Astrocyte‐Derived Nitric Oxide Causes Both Reversible and Irreversible Damage to the Neuronal Mitochondrial Respiratory Chain

• Published in: Journal of neurochemistry Vol. 75; no. 2; pp. 694 - 700
• Main Authors: Stewart, Victoria C, Sharpe, Martyn A, Clark, John B, Heales, Simon J R
• Format: Journal Article
• Language: English
• Published: Oxford UK Blackwell Science Ltd 01.08.2000; Blackwell
• Subjects: Animals; Animals, Newborn; Astrocyte; Astrocytes - cytology; Astrocytes - physiology; Biological and medical sciences; Cell Survival; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - physiology; Citrate (si)-Synthase - metabolism; Coculture; Coculture Techniques; Electron Transport Complex II; Electron Transport Complex III - metabolism; Electron Transport Complex IV - metabolism; Fundamental and applied biological sciences. Psychology; Isolated neuron and nerve. Neuroglia; Kinetics; Mitochondria - physiology; Mitochondrial respiratory chain; Multienzyme Complexes - metabolism; NADH Dehydrogenase - metabolism; Neuron; Neurons - cytology; Neurons - physiology; Nitrates - physiology; Nitric oxide; Nitric Oxide - physiology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Oxidants; Oxidoreductases - metabolism; Oxygen Consumption - physiology; Rats; Rats, Wistar; Reversibility; Succinate Dehydrogenase - metabolism; Vertebrates: nervous system and sense organs; Vertebrata; Respiratory chain; Mixed cell culture; Mitochondria; Mammalia; Neuron; Rat; Neuroglia; Nitric oxide; Rodentia; Astrocyte; In vitro
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2000.0750694.x

Cytokine‐stimulated astrocytes produce nitric oxide (NO), which, along with its metabolite peroxynitrite (ONOO‐), can inhibit components of the mitochondrial respiratory chain. We used astrocytes as a source of NO/ONOO‐ and monitored the effects on neurons in coculture. We previously demonstrated that astrocytic NO/ONOO‐ causes significant damage to the activities of complexes II/III and IV of neighbouring neurons after a 24‐h coculture. Under these conditions, no neuronal death was observed. Using polytetrafluoroethane filters, which are permeable to gases such as NO but impermeable to NO derivatives, we have now demonstrated that astrocyte‐derived NO is responsible for the damage observed in our coculture system. Expanding on these observations, we have now shown that 24 h after removal of NO‐producing astrocytes, neurons exhibit complete recovery of complex II/III and IV activities. Furthermore, extending the period of exposure of neurons to NO‐producing astrocytes does not cause further damage to the neuronal mitochondrial respiratory chain. However, whereas the activity of complex II/III recovers with time, 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 exposure to astrocytic‐derived NO for longer periods causes permanent damage to neuronal complex IV.