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

Abstract

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.

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…Isolated CI respiratory deficiencies are a common feature, specifically in the substantia nigra of PD patients [62,63]. The underlying pathogenic mechanisms are not well understood, although a growing body of research suggests mitochondrial respiratory dysfunction and oxidative stress contribute to disease pathogenesis [62][63][64][65].…”

Oxidative Stress and Neurotoxicity

“…The decreased activity may reflect an underproduction of certain complex I subunits (185,186), complex I misassembly, or self-inflicted oxidative damage (187). Evidence that a complex I deficiency and oxidative stress might underlie PD pathology is that selective inhibitors of complex I, such as rotenone and MPP+ (1-methyl-4-phenylpyridinium), recapitulate much of the pathology of PD (188).…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Complex I activity and expression are decreased in the SN[109Ͳ112] and cortex [113] of PD patients to a greater extent than would be expected from normal aging [107]. Oxidized, functionally impaired and misassembled complex I subunits, have been reported in PD [114].Moreover, complex I dysfunction was reported in skeletal muscle and platelets of PD patients [112].…”