Interaction among mitochondria, mitogen-activated protein kinases, and nuclear factor-kappaB in cellular models of Parkinson's disease.
Oxidative stress induced by acute complex I inhibition with 1-methyl-4-phenylpyridinium ion activated biphasically the stress-activated c-Jun N-terminal kinase (JNK) and the early transcription factor nuclear factor-kappaB (NF-kappaB) in SH-SY5Y neuroblastoma cells. Early JNK activation was dependent on mitochondrial adenine nucleotide translocator (ANT) activity, whereas late-phase JNK activation and the cleavage of signaling proteins Raf-1 and mitogen-activated protein kinase (MAPK) kinase (MEK) kinase (MEKK)-1 appeared to be ANT-independent. Early NF-kappaB activation depended on MEK, later activation required an intact electron transport chain (ETC), and Parkinson's disease (PD) cybrid (mitochondrial transgenic cytoplasmic hybrid) cells had increased basal NF-kappaB activation. Mitochondria appear capable of signaling ETC impairment through MAPK modules and inducing protective NF-kappaB responses, which are increased by PD mitochondrial genes amplified in cybrid cells. Irreversible commitment to apoptosis in this cell model may derive from loss of Raf-1 and cleavage/activation of MEKK-1, processes reported in other models to be caspase-mediated. Therapeutic strategies that reduce mitochondrial activation of proapoptotic MAPK modules, i.e., JNK, and enhance survival pathways, i.e., NF-kappaB, may offer neuroprotection in this debilitating disease.
Cassarino
D S
DS
Center for the Study of Neurodegenerative Diseases, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Halvorsen
E M
EM
Swerdlow
R H
RH
Abramova
N N
NN
Parker
W D
WD
Sturgill
T W
TW
Bennett
J P
JP
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000227:Adenine Nucleotides / Q000378:metabolism; D052160:Benzothiazoles; D004579:Electron Transport; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D008928:Mitochondria / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009447:Neuroblastoma; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D000077487:Pramipexole; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D052160:Benzothiazoles; D016166:Free Radical Scavengers; D006540:Herbicides; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D013844:Thiazoles; D000077487:Pramipexole; D013482:Superoxide Dismutase; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D015655:1-Methyl-4-phenylpyridinium