Astrocyte-derived nitric oxide causes both reversible and irreversible damage to the neuronal mitochondrial respiratory chain

Cytokine-stimulated astrocytes produce nitric oxide (NO), which, along with its metabolite peroxynitrite (ONOO-), can inhibit components of the mitoch ondrial respiratory chain. We used astrocytes as a source of NO/ONOO- and m onitored the effects on neurons in coculture. We previously demonstrated th at astrocytic NO/ONOO- causes significant damage to the activities of compl exes II/III and IV of neighbouring neurons after a 24-h coculture. Under th ese conditions, no neuronal death was observed. Using polytetrafluoroethane filters, which are permeable to gases such as NO but impermeable to NO der ivatives, we have now demonstrated that astrocyte-derived NO is responsible for the damage observed in our coculture system. Expanding on these observ ations, we have now shown that 24 h after removal of NO-producing astrocyte s, neurons exhibit complete recovery of complex II/III and IV activities. F urthermore, extending the period of exposure of neurons to NO-producing ast rocytes does not cause further damage to the neuronal mitochondrial respira tory chain. However, whereas the activity of complex II/III recovers with t ime, the damage to complex IV caused by a 48-h coculture with NO-producing astrocytes is irreversible. Therefore, it appears that neurons can recover from short-term damage to mitochondrial complex II/III and IV, whereas expo sure to astrocytic-derived NO for longer periods causes permanent damage to neuronal complex IV.