Mitochondrial toxins in models of neurodegenerative diseases. I: in vivo brain hydroxyl radical production during sytemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions

Smith, Trisha S.; Bennett, James P.

doi:10.1016/s0006-8993(97)00429-0

Cited by 119 publications

(46 citation statements)

References 46 publications

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“…mitochondrial dysfunction and oxidative phosphorylation. Elevated levels of HO ⅐ were also observed in the striatum and ventral midbrain regions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice (56), a commonly used model for PD, supporting that many mitochondrial proteins may have an elevated level of DOPA/DQ as induced by an increased level of HO ⅐ .…”

Section: Discussionmentioning

confidence: 86%

Endogenous 3,4-Dihydroxyphenylalanine and Dopaquinone Modifications on Protein Tyrosine

Zhang

Monroe

Chen

et al. 2010

Molecular & Cellular Proteomics

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Oxidative modifications of protein tyrosines have been implicated in multiple human diseases. Among these modifications, elevations in levels of 3,4-dihydroxyphenylalanine (DOPA), a major product of hydroxyl radical addition to tyrosine, has been observed in a number of pathologies. Here we report the first proteome survey of endogenous site-specific modifications, i.e. DOPA and its further oxidation product dopaquinone in mouse brain and heart tissues. Results from LC-MS/MS analyses included 50 and 14 DOPA-modified tyrosine sites identified from brain and heart, respectively, whereas only a few nitrotyrosine-containing peptides, a more commonly studied marker of oxidative stress, were detectable, suggesting the much higher abundance for DOPA modification as compared with tyrosine nitration. Moreover, 20 and 12 dopaquinone-modified peptides were observed from brain and heart, respectively; nearly one-fourth of these peptides were also observed with DOPA modification on the same sites. For both tissues, these modifications are preferentially found in mitochondrial proteins with metal binding properties, consistent with metal-catalyzed hydroxyl radical formation from mitochondrial superoxide and hydrogen peroxide. These modifications also link to a number of mitochondrially associated and other signaling pathways. Furthermore, many of the modification sites were common sites of previously reported tyrosine phosphorylation, suggesting potential disruption of signaling pathways. Collectively, the results suggest that these modifications are linked with mitochondrially derived oxidative stress and may serve as sensitive markers for disease pathologies. Molecular & Cellular Proteomics 9:1199 -1208, 2010.

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Section: Discussionmentioning

confidence: 86%

Endogenous 3,4-Dihydroxyphenylalanine and Dopaquinone Modifications on Protein Tyrosine

Zhang

Monroe

Chen

et al. 2010

Molecular & Cellular Proteomics

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“…In contrast, ortho-tyrosine concentrations were not altered in brain tissue from MPTP-treated mice. MPTP has been proposed to enhance HO ⅐ production by impairing mitochondrial respiration (17,48,49). However, the lack of a detectable increase in ortho-tyrosine levels in the brain of MPTP-treated mice argues against a prominent role for HO ⅐ in protein damage and casts doubt on the participation of HO ⅐ in MPTP-induced neurotoxicity in vivo.…”

Section: Discussionmentioning

confidence: 99%

Mass Spectrometric Quantification of 3-Nitrotyrosine, ortho-Tyrosine, and o,o′-Dityrosine in Brain Tissue of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Mice, a Model of Oxidative Stress in Parkinson's Disease

Pennathur¹,

Jackson‐Lewis²,

Przedborski³

et al. 1999

Journal of Biological Chemistry

260

180

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Oxidative stress is implicated in the death of dopaminergic neurons in Parkinson's disease and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Oxidative species that might mediate this damage include hydroxyl radical, tyrosyl radical, or reactive nitrogen species such as peroxynitrite. In mice, we showed that MPTP markedly increased levels of o,o-dityrosine and 3-nitrotyrosine in the striatum and midbrain but not in brain regions resistant to MPTP. These two stable compounds indicate that tyrosyl radical and reactive nitrogen species have attacked tyrosine residues. In contrast, MPTP failed to alter levels of ortho-tyrosine in any brain region we studied. This marker accumulates when hydroxyl radical oxidizes protein-bound phenylalanine residues. We also showed that treating whole-brain proteins with hydroxyl radical markedly increased levels of ortho-tyrosine in vitro. Under identical conditions, tyrosyl radical, produced by the heme protein myeloperoxidase, selectively increased levels of o,o-dityrosine, whereas peroxynitrite increased levels of 3-nitrotyrosine and, to a lesser extent, of ortho-tyrosine. These in vivo and in vitro findings implicate reactive nitrogen species and tyrosyl radical in MPTP neurotoxicity but argue against a deleterious role for hydroxyl radical in this model. They also show that reactive nitrogen species and tyrosyl radical (and consequently protein oxidation) represent an early and previously unidentified biochemical event in MPTP-induced brain injury. This finding may be significant for understanding the pathogenesis of Parkinson's disease and developing neuroprotective therapies.

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“…Inhibition of COX has been shown to increase free radical generation in many systems including Drosophila (Smith and Bennett 1997;Duranteau et al 1998;Ferguson et al 2005). Excessive levels of free radicals can in turn lead to cell death via either apoptosis or necrosis (Beal 2000;Mattson and Kroemer 2003).…”

Section: /Levymentioning

confidence: 99%

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

et al. 2007

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Mitochondrial dysfunction is involved in many neurodegenerative disorders in humans. Here we report mutations in a gene (designated levy) that codes for subunit VIa of cytochrome c oxidase (COX). The mutations were identified by the phenotype of temperature-induced paralysis and showed the additional phenotypes of decreased COX activity, age-dependent bang-induced paralysis, progressive neurodegeneration, and reduced life span. Germ-line transformation using the levy 1 gene rescued the mutant flies from all phenotypes including neurodegeneration. The data from levy mutants reveal a COX-mediated pathway in Drosophila, disruption of which leads to mitochondrial encephalomyopathic effects including neurodegeneration, motor dysfunction, and premature death. The data present the first case of a mutation in a nuclear-encoded structural subunit of COX that causes mitochondrial encephalomyopathy rather than lethality, whereas several previous attempts to identify such mutations have not been successful. The levy mutants provide a genetic model to understand the mechanisms underlying COXmediated mitochondrial encephalomyopathies and to explore possible therapeutic interventions.

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Mitochondrial toxins in models of neurodegenerative diseases. I: in vivo brain hydroxyl radical production during sytemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions

Cited by 119 publications

References 46 publications

Endogenous 3,4-Dihydroxyphenylalanine and Dopaquinone Modifications on Protein Tyrosine

Endogenous 3,4-Dihydroxyphenylalanine and Dopaquinone Modifications on Protein Tyrosine

Mass Spectrometric Quantification of 3-Nitrotyrosine, ortho-Tyrosine, and o,o′-Dityrosine in Brain Tissue of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Mice, a Model of Oxidative Stress in Parkinson's Disease

Mutations in Cytochrome c Oxidase Subunit VIa Cause Neurodegeneration and Motor Dysfunction in Drosophila

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