Autophagy in the eye: from physiology to pathophysiology

Autophagy Reports · 16 authors, 15 centres

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TL;DR

This comprehensive review examines the role of autophagy—a cellular degradation pathway—across all major ocular tissues, including the cornea, lens, trabecular meshwork, retina, retinal pigment epithelium (RPE), and photoreceptors. Autophagy is essential for maintaining tissue homeostasis, responding to stress (e.g., oxidative stress, mechanical forces), and supporting the visual cycle via LC3-associated phagocytosis (LAP). Dysregulation of autophagy is implicated in major eye diseases such as glaucoma, age-related macular degeneration (AMD), cataracts, corneal dystrophies, and retinitis pigmentosa, making it a potential therapeutic target, though its effects are highly context-dependent.

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**Background:** Autophagy is a catabolic, lysosome-dependent degradation pathway that includes macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Initially understood as a starvation response, it is now recognized as critical for cellular, tissue, and organismal homeostasis by recycling cellular components and eliminating damaged organelles and proteins. This review synthesizes the role of autophagy in the physiology and pathophysiology of all major ocular tissues, highlighting its dual role in protection and disease progression.

**Methods:** This is a narrative review summarizing a large body of experimental evidence, including studies using transgenic mouse models (e.g., GFP-LC3, mCherry-GFP-LC3 [auto-QC], mito-QC), knockout animals (e.g., Atg5, Atg7, Becn1, Ambra1), cell culture models, human tissue samples, and various animal models of ocular disease (e.g., DBA/2J glaucoma model, sodium iodate AMD model, P23H retinitis pigmentosa model). The review covers studies on the cornea, lens, trabecular meshwork (TM), Schlemm's canal (SC), retinal ganglion cells (RGCs), retinal pigment epithelium (RPE), and photoreceptors (PRs).

**Key Results:** - **Cornea:** Autophagy is essential for limbal stem cell regeneration (regulated by MIR103-107). In dry eye, lacritin accelerates autophagic flux via FOXO3 acetylation. Keratoconus patient samples show decreased LC3-II and LAMP1, and increased SQSTM1. HSV-1 both triggers and antagonizes autophagy via ICP34.5. In corneal endothelial dystrophies, a late autophagic block is seen in SLC4A11 null cells, while Col8a2^Q455K/Q455K mice show increased LC3-I and DRAM1. - **Lens:** Lens-specific Atg5-deficient mice develop age-associated cataracts with accumulation of polyubiquitinated proteins and SQSTM1. However, organelle degradation during lens fiber differentiation is autophagy-independent and mediated by cytosolic PLAAT-family phospholipases (PLAAT3 in mice, Plaat1 in zebrafish). Mutations in FYCO1, CHMP4B, EPG5, TBC1D20, TDRD7, RRAGA, PIKFYVE, and GJA8 are linked to cataracts with associated autophagy defects. - **Trabecular Meshwork (TM) and Outflow Pathway:** Mechanical stretch activates autophagy in TM cells within 30 minutes, mediated by primary cilia and a cross-talk between AKT1 (inhibitor) and SMAD2/3 (activator). In aging TM, LC3-II and oxidative damage increase in parallel. Glaucomatous TM cells show lower LC3-II and SQSTM1, constitutive mTOR activation, and failure to activate autophagy under hyperoxia. In MYOC^Y437H^ mice, autophagy flux is impaired due to chronic ER stress and CHOP; tat-BECN1 peptide or torin reduces IOP. - **Retinal Ganglion Cells (RGCs) and Glaucoma:** Autophagy's role is context-dependent. In chronic ocular hypertension models, inhibition with 3-MA prevented RGC loss in some studies, while rapamycin was neuroprotective in others. In acute OHT models, Ambra1^+/gt^ mice show decreased RGC survival, and rapamycin or fasting prevented RGC loss. After optic nerve crush, RGC-specific deletion of Atg5 reduced survival, while rapamycin was protective. The E50K mutation in OPTN leads to mitochondrial fission and mitophagy in RGC axons. - **RPE and AMD:** Autophagy is critical for RPE metabolic homeostasis, including fatty acid oxidation from phagocytosed outer segments. LC3-associated phagocytosis (LAP) is essential for outer segment degradation and retinoid recovery for the visual cycle. Atg5ΔRPE and Atg7ΔRPE mice show uneven RPE thickness, hypertrophy, and choroidal neovascularization. Ambra1^+/gt^ mice show lipofuscin accumulation, increased ROS, and higher sensitivity to sodium iodate. LCN2 forms a complex with ATG4B and LC3B; its dysregulation leads to iron accumulation, inflammasome activation, and ferroptosis. - **Photoreceptors (PRs):** Autophagy in PRs shows a bimodal circadian pattern linked to transducin and arrestin translocation. In retinal detachment, autophagy is activated via HIF-1α and is neuroprotective; calpain activation cleaves ATG5, reducing autophagy and increasing cell death. In the P23H rhodopsin model of retinitis pigmentosa, elevated autophagy flux is detrimental; reducing autophagy or increasing proteasome activity improves PR survival.

