Monitoring ATP dynamics in electrically active white matter tracts
Open accessAbstract
In several neurodegenerative diseases and myelin disorders, the degeneration profiles of myelinated axons are compatible with underlying energy deficits. However, it is presently impossible to measure selectively axonal ATP levels in the electrically active nervous system. We combined transgenic expression of an ATP-sensor in neurons of mice with confocal FRET imaging and electrophysiological recordings of acutely isolated optic nerves. This allowed us to monitor dynamic changes and activity-dependent axonal ATP homeostasis at the cellular level and in real time. We find that changes in ATP levels correlate well with compound action potentials. However, this correlation is disrupted when metabolism of lactate is inhibited, suggesting that axonal glycolysis products are not sufficient to maintain mitochondrial energy metabolism of electrically active axons. The combined monitoring of cellular ATP and electrical activity is a novel tool to study neuronal and glial energy metabolism in normal physiology and in models of neurodegenerative disorders.
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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.”
From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [20]
The Results sections on high-frequency stimulation and energy deprivation report falling axonal ATP during electrical stimulation and after mitochondrial respiration was blocked with azide (page not provided). But the paper also reports ATP decline after glucose deprivation, so it does not support “only” those conditions. The passages do not report an experiment exposing these axons to exogenous glutamate. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe model of glycolytic oligodendrocytes providing metabolic support is supported by ex vivo electrophysiological recordings of compound action potentials in optic nerves and by neuronally expressed ATP sensors.
“The model is further supported by ex vivo electrophysiological recordings of compound action potentials in optic nerves under defined metabolic conditions and with the help of neuronally expressed ATP sensors (Saab et al., 2016;Trevisiol et al., 2017).”
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 Trevisiol et al., 2017
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References 33 · Cited by 151
- Authors
- Trevisiol, A., Saab, A. S., Winkler, U., Marx, G., Imamura, H., Möbius, W., Kusch, K., Nave, K.-A., & Hirrlinger, J.
- Affiliations
- Max Planck Institute of Experimental Medicine (DE)
- University of Zurich (CH)
- Leipzig University (DE)
- Kyoto University (JP)
- Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
- Corresponding author
- Nave, Klaus-Armin
- Hirrlinger, Johannes
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-04-17
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5415357
- OpenAlex
- W2607504352
- Cited by
- 151
- References
- 33
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 15 · 2023: 16 · 2022: 19 · 2021: 19 · 2020: 19 · 2019: 10 · 2018: 14 · 2017: 9
- FWCI
- 5.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft
- H2020 European Research Council
- European Molecular Biology Organization
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- white matter tracts, axonal energy metabolism, FRET imaging, optic nerve, compound action potential, lactate metabolism, mitochondrial bioenergetics, myelinated axons, neurodegenerative diseases, myelin disorders
- MeSH terms
- Adenosine Triphosphate, Animals, Electroencephalography, Mice, Transgenic, Optic Nerve, Genes, Reporter, Microscopy, Confocal, Fluorescence Resonance Energy Transfer, Mice, Optical Imaging, White Matter
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