MITOCHONDRIAL FREE-RADICAL SIGNAL IN CERAMIDE-DEPENDENT APOPTOSIS - APUTATIVE MECHANISM FOR NEURONAL DEATH IN PARKINSONS-DISEASE

Activation of the apoptogenic sphingomyelin-dependent signaling pathwa y in neuronally differentiated PC12 cells with cell-permeant C-2-ceram ide resulted in a transient and short-lived emission of reactive oxyge n species that was maximal 6 h after the beginning of treatment, follo wed immediately by nuclear translocation of the transcription factor n uclear factor kappa B. The production of reactive oxygen species was n ecessary for cell death to occur. The origin of the reactive oxygen sp ecies was identified as complex I of the mitochondrial electron transp ort chain. The mitochondria were not dysfunctional, however. They main tained normal membrane potentials and ATP synthesis until the cells be gan to die and the cell nuclei to condense and to fragment, similar to 12 h after the beginning of treatment. We conclude that a mitochondri al free radical signal plays a role in the sphingomyelin-dependent tra nsduction pathway. Convergent data from postmortem brain suggest that this signaling pathway may be activated in the dopaminergic neurons th at die in patients with Parkinson's disease and would provide a mechan ism for oxidative stress implicating the mitochondria, both of which h ave long been hypothesized to play a role in the pathogenesis of this disease.