Disrupted mitochondrial electron transport function increases expression of anti-apoptotic bcl-2 and bcl-X-L proteins in SH-SY5Y neuroblastoma and inParkinson disease cybrid cells through oxidative stress

Death of dopamine neurons in Parkinson disease (PD) may arise from conseque nces of the complex I (C-l) defect in the mitochondrial electron transport chain (ETC). Whether cells activate programmed death (apoptosis) pathways d erives, in part, from relative activities of proteins such as bcl-2 and bcl -X-L, that have anti-apoptotic actions. We studied the responses of bcl-2 a nd bcl-X, genes in pharmacologic (acute incubation with methylpyridinium (M PP+)) and mitochondrial transgenic ("cybrid") models of Parkinson disease C -l defects. MPP+ incubation increased levels of bcl-2 acid bcl-X, proteins in native SH-SY5Y cells but not in rho(0) cells devoid of ETC activity. MPP + increased bcl-2 mRNA levels by 40% at 8 hr, Confocal microscopic imaging showed that the intracellular distribution of immunoreactive bcl-2 was not significantly associated with mitochondrial membranes at baseline but was a ssociated with mitochondria after 12 hr of MPP+, Immunoreactive bcl-X, prot ein was significantly and equally associated with mitochondrial membranes b oth at baseline and after MPP+, PD cybrids showed increased basal levels of bcl-2 and bcl-X-L proteins, similar to the maximum levels found after MPP treatment of control SY5Y cells, After MPP+ exposure, bcl-2 protein levels increased in control cybrids but did not increase further in PD cybrids. B oth pharmacologically generated and transgenically induced C-I inhibition i ncreases levels of anti-apoptotic bcl proteins, possibly from increased gen e transcription. Augmentation of bcl-2 and bcl-X, expression may delay neur odegeneration in PD, (C) 2000 Wiley-Liss, Inc.