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Autophagy Lysosomal Pathway in Ocular Physiology and Pathophysiology

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 16968

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Special Issue Editor

Dr. Paloma B. Liton

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Guest Editor

Departments of Ophthalmology & Pathology, Duke University, Durham, NC, USA
Interests: autophagy; trabecular meshwork; glaucoma; mechanotransduction; retinal ganglion cell; lysosomal enzymes; fibrosis

Special Issue Information

Dear Colleagues,

Autophagy is a dynamic catabolic process by which cytosolic material, including organelles, proteins, and pathogens, are delivered to the lysosome for degradation by the action of lysosomal hydrolases. Although autophagy was initially thought to be a bulk cytoplasmic degradation mechanism in response to starvation, numerous studies now support a key role of autophagy in maintaining cellular and tissue homeostasis. Autophagy occurs at basal levels in all cell types and is upregulated under stress conditions, as part of the adaptive cellular response to stress, providing protective functions during tissue injury. Dysregulation of the autophagy lysosomal pathway, either by overactivation or deficiency, is associated with an array of diseases and disorders.

In the eye, autophagy has been shown to play a key role in an array of physiological functions, from development to aging in all ocular tissues, including lens, retina, outflow pathway, and cornea. Non-canonical autophagy has also been implicated in promoting the visual cycle. Pathologically, defective autophagy and lysosomal degradation has been linked to the development and progression of a number of eye diseases and proposed as a therapeutic target in ocular pathology.

The aim of this Special Issue of Cells is to collect the current knowledge and advances on autophagy and lysosomal pathways in the context of ocular physiology and pathophysiology. I invite you to contribute papers in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the role of autophagy in ocular physiology and pathophysiology. Expert articles describing future therapeutics are highly welcome. I look forward to your contributions.

Dr. Paloma B. Liton
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

autophagy
lysosomes
eye
ocular diseases

Published Papers (4 papers)

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Research

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24 pages, 4490 KiB

Open AccessArticle

Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway

by Avinash Soundararajan, Sachin Anil Ghag, Sai Supriya Vuda, Ting Wang and Padmanabhan Paranji Pattabiraman

Cells 2021, 10(11), 2864; https://doi.org/10.3390/cells10112864 - 24 Oct 2021

Cited by 10 | Viewed by 2960

Abstract

The homeostasis of extracellular matrix (ECM) and actin dynamics in the trabecular meshwork (TM) outflow pathway plays a critical role in intraocular pressure (IOP) regulation. We studied the role of cathepsin K (CTSK), a lysosomal cysteine protease and a potent collagenase, on ECM modulation and actin cytoskeleton rearrangements in the TM outflow pathway and the regulation of IOP. Initially, we found that CTSK was negatively regulated by pathological stressors known to elevate IOP. Further, inactivating CTSK using balicatib, a pharmacological cell-permeable inhibitor of CTSK, resulted in IOP elevation due to increased levels and excessive deposition of ECM-like collagen-1A in the TM outflow pathway. The loss of CTSK activity resulted in actin-bundling via fascin and vinculin reorganization and by inhibiting actin depolymerization via phospho-cofilin. Contrarily, constitutive expression of CTSK decreased ECM and increased actin depolymerization by decreasing phospho-cofilin, negatively regulated the availability of active TGFβ2, and reduced the levels of alpha-smooth muscle actin (αSMA), indicating an antifibrotic action of CTSK. In conclusion, these observations, for the first time, demonstrate the significance of CTSK in IOP regulation by maintaining the ECM homeostasis and actin cytoskeleton-mediated contractile properties of the TM outflow pathway. Full article

(This article belongs to the Special Issue Autophagy Lysosomal Pathway in Ocular Physiology and Pathophysiology)

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13 pages, 1931 KiB

Open AccessArticle

Conditional Knock out of High-Mobility Group Box 1 (HMGB1) in Rods Reduces Autophagy Activation after Retinal Detachment

by Bing X. Ross, Lin Jia, Dejuan Kong, Tiantian Wang, Heather M. Hager, Steven F. Abcouwer and David N. Zacks

