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.
"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         . In addition, mutations in PINK- 1, a mitochondrial kinase involved in mitochondrial fission, mitophagy, and quality control    , can lead to the onset of familial forms of PD  . "
[Show abstract][Hide abstract] ABSTRACT: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. These are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic protein α-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction and α-synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come first in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either that α-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deficits lead to neuronal dysfunction and α-synuclein synaptic accumulation. The present overview shows that it is still difficult to establish the exact temporal sequence and contribution of these events to PD.
"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 . 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  . 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 . "
[Show abstract][Hide abstract] ABSTRACT: Natural molecules are under intensive study for their potential as preventive and/or adjuvant therapies for neurodegenerative disorders such as Parkinson’s disease (PD). We evaluated the neuroprotective potential of Cucurbitacin E (CuE), a tetracyclic triterpenoid phytosterol extracted from the Ecballium elaterium (Cucurbitaceae), using a known cellular model of PD, NGF-differentiated PC12. In our post-mitotic experimental paradigm, neuronal cells were treated with the parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP+) to provoke significant cellular damage and apoptosis, or with the potent N,N-diethyldithiocarbamate (DDC) to induce superoxide (O2•-) production, and CuE was administered prior and during the neurotoxic treatment. We measured cellular death and reactive oxygen species to evaluate the antioxidant and anti-apoptotic properties of CuE. In addition, we analyzed cellular macroautophagy, a bulk degradation process involving the lysosomal pathway. CuE showed Neuroprotective effects on MPP+ -induced cell death. However, CuE failed to rescue neuronal cells from oxidative stress induced by MPP+ or DDC. Microscopy and Western blot data show an intriguing involvement of CuE in maintaining lysosomal distribution and decreasing autophagy flux. Altogether these data indicate that CuE decreases neuronal death and autophagic flux in a post-mitotic cellular model of PD.
Oxidative Medicine and Cellular Longevity 12/2014; 2014(Article ID 425496):15 pages. DOI:10.1155/2014/425496 · 3.36 Impact Factor
"ROS have several physiologically important functions in cells but can also cause cellular injury if produced in excess (Halliwell and Gutteridge, 2007). ROS-induced oxidative stress is implicated in the neuronal damage occurring in ischemia (Abramov et al., 2007), Alzheimer's disease (Pratico et al., 2001; Lin and Beal, 2006), Parkinson's disease (Sherer et al., 2003; Keeney et al., 2006), and many other neuronal and non-neuronal pathologies (Halliwell and Gutteridge, 2007). Evidence also suggests that ROS have a role in the degenerative physical transformations occurring in the aging brain and other aging organ systems (Kokoszka et al., 2001; Pollack et al., 2002; Barja, 2004; Maklashina and Ackrell, 2004; Melov, 2004; Miller, 2004). "
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial dysfunction and oxidative stress are implicated in many neurodegenerative diseases. Mitochondria-targeted drugs that effectively decrease oxidative stress, protect mitochondrial energetics, and prevent neuronal loss may therefore lend therapeutic benefit to these currently incurable diseases. To investigate the efficacy of such drugs, we examined the effects of mitochondria-targeted antioxidants MitoQ10 and MitoE2 on neuronal death induced by neurotrophin deficiency. Our results indicate that MitoQ10 blocked apoptosis by preventing increased mitochondria-derived reactive oxygen species (ROS) and subsequent cytochrome c release, caspase activation, and mitochondrial damage in nerve growth factor (NGF)-deprived sympathetic neurons, while MitoE2 was largely ineffective. In this paradigm, the most proximal point of divergence was the ability of MitoQ10 to scavenge mitochondrial superoxide (O2(-)). MitoQ10 also prevented caspase-independent neuronal death in these cells demonstrating that the mitochondrial redox state significantly influences both apoptotic and nonapoptotic pathways leading to neuronal death. We suggest that mitochondria-targeted antioxidants may provide tools for delineating the role and significance of mitochondrial ROS in neuronal death and provide a new therapeutic approach for neurodegenerative conditions involving trophic factor deficits and multiple modes of cell death.
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