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

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 SungAnuradha Dhingra, Kathleen Boesze-Battaglia, Venkata R.M. Chavali, Joshua D. Rabinowitz, Claire H. Mitchell, Joshua L. Dunaief

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly, with retinal pigment epithelial (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 iPS-RPE cells increased lysosomal abundance, impaired proteolysis, and reduced the activity of a subset of lysosomal enzymes, including lysosomal acid lipase and acid sphingomyelinase. In a 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 had impaired maturation. A large proportion of lysosomes were galectin-3 positive, suggesting cytotoxic lysosomal membrane permeabilization (LMP). 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.

Original languageEnglish (US)
JournalDMM Disease Models and Mechanisms
Volume16
Issue number7
DOIs
StatePublished - Jul 2023

All Science Journal Classification (ASJC) codes

  • Immunology and Microbiology (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology
  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)

Keywords

  • Oxidative stress
  • age-related macular degeneration
  • aging
  • lysosome
  • retina

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