Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
1-Methyl-4-phenylpyridinium / pharmacology
-
Adenine Nucleotides / metabolism
-
Benzothiazoles
-
Electron Transport
-
Enzyme Activation / drug effects
-
Free Radical Scavengers / pharmacology
-
Herbicides / pharmacology
-
Humans
-
JNK Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase Kinase 1*
-
Mitochondria / enzymology*
-
Mitogen-Activated Protein Kinases / metabolism
-
NF-kappa B / antagonists & inhibitors
-
NF-kappa B / metabolism*
-
Neuroblastoma
-
Neurons / chemistry
-
Neurons / cytology
-
Neurons / enzymology*
-
Oxidative Stress / physiology
-
Parkinson Disease / metabolism*
-
Peptides / pharmacology
-
Pramipexole
-
Protein Serine-Threonine Kinases / analysis
-
Protein Serine-Threonine Kinases / metabolism*
-
Proto-Oncogene Proteins c-raf / analysis
-
Proto-Oncogene Proteins c-raf / metabolism
-
Signal Transduction / drug effects
-
Signal Transduction / physiology
-
Superoxide Dismutase / metabolism
-
Thiazoles / pharmacology
-
Tumor Cells, Cultured
Substances
-
Adenine Nucleotides
-
Benzothiazoles
-
Free Radical Scavengers
-
Herbicides
-
NF-kappa B
-
Peptides
-
SN50 peptide
-
Thiazoles
-
Pramipexole
-
Superoxide Dismutase
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-raf
-
JNK Mitogen-Activated Protein Kinases
-
Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase Kinase 1
-
MAP3K1 protein, human
-
1-Methyl-4-phenylpyridinium