دورية أكاديمية
Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells
| العنوان: | Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells |
|---|---|
| المؤلفون: | 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 |
| المصدر: | The Company of Biologists |
| بيانات النشر: | The Company of Biologists Ltd |
| سنة النشر: | 2023 |
| المجموعة: | University of Pennsylvania: ScholaryCommons@Penn |
| مصطلحات موضوعية: | Dentistry, Oxidative stress, Aging, Retina, Age-related macular degeneration, Lysosome |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| العلاقة: | https://repository.upenn.edu/handle/20.500.14332/59810Test |
| الإتاحة: | https://doi.org/20.500.14332/59810Test https://repository.upenn.edu/handle/20.500.14332/59810Test https://hdl.handle.net/20.500.14332/59810Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.CEF2158 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |