Effects of lipid peroxidation products on lipofuscinogenesis and autophagy in human retinal pigment epithelial cells

Krohne, Tim U.; Stratmann, N.; Kopitz, Jürgen; Holz, Frank G.

doi:10.1016/j.exer.2009.12.011

Cited by 145 publications

(143 citation statements)

References 45 publications

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“…This finding essentially corroborates reports in the literature that loss of autophagy-lysosomal degradation can contribute to buildup of lipofuscin. 22,29,54,55 Although in our studies we did not witness a change in mitochondrial density by enhancing autophagy with rapamycin, we found that reduction in the intracellular GSH:GSSG ratio after oxidative stress was attenuated by rapamycin suggesting that enhancing autophagy may offer protection to RPE by increasing the antioxidant activity of glutathione.…”

Section: Discussionmentioning

confidence: 56%

“…13,14,[28][29][30][31] Recent studies from our laboratory and others indicate a potential role of autophagy either pretreated or not treated with rapamycin (100 nM) for 3 h. Data were analyzed using oneway ANOVA and differences between means were considered statistically significant when P < 0.05. in lipofuscin accumulation, drusen formation, and AMD pathogenesis. 14,22,31 We found that with aging there seemed to be a dramatic increase in LC3, ATG7, and ATG9 in the RPE as well as other retinal layers of non-AMD human donors and our rodent models.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

et al. 2014

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Autophagic dysregulation has been suggested in a broad range of neurodegenerative diseases including agerelated macular degeneration (AMD). To test whether the autophagy pathway plays a critical role to protect retinal pigmented epithelial (RPE) cells against oxidative stress, we exposed ARPE-19 and primary cultured human RPE cells to both acute (3 and 24 h) and chronic (14 d) oxidative stress and monitored autophagy by western blot, PCR, and autophagosome counts in the presence or absence of autophagy modulators. Acute oxidative stress led to a marked increase in autophagy in the RPE, whereas autophagy was reduced under chronic oxidative stress. Upregulation of autophagy by rapamycin decreased oxidative stress-induced generation of reactive oxygen species (ROS), whereas inhibition of autophagy by 3-methyladenine (3-MA) or by knockdown of ATG7 or BECN1 increased ROS generation, exacerbated oxidative stress-induced reduction of mitochondrial activity, reduced cell viability, and increased lipofuscin. Examination of control human donor specimens and mice demonstrated an age-related increase in autophagosome numbers and expression of autophagy proteins. However, autophagy proteins, autophagosomes, and autophagy flux were significantly reduced in tissue from human donor AMD eyes and 2 animal models of AMD. In conclusion, our data confirm that autophagy plays an important role in protection of the RPE against oxidative stress and lipofuscin accumulation and that impairment of autophagy is likely to exacerbate oxidative stress and contribute to the pathogenesis of AMD.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

et al. 2014

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“…HNEadducted POS proteins are much less degraded by lysosomes and global proteolysis is decreased in RPE cells. Regarding that point, Krohne et al 133 have demonstrated that HNE-adducted POS directly reduces autophagy in RPE cells, leading to apoptosis induction. 134 Therefore, VSMC exhibit a more adaptative capacity to survive HNE and oxidative stress than 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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“…As autophagy is important in clearing damaged proteins and organelles, 29,30 particularly during oxidative stress, changes in autophagic activity can modulate the effects of HNE on cellular bioenergetics and therefore have an impact on cell death. So far, there have been a limited number of studies on how HNE affects autophagy and cell survival, for example in the eye and smooth muscle cells, 31,32 but no studies of HNE effects on neuronal autophagy have been reported. Cellular bioenergetics at the level of the mitochondrion is intimately linked to glucose metabolism through the provision of pyruvate as a substrate for respiration and NADPH for protection against oxidative stress.…”

Section: Basic Research Papermentioning

confidence: 99%

Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

et al. 2013

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Effects of lipid peroxidation products on lipofuscinogenesis and autophagy in human retinal pigment epithelial cells

Cited by 145 publications

References 45 publications

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

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

Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

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