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The Journal of Neuroscience, May 10, 2006, 26(19):5256-5264; doi:10.1523/JNEUROSCI.0984-06.2006
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Neurobiology of Disease
Parkinson's Disease Brain Mitochondrial Complex I Has Oxidatively Damaged Subunits and Is Functionally Impaired and Misassembled
Paula M. Keeney,1 Jing Xie,2 Roderick A. Capaldi,2,3 andJames P. Bennett, Jr1 1Center for the Study of Neurodegenerative Diseases, University of Virginia, Charlottesville, Virginia 22908, 2Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, and 3MitoSciences, Inc., Eugene, Oregon 97403
Correspondence should be addressed to Dr. James P. Bennett Jr, P.O. Box 800394, Charlottesville, VA 22908. Email: bennett{at}virginia.edu
Loss of mitochondrial complex I catalytic activity in the electron transport chain (ETC) is found in multiple tissues from individuals with sporadic Parkinson's disease (PD) and is a property of some PD model neurotoxins. Using special ETC subunit-specific and complex I immunocapture antibodies directed against the entire complex I macroassembly, we quantified ETC proteins and protein oxidation of complex I subunits in brain mitochondria from 10 PD and 12 age-matched control (CTL) samples. We measured nicotinamide adenine dinucleotide (NADH)-driven electron transfer rates through complex I and correlated these with complex I subunit oxidation levels and reductions of its 8 kDa subunit. PD brain complex I shows 11% increase in ND6, 34% decrease in its 8 kDa subunit and contains 47% more protein carbonyls localized to catalytic subunits coded for by mitochondrial and nuclear genomes We found no changes in levels of ETC proteins from complexes II–V. Oxidative damage patterns to PD complex I are reproduced by incubation of CTL brain mitochondria with NADH in the presence of rotenone but not by exogenous oxidant. NADH-driven electron transfer rates through complex I inversely correlate with complex I protein oxidation status and positively correlate with reduction in PD 8 kDa subunit. Reduced complex I function in PD brain mitochondria appears to arise from oxidation of its catalytic subunits from internal processes, not from external oxidative stress, and correlates with complex I misassembly. This complex I auto-oxidation may derive from abnormalities in mitochondrial or nuclear encoded subunits, complex I assembly factors, rotenone-like complex I toxins, or some combination.
Key words: complex I; Parkinson's disease; electron transport chain; protein oxidation; oxygenase; mitochondria
Received Jan. 10, 2006; revised April 5, 2006; accepted April 7, 2006.
Correspondence should be addressed to Dr. James P. Bennett Jr, P.O. Box 800394, Charlottesville, VA 22908. Email: bennett{at}virginia.edu
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