ArticleeLife2022
Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 35 citations in OpenAlex.
- Brain mitochondria as key drivers of cognition and behaviour.Nature reviews. Neuroscience · 2026Review
- SGK1 inhibition restores excitability of cortical neurons derived from Alzheimer's disease patients.Neurobiology of disease · 2026Article
- Mitochondrial CaBiomolecules · 2026Review
- Article
- Providing alternative fuel for the brain in anorexia nervosa: a review of the literature on ketones and their effects on metabolism and the brain.Translational psychiatry · 2025Review
- Two-point calibration protocol for the Förster Resonance Energy Transfer indicator Pyronic in neurons.Neurophotonics · 2025Article
- Alzheimer's disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication.Molecular neurodegeneration · 2025Article
- Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.Science advances · 2024Article
- Serotonin effects on human iPSC-derived neural cell functions: from mitochondria to depression.Molecular psychiatry · 2024Article
- Alzheimer's disease protective allele ofmedRxiv : the preprint server for health sciences · 2024Article
- Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.bioRxiv : the preprint server for biology · 2024Article
- Glucose-derived glutamate drives neuronal terminal differentiation in vitro.EMBO reports · 2024Article
- Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease.International journal of molecular sciences · 2024Article
- Ketogenic diet and behavior: insights from experimental studies.Frontiers in nutrition · 2024Review
- Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants.Human molecular genetics · 2023Article
- Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants.bioRxiv : the preprint server for biology · 2023Article
- Informing the Cannabis Conjecture: From Life's Beginnings to Mitochondria, Membranes and the Electrome-A Review.International journal of molecular sciences · 2023Review
- Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition.Acta physiologica (Oxford, England) · 2023Review
- Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells.Science advances · 2023Article
- The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease.Biomolecules · 2023Review
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.