Institute of Functional Biology and Genomics (IBFG), Universidad de Salamanca, CSIC, Salamanca, Spain.
Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, Salamanca, Spain.
Nat Metab. 2019 Feb;1(2):201-211. doi: 10.1038/s42255-018-0031-6. Epub 2019 Feb 4.
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.
为了满足其高能量需求，大脑依赖于各种细胞类型的代谢合作。例如，星形胶质细胞衍生的乳酸通过作为神经元的可氧化能量底物和信号分子来维持记忆巩固。星形胶质细胞和神经元在糖酵解酶的调节和线粒体呼吸链的组织方面也存在差异。与神经元不同，星形胶质细胞依赖糖酵解产生能量，因此，其线粒体呼吸链组装松散，与更高水平的线粒体活性氧（ROS）产生相关。然而，星形胶质细胞中这种丰富的线粒体 ROS 是否具有特定的生理作用尚不清楚。在这里，我们表明星形胶质细胞的线粒体 ROS 是大脑代谢和神经元功能的生理调节剂。我们生成了在星形胶质细胞中可诱导过表达线粒体标记的过氧化氢酶的小鼠，并表明这种过表达在成年期降低了这些细胞中线粒体 ROS 的产生。对这些小鼠的转录组、代谢组、生化、免疫组织化学和行为分析显示，与神经元功能和小鼠行为改变相关的大脑氧化还原、碳水化合物、脂质和氨基酸代谢途径发生了改变。我们发现星形胶质细胞的线粒体 ROS 通过戊糖磷酸途径和谷胱甘肽代谢调节葡萄糖利用，从而调节神经元的氧化还原状态和潜在存活。我们的数据为星形胶质细胞和神经元之间的代谢合作提供了进一步的分子见解，并表明线粒体 ROS 是体内生物体生理学的重要调节剂。
