Abstract
BackgroundMany studies have shown that mitochondrial dysfunction, complex I inhibition in particular, is involved in the pathogenesis of Parkinson's disease (PD). Rotenone, a specific inhibitor of mitochondrial complex I, has been shown to produce neurodegeneration in rats as well as in many cellular models that closely resemble PD. However, the mechanisms through which complex I dysfunction might produce neurotoxicity are as yet unknown. A comprehensive analysis of the mitochondrial protein expression profile affected by rotenone can provide important insight into the role of mitochondrial dysfunction in PD.ResultsHere, we present our findings using a recently developed proteomic technology called SILAC (stable isotope labeling by amino acids in cell culture) combined with polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry to compare the mitochondrial protein profiles of MES cells (a dopaminergic cell line) exposed to rotenone versus control. We identified 1722 proteins, 950 of which are already designated as mitochondrial proteins based on database search. Among these 950 mitochondrial proteins, 110 displayed significant changes in relative abundance after rotenone treatment. Five of these selected proteins were further validated for their cellular location and/or treatment effect of rotenone. Among them, two were confirmed by confocal microscopy for mitochondrial localization and three were confirmed by Western blotting (WB) for their regulation by rotenone.ConclusionOur findings represent the first report of these mitochondrial proteins affected by rotenone; further characterization of these proteins may shed more light on PD pathogenesis.
Highlights
Many studies have shown that mitochondrial dysfunction, complex I inhibition in particular, is involved in the pathogenesis of Parkinson's disease (PD)
SDS-PAGE combined with twodimensional liquid chromatography (LC) followed by tandem mass spectrometry (MS) (MS/MS) analysis identified a total of 1864 proteins with more than 2 peptides [see Additional file 1]
One obvious question is how many of the remaining proteins were mitochondrial proteins? To address this, we searched all the identified proteins against the most comprehensive mitochondrial proteome database, MitoP2, which combines information regarding the genetic, functional and pathogenetic aspects of nuclear-encoded mitochondrial proteins
Summary
Many studies have shown that mitochondrial dysfunction, complex I inhibition in particular, is involved in the pathogenesis of Parkinson's disease (PD). A specific inhibitor of mitochondrial complex I, has been shown to produce neurodegeneration in rats as well as in many cellular models that closely resemble PD. BMC Neuroscience 2007, 8:67 http://www.biomedcentral.com/1471-2202/8/67 tive damage, excitotoxicity, and inflammation are contributing factors [4,5]. Of these potential mechanisms, mitochondrial dysfunction has been studied most extensively. The importance of complex I inhibition is further substantiated by the fact that mitochondrial toxicants, e.g. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [9], a contaminant of a synthetic heroin, and rotenone [10], a plant-derived pesticide, recapitulate parkinsonism in animals that closely resembles human PD
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