Cells 2021, 10(8), 2010; https://doi.org/10.3390/cells10082010 - 06 Aug 2021

Cited by 5 | Viewed by 1807

Abstract

After retinal detachment (RD), the induction of autophagy protects photoreceptors (PR) from apoptotic cell death. The cytoplasmic high-mobility group box 1 (HMGB1) promotes autophagy. We previously demonstrated that the deletion of HMGB1 from rod PRs results in a more rapid death of these cells after RD. In this work, we tested the hypothesis that the lack of HMGB1 accelerates PR death after RD due to the reduced activation of protective autophagy in the retina after RD. The injection of 1% hyaluronic acid into the subretinal space was used to create acute RD in mice with a rhodopsin-Cre-mediated conditional knockout (cKO) of HMGB1 in rods (HMGB1Δrod) and littermate controls. RD sharply increased the number of apoptotic cells in the outer nuclear layer (ONL), and this number was further increased in HMGB1Δrod mouse retinas. The activation of autophagy after RD was reduced in the HMGB1Δrod mouse retinas compared to controls, as evidenced by diminished levels of autophagy regulatory proteins LC3-II, Beclin1, ATG5/12, and phospho-ATG16L1. The cKO of HMGB1 in rods increased the expression of Fas and the Bax/Bcl-2 ratio in detached retinas, promoting apoptotic cell death. In conclusion, endogenous HMGB1 facilitates autophagy activation in PR cells following RD to promote PR cell survival and reduce programmed apoptotic cell death. Full article

(This article belongs to the Special Issue Autophagy Lysosomal Pathway in Ocular Physiology and Pathophysiology)

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28 pages, 5167 KiB

Open AccessArticle

Oligomeric Aβ_1-42 Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function

by Savannah A. Lynn, David A. Johnston, Jenny A. Scott, Rosie Munday, Roshni S. Desai, Eloise Keeling, Ruaridh Weaterton, Alexander Simpson, Dillon Davis, Thomas Freeman, David S. Chatelet, Anton Page, Angela J. Cree, Helena Lee, Tracey A. Newman, Andrew J. Lotery and J. Arjuna Ratnayaka

Cells 2021, 10(2), 413; https://doi.org/10.3390/cells10020413 - 17 Feb 2021

Cited by 9 | Viewed by 6894

Abstract

Alzheimer’s disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ_1-42, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes. Full article

(This article belongs to the Special Issue Autophagy Lysosomal Pathway in Ocular Physiology and Pathophysiology)

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Review

Jump to: Research

10 pages, 784 KiB

Open AccessReview

Mitochondrial Dysfunction and Mitophagy in Fuchs Endothelial Corneal Dystrophy

by Varun Kumar and Ula V. Jurkunas

Cells 2021, 10(8), 1888; https://doi.org/10.3390/cells10081888 - 26 Jul 2021

Cited by 17 | Viewed by 4167

Abstract

Fuchs endothelial corneal dystrophy (FECD) is a genetically complex, heterogenous, age-related degenerative disease of corneal endothelial cells (CEnCs), occurring in the fifth decade of life with a higher incidence in females. It is characterized by extracellular matrix (ECM) protein deposition called corneal guttae, causing light glare and visual complaints in patients. Corneal transplantation is the only treatment option for FECD patients, which imposes a substantial socioeconomic burden. In FECD, CEnCs exhibit stress-induced senescence, oxidative stress, DNA damage, heightened reactive oxygen species (ROS) production, mitochondrial damage, and dysfunction as well as sustained endoplasmic reticulum (ER) stress. Among all of these, mitochondrial dysfunction involving altered mitochondrial bioenergetics and dynamics plays a critical role in FECD pathogenesis. Extreme stress initiates mitochondrial damage, leading to activation of autophagy, which involves clearance of damaged mitochondria called auto(mito)phagy. In this review, we discuss the role of mitochondrial dysfunction and mitophagy in FECD. This will provide insights into a novel mechanism of mitophagy in post-mitotic ocular cell loss and help us explore the potential treatment options for FECD. Full article

(This article belongs to the Special Issue Autophagy Lysosomal Pathway in Ocular Physiology and Pathophysiology)

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