Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes
Open accessAbstract
During synaptic activity, the clearance of neuronally released glutamate leads to an intracellular sodium concentration increase in astrocytes that is associated with significant metabolic cost. The proximity of mitochondria at glutamate uptake sites in astrocytes raises the question of the ability of mitochondria to respond to these energy demands. We used dynamic fluorescence imaging to investigate the impact of glutamatergic transmission on mitochondria in intact astrocytes. Neuronal release of glutamate induced an intracellular acidification in astrocytes, via glutamate transporters, that spread over the mitochondrial matrix. The glutamate-induced mitochondrial matrix acidification exceeded cytosolic acidification and abrogated cytosol-to-mitochondrial matrix pH gradient. By decoupling glutamate uptake from cellular acidification, we found that glutamate induced a pH-mediated decrease in mitochondrial metabolism that surpasses the Ca 2+-mediated stimulatory effects. These findings suggest a model in which excitatory neurotransmission dynamically regulates astrocyte energy metabolism by limiting the contribution of mitochondria to the metabolic response, thereby increasing the local oxygen availability and preventing excessive mitochondrial reactive oxygen species production.
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Astrocytes may become acidified due to proton cotransport during glutamate reuptake, which could lead to reduced mitochondrial oxygen consumption within astrocytes.
“Astrocytes may become acidified due to proton cotransport during glutamate reuptake, which could lead to reduced mitochondrial oxygen consumption within astrocytes66.”
From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [66]
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Cites
Mitochondria, Oxidants, and Aging
Balaban, R. S., Nemoto, S., & Finkel, T. (2005) · Cell · doi:10.1016/j.cell.2005.02.001 · Cited by 4,388 · see citing works
Pellerin, L., & Magistretti, P. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.22.10625 · Cited by 2,927 · see citing works
Sensors and regulators of intracellular pH
Casey, J. R., Grinstein, S., & Orlowski, J. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2820 · Cited by 2,276 · see citing works
Mitochondrial Transport of Cations: Channels, Exchangers, and Permeability Transition
Bernardi, P. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.4.1127 · Cited by 1,534 · see citing works
Uniquely Hominid Features of Adult Human Astrocytes
Oberheim, N. A., Takano, T., Han, X., He, W., Lin, J. H. C., Wang, F., Xu, Q., Wyatt, J. D., Pilcher, W., Ojemann, J. G., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4707-08.2009 · Cited by 1,488 · see citing works
Magistretti, P. J., Pellerin, L., Rothman, D. L., & Shulman, R. G. (1999) · Science · doi:10.1126/science.283.5401.496 · Cited by 1,170 · see citing works
Self-citationDecoding of cytosolic calcium oscillations in the mitochondria
Hajnóczky, G., Gaspers, L. D., Seitz, M. B., & Thomas, A. P. (1995) · Cell · doi:10.1016/0092-8674(95)90430-1 · Cited by 1,110 · see citing works
Metabolic coupling between glia and neurons
Tsacopoulos, M., & Magistretti, P. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-03-00877.1996 · Cited by 1,006 · see citing works
Self-citationStoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity.
Sibson, N. R., Dhankhar, A., Mason, G. F., Rothman, D. L., Behar, K. L., & Shulman, R. G. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.316 · Cited by 897 · see citing works
Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission
Rouach, N., Koulakoff, A., Abudara, V., Willecke, K., & Giaume, C. (2008) · Science · doi:10.1126/science.1164022 · Cited by 861 · see citing works
Herrero-Mendez, A., Almeida, A., Fernández, E., Maestre, C., Moncada, S., & Bolaños, J. P. (2009) · Nature Cell Biology · doi:10.1038/ncb1881 · Cited by 844 · see citing works
Chaudhry, F. A., Lehre, K. P., Campagne, M. V. L., Ottersen, O. P., Danbolt, N. C., & Storm‐Mathisen, J. (1995) · Neuron · doi:10.1016/0896-6273(95)90158-2 · Cited by 827 · see citing works
Selective fluorescent imaging of superoxide <i>in vivo</i> using ethidium-based probes
Robinson, K. M., Janes, M. S., Pehar, M., Monette, J. S., Ross, M. F., Hagen, T. M., Murphy, M. P., & Beckman, J. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601945103 · Cited by 777 · see citing works
Keilin's Respiratory Chain Concept and Its Chemiosmotic Consequences
Mitchell, P. (1979) · Science · doi:10.1126/science.388618 · Cited by 738 · see citing works
Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate
Bezzi, P., Gundersen, V., Galbete, J. L., Seifert, G., Steinhäuser, C., Pilati, E., & Volterra, A. (2004) · Nature Neuroscience · doi:10.1038/nn1246 · Cited by 737 · see citing works
Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells
Grosche, J., Matyash, V., Möller, T., Verkhratsky, A., Reichenbach, A., & Kettenmann, H. (1999) · Nature Neuroscience · doi:10.1038/5692 · Cited by 700 · see citing works
Tuned Responses of Astrocytes and Their Influence on Hemodynamic Signals in the Visual Cortex
Schummers, J., Yu, H., & Sur, M. (2008) · Science · doi:10.1126/science.1156120 · Cited by 632 · see citing works
Hertz, L., Peng, L., & Dienel, G. A. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600343 · Cited by 587 · see citing works
Levy, L. M., Warr, O., & Attwell, D. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09620.1998 · Cited by 490 · see citing works
Brain Glutamate Transporter Proteins Form Homomultimers
Haugeto, Ø., Ullensvang, K., Levy, L. M., Chaudhry, F. A., Honoré, T., Nielsen, M., Lehre, K. P., & Danbolt, N. C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27715 · Cited by 489 · see citing works
Verkhratsky, A., & Steinhäuser, C. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(99)00093-4 · Cited by 489 · see citing works
The Transcriptome and Metabolic Gene Signature of Protoplasmic Astrocytes in the Adult Murine Cortex
Lovatt, D., Sonnewald, U., Waagepetersen, H. S., Schousboe, A., He, W., Lin, J. H.-C., Han, X., Takano, T., Wang, S., Sim, F. J., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3404-07.2007 · Cited by 488 · see citing works
Energy-Efficient Action Potentials in Hippocampal Mossy Fibers
Alle, H., Roth, A., & Geiger, J. R. P. (2009) · Science · doi:10.1126/science.1174331 · Cited by 429 · see citing works
Ca2+-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons
Duchen, M. R. (1992) · Biochemical Journal · doi:10.1042/bj2830041 · Cited by 338 · see citing works
Dynamic Regulation of the Mitochondrial Proton Gradient during Cytosolic Calcium Elevations
Poburko, D., Domingo, J. S., & Demaurex, N. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159962 · Cited by 332 · see citing works
Self-citationPorcelli, A. M., Ghelli, A. M., Zanna, C., Pinton, P., Rizzuto, R., & Rugolo, M. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.105 · Cited by 302 · see citing works
Voutsinos‐Porche, B., Bonvento, G., Tanaka, K., Steiner, P., Welker, E., Chatton, J., Magistretti, P. J., & Pellerin, L. (2003) · Neuron · doi:10.1016/s0896-6273(02)01170-4 · Cited by 293 · see citing works
Self-citationMitochondrial pH Monitored by a New Engineered Green Fluorescent Protein Mutant
Cano‐Abad, M. F., Benedetto, G. D., Magalhães, P. J., Filippin, L., & Pozzan, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306766200 · Cited by 258 · see citing works
Intracellular pH transients of mammalian astrocytes
Chesler, M., & Kraig, R. P. (1989) · Journal of Neuroscience · doi:10.1523/jneurosci.09-06-02011.1989 · Cited by 193 · see citing works
Sorg, O., & Magistretti, P. J. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-12-04923.1992 · Cited by 193 · see citing works
Self-citationFood for Thought: Challenging the Dogmas
Pellerin, L., & Magistretti, P. J. (2003) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000096064.12129.3d · Cited by 186 · see citing works
Self-citationChatton, J., Pellerin, L., & Magistretti, P. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2132096100 · Cited by 180 · see citing works
Self-citationBlachly‐Dyson, E., & Forte, M. A. (2001) · IUBMB Life · doi:10.1080/15216540152845902 · Cited by 159 · see citing works
Synaptically induced sodium signals in hippocampal astrocytes in situ
Langer, J., & Rose, C. R. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.182279 · Cited by 155 · see citing works
Chatton, J., Marquet, P. P., & Magistretti, P. J. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00269.x · Cited by 138 · see citing works
Self-citationThe Role of External and Matrix pH in Mitochondrial Reactive Oxygen Species Generation
Selivanov, V. A., Zeak, J. A., Roca, J., Cascante, M., Trucco, M., & Votyakova, T. V. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801019200 · Cited by 137 · see citing works
Rose, C. R., & Ransom, B. R. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-17-05393.1996 · Cited by 108 · see citing works
Strathmann, J., Klimo, K., Sauer, S. W., Okun, J. G., Prehn, J. H. M., & Gerhäuser, C. (2010) · The FASEB Journal · doi:10.1096/fj.10-155846 · Cited by 82 · see citing works
