Interaction Among Mitochondria, Mitogen‐Activated Protein Kinases, and Nuclear Factor‐κB in Cellular Models of Parkinson's Disease

• Published in: Journal of neurochemistry 2000-04, Vol.74 (4), p.1384-1392
• Main Authors: Cassarino, David S., Halvorsen, Erik M., Swerdlow, Russell H., Abramova, Nicole N., Parker, W. Davis, Sturgill, Thomas W., Bennett, James P.
• Format: Article
• Language: English
• Subjects: Adenine nucleotide translocator; Biological and medical sciences; c‐Jun terminal kinase; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Electron transport chain; Medical sciences; Mitochondria; Mitogenactivated protein kinases; Neurology; Nuclear factor‐κB; Oxidative stress; Parkinson's disease; Stress‐activated protein kinase
• ISSN: 0022-3042; 1471-4159
• 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‐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.