Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

To satisfy its high energetic demand1, the brain depends on the metabolic cooperation of various cell types2–4. For example, astrocytic-derived lactate sustains memory consolidation5 by serving both as an oxidizable energetic substrate for neurons6 and as a signalling molecule7,8. Astrocytesand neurons also differ in the regulation of glycolytic enzymes9 and in the organization of their mitochondrial respiratory chain10. Unlike neurons, astrocytesrely 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 ROSin astrocytesfulfils a specific physiological role is unknown. Here we show that astrocytic mitochondrial ROSare physiological regulators of brain metabolism and neuronal function. We generated mice that inducibly overexpress mitochondrial-tagged catalase in astrocytesand show that this overexpression decreases mitochondrial ROSproduction in these cells during adulthood. Transcriptomic, metabolomic, biochemical, immunohistochemical and behavioural analysisof 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 ROSregulate glucose utilization via the pentose-phosphate pathwayand glutathione metabolism, which modulates the redox status and potentially the survival of neurons. Our data provide further molecular insight into the metabolic cooperation between astrocytesand neurons and demonstrate that mitochondrial ROSare important regulators of organismal physiology in vivo.