ArticlePloS one2012
Mechanism of RPE cell death in α-crystallin deficient mice: a novel and critical role for MRP1-mediated GSH efflux.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 53 citations in OpenAlex.
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- Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood-Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations.International journal of molecular sciences · 2022Article
- Clusterin, other extracellular chaperones, and eye disease.Progress in retinal and eye research · 2022Review
- The gut efflux pump MRP-1 exports oxidized glutathione as a danger signal that stimulates behavioral immunity and aversive learning.Communications biology · 2022Article
- Mechanisms of RPE senescence and potential role of αB crystallin peptide as a senolytic agent in experimental AMD.Experimental eye research · 2022Article
- Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration.Antioxidants (Basel, Switzerland) · 2021Review
- Hydrogen Sulfide: Novel Endogenous and Exogenous Modulator of Oxidative Stress in Retinal Degeneration Diseases.Molecules (Basel, Switzerland) · 2021Review
- Article
- Retinal pigment epithelium and age-related macular degeneration: A review of major disease mechanisms.Clinical & experimental ophthalmology · 2020Review
- Roles of ABCC1 and ABCC4 in Proliferation and Migration of Breast Cancer Cell Lines.International journal of molecular sciences · 2020Article
- Characterisation of Glutathione Export from Human Donor Lenses.Translational vision science & technology · 2020Article
- Transporter-Mediated Mitochondrial GSH Depletion Leading to Mitochondrial Dysfunction and Rescue with αB Crystallin Peptide in RPE Cells.Antioxidants (Basel, Switzerland) · 2020Article
- A Novel HDL-Mimetic Peptide HM-10/10 Protects RPE and Photoreceptors in Murine Models of Retinal Degeneration.International journal of molecular sciences · 2019Article
- Characterization and Regulation of Carrier Proteins of Mitochondrial Glutathione Uptake in Human Retinal Pigment Epithelium Cells.Investigative ophthalmology & visual science · 2019Article
- Roles of Drug Transporters in Blood-Retinal Barrier.Advances in experimental medicine and biology · 2019Review
- Intra-vitreal αB crystallin fused to elastin-like polypeptide provides neuroprotection in a mouse model of age-related macular degeneration.Journal of controlled release : official journal of the Controlled Release Society · 2018Article
- Metabolism of 4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone by Retinal Pigmented Epithelial Cells.Chemical research in toxicology · 2016Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Absence of α-crystallins (αA and αB) in retinal pigment epithelial (RPE) cells renders them susceptible to oxidant-induced cell death. We tested the hypothesis that the protective effect of α-crystallin is mediated by changes in cellular glutathione (GSH) and elucidated the mechanism of GSH efflux. In α-crystallin overexpressing cells resistant to cell death, cellular GSH was >2 fold higher than vector control cells and this increase was seen particularly in mitochondria. The high GSH levels associated with α-crystallin overexpression were due to increased GSH biosynthesis. On the other hand, cellular GSH was decreased by 50% in murine retina lacking αA or αB crystallin. Multiple multidrug resistance protein (MRP) family isoforms were expressed in RPE, among which MRP1 was the most abundant. MRP1 was localized to the plasma membrane and inhibition of MRP1 markedly decreased GSH efflux. MRP1-suppressed cells were resistant to cell death and contained elevated intracellular GSH and GSSG. Increased GSH in MRP1-supressed cells resulted from a higher conversion of GSSG to GSH by glutathione reductase. In contrast, GSH efflux was significantly higher in MRP1 overexpressing RPE cells which also contained lower levels of cellular GSH and GSSG. Oxidative stress further increased GSH efflux with a decrease in cellular GSH and rendered cells apoptosis-prone. In conclusion, our data reveal for the first time that 1) MRP1 mediates GSH and GSSG efflux in RPE cells; 2) MRP1 inhibition renders RPE cells resistant to oxidative stress-induced cell death while MRP1 overexpression makes them susceptible and 3) the antiapoptotic function of α-crystallin in oxidatively stressed cells is mediated in part by GSH and MRP1. Our findings suggest that MRP1 and α crystallin are potential therapeutic targets in pathological retinal degenerative disorders linked to oxidative stress.
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