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other·ophthalmology, retina, preclinical research, biomedical research·PMC10399446

Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells

Disease Models & Mechanisms · 26 authors, 7 centres

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TL;DR

This preclinical study used human iPS-derived retinal pigment epithelial (RPE) cells and a mouse model to investigate how iron overload induces lysosomal dysfunction.

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The researchers incubated human iPS-derived RPE cells with iron for up to 9 weeks and also studied a mouse model of systemic iron overload (LS-Hepc^KO^). The central results show that chronic iron exposure causes lysosomal accumulation, impaired proteolysis, lysosomal membrane permeabilization (LMP), and the buildup of toxic lipid peroxidation products and ceramides. In the mouse model, these changes ultimately led to RPE cell death. A key mechanistic insight is that impaired lysosomal function also reduces autophagic clearance, exacerbating cellular stress. The study provides a detailed pathway linking iron overload to the specific RPE phenotypes observed in AMD.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10399446

Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells

Disease Models & Mechanisms

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ABSTRACT

ABSTRACT Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured induced pluripotent stem cell-derived RPE cells increased lysosomal abundance, impaired proteolysis and reduced the activity of a subset of lysosomal enzymes, including lysosomal acid lipase (LIPA) and acid sphingomyelinase (SMPD1). In a liver-specific Hepc ( Hamp ) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes and ceramides. The proteolytic enzyme cathepsin D (CTSD) had impaired maturation. A large proportion of lysosomes were galectin-3 (Lgals3) positive, suggesting cytotoxic lysosomal membrane permeabilization. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely due to iron-induced lipid peroxides that can inhibit lysosomal enzymes. Keywords: Oxidative stress, Aging, Retina, Age-related macular degeneration, Lysosome

CITATION EXPORT

Kevin R Zhang, Connor S R Jankowski, Rayna Marshall et al.. Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells. Disease Models & Mechanisms. (2023). https://doi.org/10.1242/dmm.050066

AUTHORS

26 · 7 CENTRES

Kevin R Zhang, Connor S R Jankowski, Rayna Marshall, Rohini Nair, Néstor Más Gómez, Ahab Alnemri, Yingrui Liu, Elizabeth Erler, Julia Ferrante, Ying Song, Brent A Bell, Bailey H Baumann, Jacob Sterling, Brandon Anderson, Sierra Foshe, Jennifer Roof, Hossein Fazelinia, Lynn A Spruce, Jen-Zen Chuang, Ching-Hwa Sung, Anuradha Dhingra, Kathleen Boesze-Battaglia, Venkata R M Chavali, Joshua D Rabinowitz, Claire H Mitchell, Joshua L Dunaief

1F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
2Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
3Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
4Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
5CHOP-PENN Proteomics Core Facility, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA
6Department of Ophthalmology, Weill Cornell Medicine, New York, NY 10065, USA
7Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY 10065, USA