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Interaction among mitochondria, mitogen-activated protein kinases, and nuclear factor-kappaB in cellular models of
D S Cassarino1, E M Halvorsen, R H Swerdlow
1Center for the Study of Neurodegenerative Diseases, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Abstract:
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.
Insights
Oxidative stress activates stress-activated c-Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB) pathways in neuroblastoma cells. Targeting these pathways may offer neuroprotection for Parkinson's disease.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Oxidative stress is implicated in neurodegenerative diseases like Parkinson's disease (PD).
- Mitochondrial dysfunction plays a key role in the pathogenesis of PD.
- Stress-activated signaling pathways are critical in cellular responses to stress.
Purpose of the Study:
- To investigate the biphasic activation of stress-activated c-Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB) in response to complex I inhibition.
- To elucidate the role of mitochondrial adenine nucleotide translocator (ANT) and electron transport chain (ETC) in these signaling pathways.
- To explore the potential of targeting these pathways for neuroprotection in PD.
Main Methods:
- Utilized SH-SY5Y neuroblastoma cells and Parkinson's disease (PD) cybrid cells.
- Induced oxidative stress using 1-methyl-4-phenylpyridinium ion (MPP+), a complex I inhibitor.
- Assessed the activation of JNK, NF-kappaB, Raf-1, and MEKK-1 using biochemical assays.
Main Results:
- Biphasic activation of JNK and NF-kappaB was observed.
- Early JNK activation was ANT-dependent, while late-phase activation was ANT-independent.
- NF-kappaB activation showed differential dependence on MEK and ETC integrity.
- PD cybrid cells exhibited increased basal NF-kappaB activation.
- Loss of Raf-1 and MEKK-1 cleavage/activation were linked to apoptosis.
Conclusions:
- Mitochondria signal ETC impairment through MAPK pathways, inducing protective NF-kappaB responses.
- PD mitochondrial genes can amplify these protective responses.
- Therapeutic strategies targeting JNK and NF-kappaB may offer neuroprotection in PD.