Authors

Carlos Vicente-Gutierrez, Nicoló Bonora, Veronica Bobo-Jimenez, Daniel Jimenez-Blasco, Irene Lopez-Fabuel, Emilio Fernandez, Charlene Josephine,Gilles Bonvento, Jose A. Enriquez, Angeles Almeida and Juan P. Bolaños.

Abstract

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable energetic substrate for neurons and as a signalling molecule. Astrocytes and neurons also differ in the regulation of glycolytic enzymes and in the organization of their mitochondrial respiratory chain. Unlike neurons, astrocytes rely on glycolysis for energy generation and, as a consequence, have a loosely assembled mitochondrial respiratory chain that is associated with a higher generation of mitochondrial reactive oxygen species (ROS). However, whether this abundant natural source of mitochondrial ROS in astrocytes fulfils a specific physiological role is unknown. Here we show that astrocytic mitochondrial ROS are physiological regulators of brain metabolism and neuronal function. We generated mice that inducibly overexpress mitochondrial tagged catalase in astrocytes and show that this overexpression decreases mitochondrial ROS production in these cells during adulthood. Transcriptomic, metabolomic, biochemical, immunohistochemical and behavioural analysis of these mice revealed alterations in brain redox, carbohydrate, lipid and amino acid metabolic pathways associated with altered neuronal function and mouse behaviour. We found that astrocytic mitochondrial ROS regulate glucose utilization via the pentose-phosphate pathway and glutathione metabolism, which modulates the redox status and potentially the survival of neurons. Our data provide further molecular insight into the metabolic cooperation between astrocytes and neurons and demonstrate that mitochondrial ROS are important regulators of organismal physiology in vivo.

Description

La generación mitocondrial de especies reactivas de oxígeno (ROS) en el cerebro es mucho menor en las neuronas que en los astrocitos. Nuestro trabajo pone de manifiesto la relevancia de los ROS mitocondriales astrocíticos en la coordinación del metabolismo y el estado redox cerebral, así como en la regulación de funciones superiores como la conducta animal. Estos resultados contribuyen a la consideración de nuevos factores que deberán tenerse en cuenta en la búsqueda de nuevas estrategias terapéuticas basadas en el uso de sistemas antioxidantes, como son el origen celular y el papel fisiológico de los ROS en el sistema nervioso central.

 

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REFERENCIA DEL GRUPO INVESTIGADOR

Nuestro laboratorio está interesado en comprender los mecanismos moleculares que regulan la homeostasis energética y redox en las células del sistema nervioso central. Para ello, estudiamos cultivos primarios de neuronas y astrocitos murinas, además de modelos de ratón modificados genéticamente. En particular, nos interesa investigar las proteínas y las vías de señalización diferenciales entre astrocitos y neuronas, que son responsables de la adaptación del metabolismo neural a la continua y elevada demanda energética y antioxidante impuesta por la neurotransmisión.

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