Reactive oxygen species (ROS) are implicated in the modulation of diverse processes including glial activation. To evaluate the effects of metabolic ROS produced by mitochondria on astrocyte activation, we created transgenic mice expressing a phosphorylation-defective mutant of succinate dehydrogenase A in astrocytes (aSDHA^Y215F). Astrocytes in substantia nigra of in male aSDHA^Y215F mice produced three times more ROS than those in control mice, and increased the levels of GFAP expression. On the other hands, the number of TH-positive neurons was significantly reduced. We identified several novel secretion factors from the aSDHA^Y215F mice as an inducer of neuronal apoptosis. These results suggest that mitochondrial ROS may regulate dopaminergic neuronal death in substantia nigra through modulation of astrocyte activation. Exact molecular targets for mitochondrial ROS will be discussed.