Parkinson's Disease Brain Mitochondrial Complex I Has Oxidatively Damaged Subunits and Is Functionally Impaired and Misassembled

Parkinson’s disease 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 electron transport chain proteins from complexes II–V

P. M. Keeney

2006

Scholarcy highlights

  • Parkinson’s disease is a neurodegenerative disease that produces diffuse protein aggregation pathology but relatively selective death of substantia nigra dopaminergic neurons, resulting in the movement abnormalities first described by James Parkinson in 1817 that are treated by dopaminergic therapies
  • 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 electron transport chain proteins from complexes II–V
  • We have used mitochondrial preparations from PD and CTL frontal cortex samples matched for age at death and postmortem intervals to examine complex I protein composition, electron transfer function, and oxidation state
  • In PD brain, complex I has approximately half again as much oxidative damage as in CTL, reflected in increased protein carbonyl content, and that this increased oxidation is localized to several bands that contain catalytic subunits encoded by both nuclear and mitochondrial genomes
  • Our limited analysis provides a list of complex I subunits potentially damaged by ROS, and it was of interest that all of the complex I subunits we identified in the bands containing increased protein carbonyls belong to the minimum essential ensemble, a group of 14 hydrophobic proteins believed to form the catalytic core of complex I
  • We have not yet identified the specific residues in the ϳ50 kDa subunits that are oxidatively damaged in PD brain mitochondrial complex I, but our preliminary results suggest that a similar process may be occurring and that a more detailed mass spectrometric analysis of protein oxidation would be of value
  • Based on the multitude of abnormalities produced by expression of Parkinson’s disease mtDNA in cybrids, it is tempting to speculate that mutations in catalytic mitochondrial complex I genes are driving the ROS production, oxidative damage, and complex I misassembly we observe in brain samples after years of clinical symptoms

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