Matrix alkalinization: a novel mitochondrial signal for sustained pancreatic β‐cell activation
Wiederkehr, A., Park, K., Dupont, O.-N., Demaurex, N., Pozzan, T., Cline, G. W., & Wollheim, C. B. (2009) · The EMBO Journal · doi:10.1038/emboj.2008.302 · Cited by 72 · see citing works
Self-citationSerres, S., Raffard, G., Franconi, J., & Merle, M. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600568 · Cited by 64 · see citing works
In situ fluorescence imaging of glutamate‐evoked mitochondrial Na+ responses in astrocytes
Bernardinelli, Y., Azarias, G., & Chatton, J. (2006) · Glia · doi:10.1002/glia.20387 · Cited by 55 · see citing works
Self-citationIntracellular pH changes produced by glutamate uptake in rat hippocampal slices
Amato, A., Ballerini, L., & Attwell, D. (1994) · Journal of Neurophysiology · doi:10.1152/jn.1994.72.4.1686 · Cited by 50 · see citing works
Magistretti, P. J. (2009) · Science · doi:10.1126/science.1180102 · Cited by 49 · see citing works
Self-citationWyss, M. T., Weber, B., Treyer, V., Heer, S., Pellerin, L., Magistretti, P. J., & Buck, A. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.86 · Cited by 44 · see citing works
Self-citationChatton, J., Idle, J. R., Vågbø, C. B., et al. (2001) · PubMed · Cited by 38 · see citing works
Self-citationKahlert, S., Zündorf, G., & Reiser, G. (2008) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2008.02.015 · Cited by 29 · see citing works
Chatton, J., Idle, J. R., Vågbø, C. B., et al. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29242-9 · Cited by 22 · see citing works
Self-citationChanges in the structure of pyruvate dehydrogenase complex induced by mono- and divalent ions
Pawełczyk, T., & Olson, M. S. (1995) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/1357-2725(95)00006-b · Cited by 4 · see citing works
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Magistretti, P. J., & Allaman, I. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.035 · Cited by 1,285 · see citing works
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Petit, J.-M., & Magistretti, P. J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.12.007 · Cited by 92 · see citing works
Self-citationEnergy demand of synaptic transmission at the hippocampal Schaffer-collateral synapse
Liotta, A., Rösner, J., Huchzermeyer, C., Wojtowicz, A., Kann, O., Schmitz, D., Heinemann, U., & Kovács, R. (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.116 · Cited by 48 · see citing works
Shashidharan, P., & Plaitakis, A. (2014) · Neurochemical Research · doi:10.1007/s11064-013-1227-5 · Cited by 43 · see citing works
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Ikoma, Y., Takahashi, Y., Sasaki, D., & Matsui, K. (2023) · Brain · doi:10.1093/brain/awac499 · Cited by 33 · see citing works
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Ikoma, Y., Sasaki, D., & Matsui, K. (2023) · Brain · doi:10.1093/brain/awac355 · Cited by 26 · see citing works
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Takahashi, Y., Ikoma, Y., & Matsui, K. (2026) · Communications Biology · doi:10.1038/s42003-026-10646-6 · Cited by 1 · see citing works
“Astrocytes may become acidi fi ed due to proton cotransport during glutamate reuptake, which could lead to reduced mitochondrial oxygen consumption within astrocytes 66 .”
- Authors
- Azarias, G., Perreten, H., Lengacher, S., Poburko, D., Demaurex, N., Magistretti, P. J., & Chatton, J.-Y.
- Affiliations
- University of Lausanne (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Geneva (CH)
- Corresponding author
- Chatton, Jean-Yves
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-03-09
- Volume
- 31
- Issue
- 10
- Pages
- 3550-3559
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6622778
- OpenAlex
- W2084578352
- Cited by
- 107
- References
- 48
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 9 · 2018: 14 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 11 · 2013: 8 · 2012: 12
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- IRIS (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (119827, 3100A0)
- Università di Bologna
- Università degli Studi di Ferrara
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glutamate uptake, astrocytes, mitochondrial pH, oxidative metabolism, intracellular sodium, excitatory neurotransmission, reactive oxygen species, astrocyte energy metabolism, calcium signaling
- MeSH terms
- Analysis of Variance, Animals, Astrocytes, Biological Transport, Cells, Cultured, Cerebral Cortex, Energy Metabolism, Hydrogen-Ion Concentration, Mitochondria, Neurons, Oxygen, Glutamic Acid, Amino Acid Transport System X-AG, Mice
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