Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

Abstract

To satisfy its high energetic demand¹, the brain depends on the metabolic cooperation of various cell types^2-4. For example, astrocytic-derived lactate sustains memory consolidation⁵ by serving both as an oxidizable energetic substrate for neurons⁶ and as a signalling molecule^7,8. Astrocytes and neurons also differ in the regulation of glycolytic enzymes⁹ and in the organization of their mitochondrial respiratory chain¹⁰. Unlike neurons, astrocytes rely on glycolysis for energy generation⁹ and, as a consequence, have a loosely assembled mitochondrial respiratory chain that is associated with a higher generation of mitochondrial reactive oxygen species (ROS)¹⁰. 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.