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

Oxidative stress induced by acute complex I inhibition with 1-methyl-4-phen ylpyridinium ion activated biphasically the stress-activated c-Jun N-termin al kinase (JNK) and the early transcription factor nuclear factor-kappa B ( NF-kappa B) in SH-SY5Y neuroblastoma cells. Early JNK activation was depend ent on mitochondrial adenine nucleotide translocator (ANT) activity, wherea s late-phase JNK activation and the cleavage of signaling proteins Raf-1 an d mitogen-activated protein kinase (MAPK) kinase (MEK) kinase (MEKK)-1 appe ared to be ANT-independent. Early NF-kappa B activation depended on MEK, la ter activation required an intact electron transport chain (ETC), and Parki nson's disease (PD) cybrid (mitochondrial transgenic cytoplasmic hybrid) ce lls 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 m ay derive from loss of Raf-1 and cleavage/activation of MEKK-1, processes r eported in other models to be caspase-mediated. Therapeutic strategies that reduce mitochondrial activation of proapoptotic MAPK modules, i.e., JNK, a nd enhance survival pathways, i.e., NF-kappa B, may offer neuroprotection i n this debilitating disease.