Proteins Modified by Malondialdehyde, 4-Hydroxynonenal, or Advanced Glycation End Products in Lipofuscin of Human Retinal Pigment Epithelium

Schütt, F.; Bergmann, Marion; Holz, Frank G.; Kopitz, Jürgen

doi:10.1167/iovs.03-0172

Cited by 234 publications

(196 citation statements)

References 27 publications

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“…Other oxidative protein modifications reported previously in RPE lipofuscin include malondialdehyde and hydroxynonenal adducts and advanced glycation end products (10). It remains to be determined whether these other modifications are actually associated with the granules because the analyses were performed with crude lipofuscin preparations (10). Such protein modifications have the potential to mask proteolytic cleavage sites, inactivate enzymes (42), and contribute to the accumulation of partially degraded, cross-linked proteinaceous material.…”

Section: Fig 4 Phototoxicity Of Lipofuscinmentioning

confidence: 98%

“…A number of inflammatory and neurodegenerative disorders have been associated with tyrosine nitration including Parkinson, Alzheimer, and Huntington diseases (41). Other oxidative protein modifications reported previously in RPE lipofuscin include malondialdehyde and hydroxynonenal adducts and advanced glycation end products (10). It remains to be determined whether these other modifications are actually associated with the granules because the analyses were performed with crude lipofuscin preparations (10).…”

Section: Fig 4 Phototoxicity Of Lipofuscinmentioning

confidence: 98%

“…From 2002 to 2007 proteomics investigations have reported protein compositions for RPE lipofuscin (6,7) and RPE melanolipofuscin (8,9). Oxidative protein modifications have also been associated with lipofuscin (6,7,10), but studies to date have not demonstrated that the identified proteins and oxidative modifications are from the granules rather than from the contaminating material that co-purifies with the gran-ules. Because in vitro bioactivity studies of lipofuscin have also utilized preparations that contain extragranular contaminants, a clear understanding of the source of the bioactivities demonstrated in these studies remains elusive.…”

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confidence: 99%

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Retinal Pigment Epithelium Lipofuscin Proteomics

Gugiu

Renganathan

et al. 2008

Molecular & Cellular Proteomics

157

136

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Lipofuscin accumulates with age in the retinal pigment epithelium (RPE) in discrete granular organelles and may contribute to age-related macular degeneration. Because previous studies suggest that lipofuscin contains protein that may impact pathogenic mechanisms, we pursued proteomics analysis of lipofuscin. The composition of RPE lipofuscin and its mechanisms of pathogenesis are poorly understood in part because of the heterogeneity of isolated preparations. We purified RPE lipofuscin granules by treatment with proteinase K or SDS and showed by light, confocal, and transmission electron microscopy that the purified granules are free of extragranular material and associated membranes. Crude and purified lipofuscin preparations were quantitatively compared by (i) LC MS/MS proteomics analyses, (ii) immunoanalyses of oxidative protein modifications, (iii) amino acid analysis, (iv) HPLC of bisretinoids, and (v) assaying phototoxicity to RPE cells. From crude lipofuscin preparations 186 proteins were identified, many of which appeared to be modified. In contrast, very little protein (ϳ2% (w/w) by amino acid analysis) and no identifiable protein were found in the purified granules, which retained full phototoxicity to cultured RPE cells. Our analyses showed that granules in purified and crude lipofuscin preparations exhibit no statistically significant differences in diameter or circularity or in the content of the bisretinoids A2E, isoA2E, and all-trans-retinal dimer-phosphatidylethanolamine. The finding that the purified granules contain minimal protein yet retain phototoxic activity suggests that RPE lipofuscin pathogenesis is largely independent of associated protein. The purified granules also exhibited oxidative protein modifications, including nitrotyrosine generated from reactive nitrogen oxide species and carboxyethylpyrrole and iso[4]levuglandin E 2 adducts generated from reactive lipid fragments. This finding is consistent with previous studies demonstrating RPE lipofuscin to be a potent generator of reactive oxygen species and supports the hypothesis that such species, including reactive fragments from lipids and retinoids, contribute to the mechanisms of RPE lipofuscin pathogenesis.

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Section: Fig 4 Phototoxicity Of Lipofuscinmentioning

confidence: 98%

Section: Fig 4 Phototoxicity Of Lipofuscinmentioning

confidence: 98%

mentioning

confidence: 99%

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Retinal Pigment Epithelium Lipofuscin Proteomics

Gugiu

Renganathan

et al. 2008

Molecular & Cellular Proteomics

157

136

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“…This tissue is the site of high and permanent oxidative stress because the cells are prominent oxygen consumers and exposed to light. When LPO is high, it increases HNE adduction to proteins, 132 among which are proteins of the photoreceptor outer segments (POS). HNEadducted POS proteins are much less degraded by lysosomes and global proteolysis is decreased in RPE cells.…”

Section: -Hydroxynonenal and Mechanisms Of Cell Death S Dalleau Et Almentioning

confidence: 99%

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

et al. 2013

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During the last three decades, 4-hydroxy-2-nonenal (HNE), a major a,b-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of numerous cell processes such as oxidative stress signaling, cell proliferation, transformation or cell death. The main objective of this review is to focus on the different aspects of HNE-induced cell death, with a particular emphasis on apoptosis. HNE is a special apoptotic inducer because of its abilities to form protein adducts and to propagate oxidative stress. It can stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators. At the same time, due to its oxidant status, it can also induce some cellular defense mechanisms against oxidative stress, thus being involved in its own detoxification. These processes in turn limit the apoptotic potential of HNE. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify.

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“…Nevertheless, several proteomic investigations have identified proteins involved in energy metabolism and production, stress resistance, and cellular structural integrity as targets of oxidative modification during aging [14][15][16][17]. However, the functional consequences of in vivo oxidatively damaged proteins have rarely been demonstrated or remain unclear.…”

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confidence: 99%

Aconitase and ATP synthase are targets of malondialdehyde modification and undergo an age-related decrease in activity in mouse heart mitochondria

Yarian

Rebrin

Sohal

2005

Biochemical and Biophysical Research Communications

101

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The main purpose of this study was to identify mitochondrial proteins that exhibit post-translational oxidative modifications during the aging process and to determine the resulting functional alterations. Proteins forming adducts with malondialdehyde (MDA), a product of lipid peroxidation, were identified by immunodetection in mitochondria isolated from heart and hind leg skeletal muscle of 6-, 16-, and 24-month-old mice. Aconitase, very long chain acyl coenzyme A dehydrogenase, ATP synthase, and α-ketoglutarate dehydrogenase were detected as putative targets of oxidative modification by MDA. Aconitase and ATP synthase from heart exhibited significant decreases in activity with age. Very long chain acyl coenzyme A dehydrogenase and α-ketoglutarate dehydrogenase activities were unaffected during aging in both heart and skeletal muscle. This suggests that the presence of a post-translational oxidative modification in a protein does not a priori reflect an alteration in activity. The biological consequences of an age-related decrease in aconitase and ATP synthase activities may contribute to the decline in mitochondrial bioenergetics evident during aging.

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Proteins Modified by Malondialdehyde, 4-Hydroxynonenal, or Advanced Glycation End Products in Lipofuscin of Human Retinal Pigment Epithelium

Cited by 234 publications

References 27 publications

Retinal Pigment Epithelium Lipofuscin Proteomics

Retinal Pigment Epithelium Lipofuscin Proteomics

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

Aconitase and ATP synthase are targets of malondialdehyde modification and undergo an age-related decrease in activity in mouse heart mitochondria

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