directly tested. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe primarily glycolytic metabolism of astrocytes has been previously demonstrated in non-proliferating astrocytes, which were able to survive without mitochondrial respiration.
“The primarily glycolytic metabolism of astrocytes has been previously demonstrated in non-proliferating astrocytes, which were able to survive without mitochondrial respiration [18].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [18]
The Abstract and Discussion (page unavailable) report that respiration-deficient adult Bergmann glia survived for up to a year by aerobic glycolysis, supporting the claim about survival without mitochondrial respiration in a steady-state setting. But the Discussion calls the findings strong support for a model of naturally glycolytic astrocytes, not a demonstration that unmodified astrocytes have primarily glycolytic metabolism; it notes that lactate flux may differ in wild-type mice. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAstrocytes do not vitally depend on their mitochondrial energy metabolism.
“Moreover, astrocytes do not vitally depend on their mitochondrial energy metabolism (Rose et al., 2020; Supplie et al., 2017).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Supplie et al., 2017
The Abstract reports that respiration-deficient cerebellar Bergmann glia survived for a year, supporting the claim that these astrocytes do not depend on mitochondrial respiration for survival under the conditions studied. The Discussion limits that finding to the adult steady state and says mitochondrial ATP generation may be required during postnatal growth or after CNS injury. The unqualified statement about astrocytes is therefore broader than the paper's finding. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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- Authors
- Supplie, L. M., Düking, T., Campbell, G., Diaz, F., Moraes, C. T., Götz, M., Hamprecht, B., Boretius, S., Mahad, D., & Nave, K.-A.
- Affiliations
- Max Planck Institute of Experimental Medicine (DE)
- University of Edinburgh (GB)
- University of Miami (US)
- Helmholtz Munich (DE)
- German Primate Center (DE)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-03-17
- Volume
- 37
- Issue
- 16
- Pages
- 4231-4242
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6596567
- OpenAlex
- W2595697715
- Cited by
- 153
- References
- 13
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 28 · 2023: 24 · 2022: 18 · 2021: 11 · 2020: 17 · 2019: 18 · 2018: 9 · 2017: 4
- FWCI
- 6.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- International Progressive MS Alliance
- Deutsche Forschungsgemeinschaft (SPP-1757)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- astrocytes, aerobic glycolysis, lactate shuttle, mitochondrial respiration, cytochrome c oxidase, COX10, Bergmann glia, astrocyte survival, conditional knockout mice
- MeSH terms
- Animals, Astrocytes, Cells, Cultured, Cerebellum, Glucose, Glycolysis, Membrane Proteins, Mice, Inbred C57BL, Neurons, Rats, Sprague-Dawley, Cell Respiration, Lactic Acid, Alkyl and Aryl Transferases, Mice, Rats
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