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Interaction Among Mitochondria, Mitogen‐Activated Protein Kinases, and Nuclear Factor‐κB in Cellular Models of Parkinson's Disease
Author(s) -
Cassarino David S.,
Halvorsen Erik M.,
Swerdlow Russell H.,
Abramova Nicole N.,
Parker W. Davis,
Sturgill Thomas W.,
Bennett James P.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0741384.x
Subject(s) - microbiology and biotechnology , mapk/erk pathway , kinase , mitochondrion , protein kinase a , ask1 , biology , transcription factor , map kinase kinase kinase , c jun , mitogen activated protein kinase , mitogen activated protein kinase kinase , chemistry , biochemistry , gene
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‐κB (NF‐κB) 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‐κB 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‐κB activation. Mitochondria appear capable of signaling ETC impairment through MAPK modules and inducing protective NF‐κB 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‐κB, may offer neuroprotection in this debilitating disease.