**Clinical Implications:** Autophagy is a fundamental process in all ocular tissues, with dysregulation linked to cataracts, glaucoma, AMD, corneal dystrophies, dry eye, and retinitis pigmentosa. However, there is no 'one-size-fits-all' approach to modulation; autophagy can be either protective or detrimental depending on the disease context, stage, and cell type. Future therapeutic strategies must consider the specific upstream activators, downstream effects, and interactions with other degradative systems (e.g., proteasome, PLAAT). The development of specific, mTOR-independent autophagy modulators is needed.

STUDY TYPE

narrative_review

SPECIALTY

ophthalmology

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88% · B

ORIGINAL PAPER

PMC10078619

Autophagy in the eye: from physiology to pathophysiology

Autophagy Reports

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ABSTRACT

ABSTRACT Autophagy is a catabolic self-degradative pathway that promotes the degradation and recycling of intracellular material through the lysosomal compartment. Although first believed to function in conditions of nutritional stress, autophagy is emerging as a critical cellular pathway, involved in a variety of physiological and pathophysiological processes. Autophagy dysregulation is associated with an increasing number of diseases, including ocular diseases. On one hand, mutations in autophagy-related genes have been linked to cataracts, glaucoma, and corneal dystrophy; on the other hand, alterations in autophagy and lysosomal pathways are a common finding in essentially all diseases of the eye. Moreover, LC3-associated phagocytosis, a form of non-canonical autophagy, is critical in promoting visual cycle function. This review collects the latest understanding of autophagy in the context of the eye. We will review and discuss the respective roles of autophagy in the physiology and/or pathophysiology of each of the ocular tissues, its diurnal/circadian variation, as well as its involvement in diseases of the eye. KEYWORDS: autophagy, eye, outflow pathway, trabecular meshwork, cornea, lens, photoreceptors, RPE, retinal epithelial cells, RGC, retina, retinal ganglion cells, glaucoma, eye diseases, AMD, corneal dystrophy, cataracts, vision cycle, lysosomes, dry eye, retinitis pigmentosa, retinal detachment

CITATION EXPORT

Paloma B Liton, Kathleen Boesze-Battaglia, Michael E Boulton et al.. Autophagy in the eye: from physiology to pathophysiology. Autophagy Reports. (2023). https://doi.org/10.1080/27694127.2023.2178996

AUTHORS

16 · 15 CENTRES

Paloma B Liton, Kathleen Boesze-Battaglia, Michael E Boulton, Patricia Boya, Thomas A Ferguson, Ian G Ganley, Anu Kauppinnen, Gordon W Laurie, Noboru Mizushima, Hideaki Morishita, Rossella Russo, Jaya Sadda, Rajalekshmy Shyam, Debasish Sinha, Debra A Thompson, David N Zacks

aDepartments of Ophthalmology & Pathology, Duke School of Medicine, Duke University, Durham, NC 27705, USA
bDepartment of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA
cDepartment of Ophthalmology and Visual Sciences, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
dDepartment of Neuroscience and Movement Science. Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland
eDepartment of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO 63110, USA
fMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
gFaculty of Health and Sciences, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland
hDepartments of Cell Biology, Ophthalmology and Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
iDepartment of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, 113-0033, Japan
jDepartment of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan
kPreclinical and Translational Pharmacology, Glaucoma Unit, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
lDepartment of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA
mSchool of Optometry, Indiana University, Bloomington, IN 47405, USA
nDepartment of Ophthalmology, Cell Biology, and Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
oWilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA