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

Institute of Molecular Biology, University of Oregon, Eugene, Oregon, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2006; 26(19):5256-64. DOI: 10.1523/JNEUROSCI.0984-06.2006
Source: PubMed


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.

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    • "These lines of evidence point out that alterations of mitochondrial pathways are involved in the pathogenesis of parkinsonian-like syndromes. Of note, mitochondrial dysfunctions have been reported in muscle tissues, platelets, lymphocytes, and fibroblasts of PD subjects, thus supporting the idea that this phenomenon does not exclusively involve central neuronal cells and represents an important feature of PD [68] [69] [70] [71] [72] [73] [74] [75] [76]. In addition, mutations in PINK- 1, a mitochondrial kinase involved in mitochondrial fission, mitophagy, and quality control [77] [78] [79] [80], can lead to the onset of familial forms of PD [81] [82]. "
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    • "In Parkinson's disease (PD), for example, these effects lead to the degeneration of the nigrostriatal dopaminergic (DAergic) pathway characterized by the selective death of DAergic neurons and dopamine content depletion [4]. The hypotheses regarding the etiology of PD pinpoint mitochondrial defects and oxidative stress, ranging from mutations in proteins regulating mitochondrial turnover to functional impairment of the respiratory chain, as major causes of neurodegeneration [5] [6]. Moreover, formation of the characteristic protein inclusions of PD, Lewy bodies, illustrates the challenge of protein misfolding and aggregation, not rescued by cellular degradation mechanisms [7]. "
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