Interaction among mitochondria, mitogen-activated protein kinases, and nuclear factor-kappaB in cellular models of Parkinson's disease

J Neurochem. 2000 Apr;74(4):1384-92. doi: 10.1046/j.1471-4159.2000.0741384.x.


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


  • 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