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The neuron–astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease

Nature Metabolism volume 7, pages 2414–2423 (2025)Cite this article

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Abstract

Over the past years, substantial advances have deepened our understanding of the cellular and molecular drivers of brain energy metabolism. Enabled by transformative technologies offering cellular-level resolution, these insights have revealed a highly regulated and dynamic metabolic interplay among brain cell types, particularly between neurons and astrocytes. In this Review, we shed light on the intricate ways in which neurons and astrocytes operate as a metabolically coupled unit, optimized to sustain the energetic demands of neurotransmission while ensuring neuroprotection. We highlight intercellular cooperation as a key determinant of brain function and provide examples of how disruption of the neuron–astrocyte metabolic unit contributes to numerous diseases of the nervous system, underscoring the critical importance of continued fundamental research to dissect the regulatory principles and vulnerabilities of this intercellular metabolic axis and identify potential therapeutic targets.

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Fig. 1: Glutamatergic neurotransmission is coupled to glycolytic activation in astrocytes.
Fig. 2: Different abundances of PFKFB3 explain high glycolysis in astrocytes and low glycolysis in neurons.
Fig. 3: Glutamatergic neurotransmission is coupled to neuronal antioxidant protection.
Fig. 4: Functional and dysfunctional neuron–astrocyte metabolic unit.

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Acknowledgements

J.P.B. is funded by MICIU/AEI (PID2022-138813OB-I00/10.13039/501100011033 and FEDER, UE), la Caixa Foundation (grant agreement LCF/PR/HR23/52430016), the European Union’s Horizon Europe research and innovation programme under the MSCA Doctoral Networks 2021 (101072759, fuel the brain in healthy ageing and age-related diseases (ETERNITY)) and the European Research Council Advanced Grant NeuroSTARS (reference 101199747). Research in P.J.M.’s laboratory is funded by King Abdullah University of Science and Technology.

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Authors and Affiliations

  1. Institute of Functional Biology and Genomics, Universidad de Salamanca, CSIC, Salamanca, Spain

    Juan P. Bolaños

  2. Institute of Biomedical Research of Salamanca, Hospital Universitario de Salamanca, CSIC, Universidad de Salamanca, Salamanca, Spain

    Juan P. Bolaños

  3. Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Madrid, Spain

    Juan P. Bolaños

  4. Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia

    Pierre J. Magistretti

Authors
  1. Juan P. Bolaños
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  2. Pierre J. Magistretti
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Contributions

J.P.B. and P.J.M. conceived the idea and wrote, edited and approved the manuscript.

Corresponding authors

Correspondence to Juan P. Bolaños or Pierre J. Magistretti.

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Competing interests

P.J.M. is the scientific founder of GliaPharm. J.P.B declares no competing interests.

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Nature Metabolism thanks L. Felipe Barros and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alfredo Gimenez-Cassina, in collaboration with the Nature Metabolism team.

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Bolaños, J.P., Magistretti, P.J. The neuron–astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease. Nat Metab 7, 2414–2423 (2025). https://doi.org/10.1038/s42255-025-01404-9

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