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Oxidative stress and dysfunctional intracellular traffic linked to an unhealthy diet results in impaired cargo transport in the Retinal Pigment Epithelium (RPE)

Oxidative stress and dysfunctional intracellular traffic linked to an unhealthy diet results in impaired cargo transport in the Retinal Pigment Epithelium (RPE)
Oxidative stress and dysfunctional intracellular traffic linked to an unhealthy diet results in impaired cargo transport in the Retinal Pigment Epithelium (RPE)
Scope: oxidative stress and dysregulated intracellular trafficking are associated with an unhealthy diet which underlies pathology. Here, we sought to study these effects on photoreceptor outer segment (POS) trafficking in the Retinal Pigment Epithelium (RPE), a major pathway of disease underlying irreversible sight-loss.

Methods and results: POS trafficking was studied in ARPE-19 cells using an algorithm-based quantification of confocal-immunofluorescence data supported by ultrastructural studies. We show that although POS are tightly regulated and trafficked via Rab5, Rab7 vesicles, LAMP1/2 lysosomes and LC3b-autophagosomes, there is also a considerable degree of variation and flexibility in this process. Treatment with H2 O2 and bafilomycin A1 revealed that oxidative stress and dysregulated autophagy target intracellular compartments and trafficking in strikingly different ways. These effects appeared limited to POS-containing vesicles, suggesting a cargo-specific effect.

Conclusions: our findings offer insights into how RPE cells cope with stress, and how mechanisms influencing POS transport/degradation can have different outcomes in the senescent retina. These shed new light on cellular processes underlying retinopathies such as Age-related Macular Degeneration. Our discoveries reveal how diet and nutrition can cause fundamental alterations at a cellular level, thus contributing to a better understanding of the diet-disease axis. This article is protected by copyright. All rights reserved.
cargo trafficking, oxidative stress, phagosome and autophagy-lysosomal pathways, retinal pigment epithelium (RPE)
1613-4133
Keeling, Eloise
abc30700-b1ed-49ed-ba1c-078856e01b7c
Chatelet, David
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Johnston, David
b41163c9-b9d2-425c-af99-2a357204014e
Page, Anton
76ebbfb8-4fe3-495c-afff-1f2f34977fee
Tumbarello, David
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Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Keeling, Eloise
abc30700-b1ed-49ed-ba1c-078856e01b7c
Chatelet, David
6371fd7a-e274-4738-9ccb-3dd4dab32928
Johnston, David
b41163c9-b9d2-425c-af99-2a357204014e
Page, Anton
76ebbfb8-4fe3-495c-afff-1f2f34977fee
Tumbarello, David
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd

Keeling, Eloise, Chatelet, David, Johnston, David, Page, Anton, Tumbarello, David, Lotery, Andrew and Ratnayaka, J. Arjuna (2019) Oxidative stress and dysfunctional intracellular traffic linked to an unhealthy diet results in impaired cargo transport in the Retinal Pigment Epithelium (RPE). Molecular Nutrition & Food Research. (doi:10.1002/mnfr.201800951).

Record type: Article

Abstract

Scope: oxidative stress and dysregulated intracellular trafficking are associated with an unhealthy diet which underlies pathology. Here, we sought to study these effects on photoreceptor outer segment (POS) trafficking in the Retinal Pigment Epithelium (RPE), a major pathway of disease underlying irreversible sight-loss.

Methods and results: POS trafficking was studied in ARPE-19 cells using an algorithm-based quantification of confocal-immunofluorescence data supported by ultrastructural studies. We show that although POS are tightly regulated and trafficked via Rab5, Rab7 vesicles, LAMP1/2 lysosomes and LC3b-autophagosomes, there is also a considerable degree of variation and flexibility in this process. Treatment with H2 O2 and bafilomycin A1 revealed that oxidative stress and dysregulated autophagy target intracellular compartments and trafficking in strikingly different ways. These effects appeared limited to POS-containing vesicles, suggesting a cargo-specific effect.

Conclusions: our findings offer insights into how RPE cells cope with stress, and how mechanisms influencing POS transport/degradation can have different outcomes in the senescent retina. These shed new light on cellular processes underlying retinopathies such as Age-related Macular Degeneration. Our discoveries reveal how diet and nutrition can cause fundamental alterations at a cellular level, thus contributing to a better understanding of the diet-disease axis. This article is protected by copyright. All rights reserved.

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Accepted/In Press date: 28 February 2019
e-pub ahead of print date: 5 March 2019
Keywords: cargo trafficking, oxidative stress, phagosome and autophagy-lysosomal pathways, retinal pigment epithelium (RPE)

Identifiers

Local EPrints ID: 429999
URI: https://eprints.soton.ac.uk/id/eprint/429999
ISSN: 1613-4133
PURE UUID: e26bf045-ec7d-407a-94d7-fd9ff126aee3
ORCID for David Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for David Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938

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Date deposited: 09 Apr 2019 16:30
Last modified: 26 Apr 2019 00:35

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