Glutamate toxicity mediated by mitochondria

Glutamate is an amino acid that is used in cells for the biosynthesis of proteins and for the generation of energy in the form of adenosine triphosphate (ATP). ATP is synthetized from glutamate in mitochondria, a subcellular organelle specialized for energy production using oxygen. In the nervous system, glutamate additionally plays an important role as an excitatory neurotransmitter necessary to conduct nerve impulses from one neuron to the other. Nerve impulses trigger the release of glutamate from the presynaptic cell into the synaptic cleft, then glutamate reacts with the glutamate receptors on the postsynaptic cell and activates it. After activation, glutamate must be quickly removed back into the cells. If its concentration remains high, this causes the overwhelmed activation of postsynaptic neurons, which exhausts these neurons causing their degradation. This process, called excitotoxicity, occurs in neurodegenerative diseases and after neuronal injury following traumatic brain injury. Preliminary data obtained in the Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA research center show that the elevated glutamate concentrations which are responsible for the excitotoxic effects are due to a defect in mitochondria. This defect prevents the consumption of glutamate for energetic purposes. The latter destabilizes glutamate metabolism causing excitotoxicity and neuronal death. The aim of this project is to identify the defect(s) in mitochondria destabilizing glutamate metabolism and to develop a pharmacological strategy able to ameliorate mitochondria-dependent glutamate toxicity and neuronal death.