期刊
JOURNAL OF NEUROCHEMISTRY
卷 74, 期 4, 页码 1384-1392出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1046/j.1471-4159.2000.0741384.x
关键词
oxidative stress; mitochondria; mitogen-activated protein kinases; nuclear factor-kappa B; Parkinson's disease; stress-activated protein kinase; c-Jun terminal kinase; electron transport chain; adenine nucleotide translocator
资金
- NIA NIH HHS [AG14373] Funding Source: Medline
- NIGMS NIH HHS [2T32GM07055-21] Funding Source: Medline
- NINDS NIH HHS [NS35325] Funding Source: Medline
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-kappa B (NF-kappa B) 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-kappa B 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-kappa B activation. Mitochondria appear capable of signaling ETC impairment through MAPK modules and inducing protective NF-kappa B 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-kappa B, may offer neuroprotection in this debilitating disease.
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