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Alterations in the Mitochondrial Proteome of Neuroblastoma Cells in Response to Complex 1 Inhibition

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School of Science and Technology, Nottingham Trent University, Clifton Lane, NG11 8NS Nottingham, U.K.
*Prof. E. Ellen Billett, School of Science and Technology, Nottingham Trent University, Clifton Lane, NG11 8NS Nottingham, U.K. Phone: 0044 (0)115 848 6356. Fax: +441158486616. E-mail: [email protected]
Cite this: J. Proteome Res. 2011, 10, 4, 1974–1986
Publication Date (Web):February 15, 2011
https://doi.org/10.1021/pr101211k
Copyright © 2011 American Chemical Society

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    Increasing evidence points to mitochondrial dysfunction in Parkinson’s disease (PD) associated with complex I dysfunction, but the exact pathways which lead to cell death have not been resolved. 2D-gel electrophoresis profiles of isolated mitochondria from neuroblastoma cells treated with subcytotoxic concentrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-characterized complex I inhibitor, were assessed to identify associated targets. Up to 27 differentially expressed proteins were observed, of which 16 were identified using peptide mass fingerprinting. Changes in protein levels were validated by immunoprobing 1D blots, confirming increases in heat shock cognate 71 kDa (Hsc70), 60 kDa heat shock protein (Hsp60), fumarase, glutamate oxaloacetate transaminase 2, ATP synthase subunit d, and voltage-dependent anion-channel 1 (VDAC1). Immunoprobing of 2D blots revealed isoform changes in Hsc70, Hsp60, and VDAC1. Subcytotoxic concentrations of MPTP modulated a host of mitochondrial proteins including chaperones, metabolic enzymes, oxidative phosphorylation-related proteins, an inner mitochondrial protein (mitofilin), and an outer mitochondrial membrane protein (VDAC1). Early changes in chaperones suggest a regulated link between complex 1 inhibition and protein folding. VDAC1, a multifunctional protein, may have a key role in signaling between mitochondria and the rest of the cell prior to cell death. Our work provides new important information of relevance to PD.

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    2DE stained with SyproRuby showing spots identified following peptide mass fingerprinting; protein identification of spots from 2DE; peptide mass fingerprinting of differentially expressed identified spots; relative distribution of subcellular markers expressed as sum of fractions following MPTP treatment compared to controls. This material is available free of charge via the Internet at http://pubs.acs.org.

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