Journal article
Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency
eLife, Vol.11, e72595
02/21/2022
DOI: 10.7554/eLife.72595.sa2
PMCID: PMC8860443
PMID: 35188099
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.
Details
- Title: Subtitle
- Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency
- Creators
- Andres De la Rossa - University of GenevaMarine H. Laporte - University of GenevaSimone Astori - École Polytechnique Fédérale de LausanneThomas Marissal - University of GenevaSylvie Montessuit - University of GenevaPreethi Sheshadri - University College LondonEva Ramos-Fernandez - École Polytechnique Fédérale de LausannePablo Mendez - Cajal InstituteAbbas Khani - University of GenevaCharles Quairiaux - University of GenevaEric B. Taylor - Fraternal Order of EaglesJared Rutter - Howard Hughes Medical InstituteJose Manuel Nunes - University of GenevaAlan Carleton - University of GenevaMichael R. Duchen - University College LondonCarmen Sandi - École Polytechnique Fédérale de LausanneJean-Claude Martinou - University of Geneva
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.11, e72595
- DOI
- 10.7554/eLife.72595.sa2
- PMID
- 35188099
- PMCID
- PMC8860443
- NLM abbreviation
- Elife
- ISSN
- 2050-084X
- eISSN
- 2050-084X
- Publisher
- eLIFE SCIENCES PUBL LTD
- Number of pages
- 30
- Grant note
- BFU2017-84490-P / Ministerio de Economia, Industria y Competitividad, Gobierno de Espana; Spanish Government 31003A_179421/1/1 / Swiss National Science Foundation; Swiss National Science Foundation (SNSF); European Commission Stiftelsen Kristian Gerhard Jebsen
- Language
- English
- Date published
- 02/21/2022
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984297512102771
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