KAUST Research Workshop on Innovative Technologies to Study Brain Energy Metabolism
University of Geneva, Switzerland
Jean-Claude Martinou, MD, PhD, is Professor and Director of the Cell Biology Department at the University of Geneva. He leads a research team internationally recognised for its work on the role of mitochondria in apoptosis and on the role of the process of mitochondrial fusion and fission in cell homeostasis.
Jean-Claude Martinou, Department of Cell Biology, University of Geneva. 1211 Geneva, Switzerland.Tight coupling of neuronal activity to energy metabolism is essential for normal brain function. To investigate the mechanisms underlying this coupling, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the mitochondrial pyruvate carrier, specifically in glutamatergic neurons. Loss of pyruvate-driven ATP generation, the major source of energy in neurons, induced dramatic hypersensitivity to pro-convulsant agents, PTZ and kainic acid due to an intrinsic hyperexcitability of the MPC-deficient neurons. From transcript profiling experiments we identified SUR1 and Kir6.2 mRNAs, which encode components of KATP channels, which were upregulated in MPC-deficient neurons. Patch clamp recordings showed that KATP channel closure accounts for the hyperexcitability of MPC-deficient neurons, and that a KATP channel opener reduced the intrinsic hyperexcitability of these neurons. In vivo, KATP channel opening suppressed PTZ-induced seizures in the KO mice, whereas in wild type mice, closure of the KATP channels led to increased sensitivity to PTZ. Our data identify KATP channels as critical mediators in the metabolic control of neuronal function, and suggest that upregulation and increased activity of these channels could explain neuronal hyperexcitability which frequently accompanies neuropathologies due to metabolic dysfunction.