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

By P. Keeney, Jing Xie, R. Capaldi, J. Bennett. Journal of Neuroscience, 2006

745 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/d6036f2a48ebe80c9aabae97327c9e1b48fa6727

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. P. Whitton
2. M. Mouradian
3. V. Dias
4. Christian Haass
5. E. Junn
6. Elias K. Michaelis
7. P. Jenner
8. S. Duty

In Molecular Biology

1. P. Whitton
2. M. Mouradian
3. V. Dias
4. A. Lutz
5. Christian Haass
6. E. Junn
7. K. Winklhofer
8. Nicole Exner

In Neurology

1. P. Whitton
2. M. Mouradian
3. V. Dias
4. A. Lutz
5. Christian Haass
6. E. Junn
7. K. Winklhofer
8. Nicole Exner

Citations in the corpus

• Inflammation as a causative factor in the aetiology of Parkinson's disease (2007, background): “Furthermore, oxidative stress has been demonstrated in PD sufferers (Halliwell and Gutteridge, 1999; Waragai et al., 2006) and evidence also clearly supports the involvement of impaired mitochondrial function in PD (Keeny et al., 2006; Schapira, 2006).”
• The Role of Oxidative Stress in Parkinson’s Disease (2013, background): “Several groups have reported decreased Complex I activity and ubiquinone in the SN of PD patients, abnormalities that may lead to neuronal degeneration [140] [141] [142].”
• Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “In mitochondrial preparations from PD frontal cortex samples, complex I subunits derived from both mitochondrial and nuclear genomes were found to be oxidatively damaged, reflected by an increase in protein carbonyls (Keeney et al , 2006).”