Protective role of MnSOD and redox regulation of neuronal cell survival.
Reactive oxygen species (ROS) play a central role in neuronal pathophysiology and in neurodegenerative disorders. However, recent evidence indicates that these molecules also operate as signaling intermediates in a variety of physiological settings, including cell protection from apoptosis. Data presented here strongly support such a dual role for oxidants in neuronal cell homeostasis. In rat pheocromocytoma cells, cell rescue by the nerve growth factor (NGF) is accompanied by a transient burst of ROS generated in the cytosol by a GTPase-dependent mechanism. Within the NGF signaling cascade, ROS lie upstream and are necessary for activation/phosphorylation of AKT/PKB and of the antiapoptotic transcription factor cAMP-responsive element-binding protein (CREB). Conversely, an increase in mitochondrial oxygen species heralds apoptosis of serum-deprived cells, and these events can be prevented by cell exposure to NGF or by treatment with the mitochondrially targeted antioxidant MitoQ. Importantly, NGF-mediated decrease of mitochondrial ROS is dependent on the transcriptional up-regulation of the manganese superoxide dismutase (MnSOD) by active CREB. These observations therefore outline a circuitry whereby cytosolic redox signaling promotes neuronal cell survival by increasing the mitochondrial antioxidant defenses.
Galeotti
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T
Institute of General Pathology and Institute of Pharmacology, Catholic University Medical School, Rome, Italy. tgaleotti@rm.unicatt.it
Pani
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Capone
C
C
Bedogni
B
B
Borrello
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S
Mancuso
C
C
Eboli
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ML
D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010673:Pheochromocytoma; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D017362:Cyclic AMP Response Element-Binding Protein; D017382:Reactive Oxygen Species; D020932:Nerve Growth Factor; D013482:Superoxide Dismutase