Cited by 127Mitochondrial Function and PathologyMetabolism, Diabetes, and CancerIon Transport and Channel Regulation

Non-Canonical Control of Neuronal Energy Status by the Na+ Pump

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Baeza-Lehnert, Felipe, Saab, Aiman S., Gutiérrez, Robin, Larenas, Valeria, Díaz, Esteban, Horn, Melanie, Vargas, Miriam, Hösli, Ladina +4 more·2019·Cell Metabolism

Abstract

Neurons have limited intracellular energy stores but experience acute and unpredictable increases in energy demand. To better understand how these cells repeatedly transit from a resting to active state without undergoing metabolic stress, we monitored their early metabolic response to neurotransmission using ion-sensitive probes and FRET sensors in vitro and in vivo. A short theta burst triggered immediate Na+ entry, followed by a delayed stimulation of the Na+/K+ ATPase pump. Unexpectedly, cytosolic ATP and ADP levels were unperturbed across a wide range of physiological workloads, revealing strict flux coupling between the Na+ pump and mitochondria. Metabolic flux measurements revealed a "priming" phase of mitochondrial energization by pyruvate, whereas glucose consumption coincided with delayed Na+ pump stimulation. Experiments revealed that the Na+ pump plays a permissive role for mitochondrial ATP production and glycolysis. We conclude that neuronal energy homeostasis is not mediated by adenine nucleotides or by Ca 2+, but by a mechanism commanded by the Na+ pump.

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Crossref · 10.1016/j.cmet.2018.11.005

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  • In vitro studies have shown that neuronal ATP levels decrease only under hyperexcitation induced by strong electrical stimulation or exogenous glutamate exposure, or following pharmacological inhibition of mitochondrial ATP production pathways.

    “Indeed, in vitro studies have shown that neuronal ATP levels decrease only under hyperexcitation induced by strong electrical stimulation or exogenous glutamate exposure, or following pharmacological inhibition of mitochondrial ATP production pathways20–22.”
  • In vivo studies have demonstrated that neuronal ATP levels remain stable in response to mild sensory stimuli in mice.

    “Consistent with these findings, in vivo studies have demonstrated that neuronal ATP levels remain stable in response to mild sensory stimuli in mice22, while a marked reduction in ATP levels is observed during epileptic seizure activity3.”

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Authors
Baeza-Lehnert, F., Saab, A. S., Gutiérrez, R., Larenas, V., Díaz, E., Horn, M., Vargas, M., Hösli, L., Stobart, J., Hirrlinger, J., Weber, B., & Barros, L. F.
Affiliations
  • University of Zurich (CH)
  • Austral University of Chile (CL)
  • Centro de Estudios Científicos (CL)
  • Max Planck Institute of Experimental Medicine (DE)
Corresponding author
Barros, L. Felipe
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2019-03
Volume
29
Issue
3
Pages
668-680.e4
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2904685632
Cited by
126
References
78
Citations by year
2026: 10 · 2025: 19 · 2024: 25 · 2023: 21 · 2022: 12 · 2021: 12 · 2020: 13 · 2019: 14
FWCI
3.47
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Funders
  • FONDECYT (1160317)
  • University of Zurich
  • National Science Foundation
  • Centro de Estudios Científicos
  • Chilean Government
  • CONICYT
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
Na+/K+-ATPase, mitochondrial energization, pyruvate, glycolysis, glucose utilization, ATP production, neurotransmission, theta burst stimulation, FRET biosensor, ion sensitive probe
MeSH terms
Sodium-Potassium-Exchanging ATPase, Adenosine Triphosphate, Animals, Astrocytes, Energy Metabolism, Glucose, Glycolysis, Homeostasis, Mice, Inbred C57BL, Mitochondria, Neurons

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