scholarly journals Multiple phosphatidylinositol(3)phosphate roles in retinal pigment epithelium membrane recycling

2020 ◽  
Author(s):  
Feng He ◽  
Melina A. Agosto ◽  
Ralph M. Nichols ◽  
Theodore G. Wensel
Keyword(s):  
Cell Death ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Membrane Dynamics ◽  
Alternative Mechanism ◽  
Membrane Recycling ◽  
Large Numbers ◽  
Late Endosomes ◽  
Retinal Pigmented Epithelial Cells ◽  
Phosphatidylinositol 3

AbstractThe low-abundance lipid phosphatidylinositol-3-phosphate (PI(3)P) is important for membrane dynamics in autophagy, endosome processing, and phagocytosis. In retinal pigmented epithelial cells (RPE) all three pathways are important, but phagocytosis of disk membranes shed from adjacent photoreceptors is especially important for ensuring health of photoreceptors and preventing retinal degeneration. By eliminating Vps34, the kinase responsible for synthesizing PI(3)P in RPE, we have found that PI(3)P plays distinct roles in each pathway. In phagocytosis it is not required for disk engulfment or phagosome transport but is essential for recruitment and lipidation of LC3. In contrast, initiation of autophagy and LC3 recruitment to autophagosomes does not require PI(3)P, which can be bypassed by an alternative mechanism of ATG16L recruitment that does not require PI(3)P, Rab11a, or WIPI2. In all three pathways, PI(3)P is essential for fusion with lysosomes; autophagosomes, phagosomes, and Rab7-positive late endosomes, as well as enlarged lysosomes, accumulate in large numbers in the absence of Vps34, leading to cell death.

Lipofuscin causes atypical necroptosis through lysosomal membrane permeabilization

2021 ◽  
Vol 118 (47) ◽  
pp. e2100122118
Author(s):  
Chendong Pan ◽  
Kalpita Banerjee ◽  
Guillermo L. Lehmann ◽  
Dena Almeida ◽  
Katherine A. Hajjar ◽  
...  
Keyword(s):  
Cell Death ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Physicochemical Characteristics ◽  
Age Related Macular Degeneration ◽  
Toxic Waste ◽  
Pharmacological Intervention ◽  
Age Related ◽  
Human Disorders ◽  
Lipofuscin Granules

Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes. In addition, like conventional lipofuscins, it appears as an autofluorescent pigment, considered toxic waste, and a biomarker of aging. Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), whereby it interferes with the support of the neuroretina. RPE cell death is the primary cause of blindness in the most prevalent incurable genetic and age-related human disorders, Stargardt disease and age-related macular degeneration (AMD), respectively. Although retinal lipofuscin is directly linked to the cell death of the RPE in Stargardt, the extent to which it contributes to AMD is a matter of debate. Nonetheless, the number of AMD clinical trials that target lipofuscin formation speaks for the potential relevance for AMD as well. Here, we show that retinal lipofuscin triggers an atypical necroptotic cascade, amenable to pharmacological intervention. This pathway is distinct from canonic necroptosis and is instead dependent on the destabilization of lysosomes. We also provide evidence that necroptosis is activated in aged human retinas with AMD. Overall, this cytotoxicity mechanism may offer therapeutic targets and markers for genetic and age-related diseases associated with lipofuscin buildups.

scholarly journals Pharmaceutical Induction of PGC-1α Promotes Retinal Pigment Epithelial Cell Metabolism and Protects against Oxidative Damage

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Sangeeta Satish ◽  
Hannah Philipose ◽  
Mariana Aparecida Brunini Rosales ◽  
Magali Saint-Geniez
Keyword(s):  
Cell Death ◽  
Antioxidant Enzymes ◽  
Oxidative Damage ◽  
Therapeutic Potential ◽  
Retinal Pigment Epithelial Cell ◽  
Cell Metabolism ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Age Related

Retinal pigment epithelium (RPE) dysfunction due to accumulation of reactive oxygen species and oxidative damage is a key event in the development of age-related macular degeneration (AMD). Here, we examine the therapeutic potential of ZLN005, a selective PGC-1α transcriptional regulator, in protecting RPE from cytotoxic oxidative damage. Gene expression analysis on ARPE-19 cells treated with ZLN005 shows robust upregulation of PGC-1α and its associated transcription factors, antioxidant enzymes, and mitochondrial genes. Energetic profiling shows that ZLN005 treatment enhances RPE mitochondrial function by increasing basal and maximal respiration rates, and spare respiratory capacity. In addition, ZLN005 robustly protects ARPE-19 cells from cell death caused by H2O2, ox-LDL, and NaIO3 without exhibiting any cytotoxicity under basal conditions. ZLN005 protection against H2O2-mediated cell death was lost in PGC-1α-silenced cells. Our data indicates that ZLN005 efficiently protects RPE cells from oxidative damage through selective induction of PGC-1α and its target antioxidant enzymes. ZLN005 may serve as a novel therapeutic agent for retinal diseases associated with RPE dystrophies.

Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death

2017 ◽  
Vol 57 (4) ◽  
pp. 252-262 ◽  
Author(s):  
Bing Lu ◽  
Pengfei Zhang ◽  
Minwen Zhou ◽  
Wenqiu Wang ◽  
Qing Gu ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Pigment Epithelium ◽  
Blue Light ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelium Cell ◽  
Epithelium Cell

scholarly journals In vitro evaluation of simulated stereotactic radiotherapy for wet age-related macular degeneration on three different cell lines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Efstathios Vounotrypidis ◽  
Anna Hillenmayer ◽  
Christian M. Wertheimer ◽  
Alexis Athanasiou ◽  
Jakob Siedlecki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Stereotactic Radiotherapy ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Low Energy ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Brdu Assay

AbstractLow energy stereotactic radiotherapy has been proposed for the treatment of neovascular age related macular degeneration. We investigated the in vitro effect of the radiotherapy on pericytes, retinal pigment epithelium and endothelial cells. Primary human retinal pigment epithelium cells, human umbilical vein endothelial cells and human pericytes from Placenta were cultivated. In a pairwise protocol, one plate was irradiated at a dose of 16 Gy, while the second plate served as a non-irradiated control. Thereafter, cells were cultivated either in serum-free (non-permissive) or serum-stimulated (permissive) conditions. A life/dead assay, an XTT and a BrdU assay were performed up to 7 days after irradiation. No cell death occurred at any timepoint in any cell line after treatment nor in the control. Compared to the unirradiated controls, cell viability and metabolic activity were significantly reduced in irradiated cells in the XTT assay, except for non-permissive RPE cells. In the BrdU assay, proliferation was inhibited. While no cell death was detected in vitro, viability and proliferative capacity of all cell lines were significantly reduced. Therefore, it seems that low energy stereotactic radiotherapy inhibits angiogenesis without a direct induction of apoptosis but influencing microvascular function and stability.

scholarly journals A Novel HDL-Mimetic Peptide HM-10/10 Protects RPE and Photoreceptors in Murine Models of Retinal Degeneration

2019 ◽  
Vol 20 (19) ◽  
pp. 4807 ◽  
Author(s):  
Feng Su ◽  
Christine Spee ◽  
Eduardo Araujo ◽  
Eric Barron ◽  
Mo Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Disease ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Mimetic Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD. Oxidative stress plays a key role in the development of AMD. We generated a chimeric high-density lipoprotein (HDL), mimetic peptide named HM-10/10, with anti-oxidant properties and investigated its potential for the treatment of retinal disease using cell culture and animal models of RPE and photoreceptor (PR) degeneration. Treatment with HM-10/10 peptide prevented human fetal RPE cell death caused by tert-Butyl hydroperoxide (tBH)-induced oxidative stress and sodium iodate (NaIO3), which causes RPE atrophy and is a model of geographic atrophy in mice. We also show that HM-10/10 peptide ameliorated photoreceptor cell death and significantly improved retinal function in a mouse model of N-methyl-N-nitrosourea (MNU)-induced PR degeneration. Our results demonstrate that HM-10/10 protects RPE and retina from oxidant injury and can serve as a potential therapeutic agent for the treatment of retinal degeneration.

scholarly journals Modulating GLUT1 expression in retinal pigment epithelium decreases glucose levels in the retina: impact on photoreceptors and Müller glial cells

2019 ◽  
Vol 316 (1) ◽  
pp. C121-C133 ◽  
Author(s):  
Aditi Swarup ◽  
Ivy S. Samuels ◽  
Brent A. Bell ◽  
John Y. S. Han ◽  
Jianhai Du ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Pigment Epithelium ◽  
Glucose Transport ◽  
Glial Cells ◽  
Photoreceptor Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Conditional Knockout ◽  
Müller Glial Cells ◽  
Outer Segments

The retina is one of the most metabolically active tissues in the body and utilizes glucose to produce energy and intermediates required for daily renewal of photoreceptor cell outer segments. Glucose transporter 1 (GLUT1) facilitates glucose transport across outer blood retinal barrier (BRB) formed by the retinal pigment epithelium (RPE) and the inner BRB formed by the endothelium. We used conditional knockout mice to study the impact of reducing glucose transport across the RPE on photoreceptor and Müller glial cells. Transgenic mice expressing Cre recombinase under control of the Bestrophin1 ( Best1) promoter were bred with Glut1flox/flox mice to generate Tg-Best1-Cre:Glut1flox/flox mice ( RPEΔGlut1). The RPEΔGlut1 mice displayed a mosaic pattern of Cre expression within the RPE that allowed us to analyze mice with ~50% ( RPEΔGlut1m) recombination and mice with >70% ( RPEΔGlut1h) recombination separately. Deletion of GLUT1 from the RPE did not affect its carrier or barrier functions, indicating that the RPE utilizes other substrates to support its metabolic needs thereby sparing glucose for the outer retina. RPEΔGlut1m mice had normal retinal morphology, function, and no cell death; however, where GLUT1 was absent from a span of RPE greater than 100 µm, there was shortening of the photoreceptor cell outer segments. RPEΔGlut1h mice showed outer segment shortening, cell death of photoreceptors, and activation of Müller glial cells. The severe phenotype seen in RPEΔGlut1h mice indicates that glucose transport via the GLUT1 transporter in the RPE is required to meet the anabolic and catabolic requirements of photoreceptors and maintain Müller glial cells in a quiescent state.

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