Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Andres de La Rossa (1, 1) , Marine Laporte (1, 1) , Simone Astori (2) , Thomas Marissal (3, 1) , Sylvie Montessuit (1, 1) , Preethi Sheshadri (4) , Eva Ramos-Fernández (2) , Pablo Mendez (5) , Abbas Khani (1) , Charles Quairiaux (1) , Eric Taylor (6) , Jared Rutter (7) , José Manuel Nunes (1) , Alan Carleton (1) , Michael Duchen (4) , Carmen Sandi (2) , Jean-Claude Martinou (1, 1)

1 UNIGE - Université de Genève = University of Geneva
2 EPFL - Ecole Polytechnique Fédérale de Lausanne
3 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
4 UCL - University College of London [London]
5 IRYCIS - Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain]
6 Carver College of Medicine [Iowa City]
7 Howard Hughes Medical Institute and Department of Chemistry and Biochemistry

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.

Domaines: Neurosciences [q-bio.NC]

Andres de La Rossa, Marine Laporte, Simone Astori, Thomas Marissal, Sylvie Montessuit, et al.. Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency. eLife, 2022, 11, ⟨10.7554/eLife.72595⟩. ⟨hal-03653817⟩