Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency
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Abstract
Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.
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Mpc1 deletion leads to complete inhibition of the MPC.
“leading to the deletion of Mpc1, which has previously been reported to lead to complete inhibition of the MPC (De La Rossa et al., 2022; Petrelli et al., 2023a)”
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 De La Rossa et al., 2022
The Introduction describes deletion of Mpc1 in adult excitatory neurons as inactivating the MPC. However, the Results section on inducible MPC1 deletion reports a significant decrease in MPC1 and MPC2 protein levels, not a measurement demonstrating complete inhibition of MPC activity. The claim’s absolute qualifier is therefore not established by this paper’s reported results. (LLM, conf=0.83)
Experimental — accuracy not yet measuredGenetic inhibition of the MPC in glutamatergic neurons renders them hyperexcitable.
“Genetic inhibition of the MPC in glutamatergic neurons renders them hyperexcitable (De La Rossa et al., 2022).”
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 De La Rossa et al., 2022
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Cites
Exosomes are released by cultured cortical neurones
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Self-citationNeuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake
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“neurons is produced in mitochondria through pyruvate-mediated oxidative phosphorylation 58 (OXPHOS), even though aerobic glycolysis, or the so-called Warburg effect, can generate 59 sufficient ATP to sustain several neuronal functions, including neuronal firing(3-7).”
BackgroundAerobic glycolysis in the human brain is associated with development and neotenous gene expression
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“3 Introduction 55 The brain is by far the main consumer of glucose and oxygen in the body, with pre- and post56 synaptic mechanisms being the primary sites of ATP consumption(1-3).”
BackgroundThiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier
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Cited by
Sorted by citations
Ceyzériat, K., Badina, A. M., Petrelli, F., Montessuit, S., Nicolaides, A., Millet, P., Savioz, A., Martinou, J.-C., & Tournier, B. B. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106623 · Cited by 18 · see citing works
Self-citation
- Authors
- De La Rossa, A., Laporte, M. H., Astori, S., Marissal, T., Montessuit, S., Sheshadri, P., Ramos-Fernández, E., Mendez, P., Khani, A., Quairiaux, C., Taylor, E. B., Rutter, J., Nunes, J. M., Carleton, A., Duchen, M. R., Sandi, C., & Martinou, J.-C.
- Affiliations
- Department of Cell Biology, University of Geneva
- University of Geneva (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University College London (GB)
- Laboratory of Behavioral Genetics, Ecole Polytechnique Fédérale de Lausanne
- Cajal Institute
- University of Iowa (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sandi, Carmen
- Martinou, Jean-Claude
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-02-21
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8860443
- OpenAlex
- W4220823537
- Cited by
- 38
- References
- 6
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 8 · 2023: 8 · 2022: 6
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- Ministerio de Economía, Industria y Competitividad, Gobierno de España (BFU2017-84490-P)
- Swiss National Science Foundation (31003A_179421/1 /1)
- Kristian Gerhard Jebsen Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Keywords
- mitochondrial pyruvate carrier, neuronal hyperexcitability, seizures, oxidative phosphorylation, glutamatergic neurons, calcium homeostasis, M-type potassium channels, ketone bodies, ketogenic diet, mitochondrial membrane potential, mitochondrial disease, cerebral ischemia
- MeSH terms
- Animals, Biological Transport, Calcium, Gene Expression Regulation, Homeostasis, Ketone Bodies, Mitochondria, Neurons, Oxidation-Reduction, Pentylenetetrazole, Phosphorylation, Seizures, Tamoxifen, Mice, Knockout, Pyruvic Acid, 3-Hydroxybutyric Acid, Anion Transport Proteins, Monocarboxylic Acid Transporters, Mitochondrial Membrane Transport Proteins, Mice
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