Subcellular Distribution and Activity of Mechanistic Target of Rapamycin in Aged Retinal Pigment Epithelium

Yu, Bo; Xu, Pei; Zhao, Zhen-Yang; Cai, Jiyang; Sternberg, Paul; Chen, Yan

doi:10.1167/iovs.14-14758

Cited by 26 publications

(47 citation statements)

References 81 publications

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“…However, the roles of mTOR in phagocytosis are not limited to its effects on autophagy initiation. We have previously shown that cells with persistent mTORC1 activation have impaired POS degradation (20) Indeed, with aging and/or degeneration, RPE cells exhibit increased mTORC1 activity (52), which correlates with the accumulation of undigested POS. Future studies will be necessary to further elucidate the downstream signaling events of mTORC1 that control vesicular trafficking and lysosome-mediated degradation via RPE-specific mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Primary cultures of human fetal RPE cells were established and cultured, as described previously (20). Cells were grown and passaged in alpha-modified Eagle’s medium (α-MEM), containing 10% FBS, 10 mL/L N1 supplements, 10 mL/L MEM nonessential amino acid (100X), 1 mM sodium pyruvate, and 2 mM glutamine on collagen-coated plates and wells (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…Whole mount tissues of RPE/choroid were prepared from 3- to 4-month-old mice, as described previously (20). The tissues were fixed in 4% paraformaldehyde and permeabilized with ice-cold acetone.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, photoreceptor outer segments (POS) that are shed daily are removed by the RPE through receptor-mediated phagocytosis (17, 19). We have previously reported that aged RPE cells have increased lysosomal mass, increased mTORC1 activity, and decreased ability to degrade phagocytosed POS (20). …”

Section: Introductionmentioning

confidence: 99%

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Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Egbejimi

Dharmat

et al. 2018

Sci. Signal.

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The retinal pigment epithelium (RPE) transports nutrients and metabolites between the microvascular bed that maintains the outer retina and photoreceptor neurons. The RPE removes photoreceptor outer segments (POS) by receptor-mediated phagocytosis, a process that peaks in the morning. Uptake and degradation of POS initiates signaling cascades in the RPE. Upstream stimuli from various metabolic activities converge on mechanistic target of rapamycin complex 1 (mTORC1), and aberrant mTORC1 signaling is implicated in aging and age-related degeneration of the RPE. In the current study, we measured mTORC1-mediated responses to RPE phagocytosis in vivo and in vitro. During the morning burst of POS shedding, there was transient activation of mTORC1-mediated signaling in the RPE. POS activated mTORC1 through lysosome-independent mechanisms and engulfed POS served as a docking platform for mTORC1 assembly. The identification of POS as endogenous stimuli of mTORC1 in the RPE provides a mechanistic link underlying the photoreceptor-RPE interaction in the outer retina.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Egbejimi

Dharmat

et al. 2018

Sci. Signal.

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“…How A2E inhibition of v-ATPase afects these cascades is not yet understood. Few studies have characterized the status of endogenous mTORC1 and TFEB in the RPE [88][89][90] and no enough data are available for LB-loaded RPE. A likely scenario is that TFEB activation by LBs provides a irst line of defense that is insuicient to address accumulating autophagosomes containing partially degraded POS.…”

Section: Inactivation Of Lysosome-dependent Degradative Processesmentioning

confidence: 99%

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Nociari¹,

Kiss²,

Rodríguez-Boulan³

2017

Lysosomes - Associated Diseases and Methods to Study Their Function

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Photoreceptors undergo a constant renewal of their light sensitive outer segments (POSs). In the renewal process, 10% of the POS mass is daily phagocytized by the adjacent retinal pigment epithelium (RPE). POS contain vast amounts of 11-cis retinal and alltrans-retinal, two highly reactive vitamin A aldehydes that spontaneously dimerize into lipid bisretinoids (LBs) and accumulate into RPE lysosomes during phagocytosis. As LBs are refractory to lysosomal hydrolases and RPE cells do not divide, this accumulation is irreversible and results in the formation of lipofuscin granules. Lipofuscin accumulation is toxic for RPE cells through a variety of light-dependent and light-independent mechanisms. Beyond a threshold, RPE cells die resulting in secondary loss of overlying photoreceptors. Currently, there are no efective treatments for retinal disorders associated with genetic or age-associated LB accumulation, such as Stargardt disease and age-related macular degeneration (AMD). Thus, there is a great need for medical interventions. Here, we discuss the current understanding of lipofuscin's pathogenicity and the status of diferent strategies under development to promote LB elimination from RPE lysosomes.Keywords: lipofuscin, Stargardt, age-related macular degeneration (AMD), bisretinoids, retinal pigment epithelium (RPE), cyclodextrins, cellular clearance, TFEB, lysosome IntroductionTo understand the origin and consequences of the lysosomal accumulation of lipofuscin in the eye, a basic knowledge of retinal function and organization is required.© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The retinal pigment epithelium (RPE) in vertebrate's eyesLight entering the eye gets refracted by the cornea and lens on the neural retina, where photoreceptors (PR) convert photons into a cascade of chemical and electrical events that propagate to second-order (horizontal, bipolar, and amacrine cells) and third-order (ganglion cells) retinal neurons, which distribute this information to various visual centers of the brain through the ibers of the optic nerve. The bodies of PR cells, rods and cones, display three sectors (Figure 1): the outer segment, illed with stacks of disks densely packed with light-sensitive photopigment; the inner segment, illed with genetic, biosynthetic, and metabolic organelles Lysosomes -Associated Diseases and Methods to Study Their Function 4(nucleus, endoplasmic reticulum, Golgi complex, ribosomes, mitochondria); and the synaptic terminal that connects with bipolar neurons of the retina. In vertebrates, the retina is inverted in the sense that light passes through secondary and tertiary neuronal layers in the inner retina before reaching the rods and cones in the outer retina (Figure 1). Photoreceptors are metabolically very active cells that req...

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Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina

et al. 2023

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Subcellular Distribution and Activity of Mechanistic Target of Rapamycin in Aged Retinal Pigment Epithelium

Abstract: Aging changes the subcellular localization and function of mTOR in the RPE. Increased mTORC1 inhibits POS degradation and may further exacerbate lysosome dysfunction of aged RPE.

Cited by 26 publications

References 81 publications

Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina

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