Graphical abstract. Macrophages are attracted by CCL2 and infiltrate the brain, phagocytose myelin and produce high amounts of ROS and TNF-α and IFN-γ. This will lead to mitochondrial stress, resulting in more mitochondrial ROS production contributing to axonal degeneration. Increased amounts of ROS induce astrocytic PGC-1α, which increases mitochondrial antioxidant capacity via upregulation of Prx3 and Trx2. Increased expression of PGC-1α, Prx3 or Trx2 protects astrocytes and surrounding neurons not only from mitochondrial stress but also against exogenous ROS. Interestingly, PGC-1α can reduce CCL2 and IL-6 production and TNF-α/IFN-γ induced ROS production, thereby dampening inflammation. Thus increased astrocytic PGC-1alpha can reduce ROS and inflammation in MS lesions which protects surrounding axons and neurons.