Disrupted mitochondrial electron transport function increases expression of anti-apoptotic bcl-2 and bcl-X(L) proteins in SH-SY5Y neuroblastoma and in Parkinson disease cybrid cells through oxidative stress.
Death of dopamine neurons in Parkinson disease (PD) may arise from consequences of the complex I (C-I) defect in the mitochondrial electron transport chain (ETC). Whether cells activate programmed death (apoptosis) pathways derives, 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 and bcl-X(L) genes in pharmacologic (acute incubation with methylpyridinium (MPP+)) and mitochondrial transgenic ("cybrid") models of Parkinson disease C-I defects. MPP+ incubation increased levels of bcl-2 and bcl-X(L) 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 associated with mitochondria after 12 hr of MPP+. Immunoreactive bcl-X(L) protein was significantly and equally associated with mitochondrial membranes both 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. Both pharmacologically generated and transgenically induced C-I inhibition increases levels of anti-apoptotic bcl proteins, possibly from increased gene transcription. Augmentation of bcl-2 and bcl-X(L) expression may delay neurodegeneration in PD.
Veech
G A
GA
Center for the Study of Neurodegenerative Diseases, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.
Dennis
J
J
Keeney
P M
PM
Fall
C P
CP
Swerdlow
R H
RH
Parker
W D
WD
Bennett
J P
JP
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D006822:Hybrid Cells; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000502:physiology*; D009447:Neuroblastoma; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004272:DNA, Mitochondrial; D006540:Herbicides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D015655:1-Methyl-4-phenylpyridinium