Proteomics analysis of mitochondrial dysfunction triggered by complex specific electron transport chain inhibitors reveals common pathways involving protein misfolding in an SH-SY5Y in vitro cell model

Authors : Betül ŞAHİN, Ahmet Tarik BAYKAL

Pages : 765-784

View : 16 | Download : 8

Publication Date : 2017-12-01

Article Type : Research Paper

Abstract :Mitochondrial dysfunction has been previously identified in neurodegenerative diseases such as Alzheimer disease, Huntington disease, and Parkinson disease. Chemical inhibition of the mitochondrial electron transport chain insert ignore into journalissuearticles values(ETC); was shown to trigger symptoms in animal models similar to those observed in human neurodegenerative diseases. In order to understand the effect of mitochondrial dysfunction on the proteome level, LC-MSE-based bottom-up, label-free differential proteomics expression analysis was used to monitor protein level changes in SH-SY5Y neuroblastoma cells induced by ETC-specific inhibitors insert ignore into journalissuearticles values(MPTP, 3-NP, sodium azide, antimycin A, and oligomycin);. A total of 379 proteins were identified across the sample set and 75 of them were found to be differentially expressed insert ignore into journalissuearticles values(>30% fold change);. Complex-specific inhibition of the five ETS complexes were expected to result in the aberrant regulation of different molecular pathways, but the bioinformatics analysis of the LC-MSMS data showed that the differentially expressed proteins were mostly involved in similar metabolic processes. The findings suggest that the complex-specific alterations may not be directly linked to neurodegenerative pathways, but could be considered contributors. Moreover, the proteins that showed the highest protein expression difference insert ignore into journalissuearticles values(>60% fold change); are involved in pathways regarding protein-folding and response to unfolded proteins. The results indicate that protein misfolding pathways might have a central role in the genesis and progression of neurodegenerative diseases and that label-free LC-MSMS proteomics analysis is an invaluable approach for studying of molecular pathways in neurodegeneration.
Keywords : NanoUPLC ESI qTOF, shotgun proteomics, mitochondrial dysfunction, neurodegeneration, protein expression, ETC complex inhibition