Dataset Information

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

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 systemiciron 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 oflysosomes 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Hossein Fazelinia

LAB HEAD: Joshua Dunaief, PhD, MD

PROVIDER: PXD043613 | Pride | 2023-07-19

REPOSITORIES: Pride

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

Zhang Kevin R KR Jankowski Connor S R CSR Marshall Rayna R Nair Rohini R Más Gómez Néstor N Alnemri Ahab A Liu Yingrui Y Erler Elizabeth E Ferrante Julia J Song Ying Y Bell Brent A BA Baumann Bailey H BH Sterling Jacob J Anderson Brandon B Foshe Sierra S Roof Jennifer J Fazelinia Hossein H Spruce Lynn A LA Chuang Jen-Zen JZ Sung Ching-Hwa CH Dhingra Anuradha A Boesze-Battaglia Kathleen K Chavali Venkata R M VRM Rabinowitz Joshua D JD Mitchell Claire H CH Dunaief Joshua L JL

Disease models & mechanisms 20230725 7

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 abu ...[more]

PMID: 37401371

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Project description:Hydrogen can be an important source of energy for chemolithotrophic acidophiles, especially in the deep terrestrial subsurface. Nevertheless, the current knowledge of microbial hydrogen utilization in acidic environments is minimal. A multi-omics analysis was applied on Acidithiobacillus ferrooxidans growing aerobically and anaerobically (with ferric iron) on hydrogen as an electron donor, and a respiratory model proposed from the results obtained. In this model, both [NiFe] hydrogenases, cytoplasmic uptake and membrane-bound respiratory, oxidize molecular hydrogen to two protons and two electrons. The electrons are used to reduce membrane-soluble ubiquinone to ubiquinol. Genetically associated [FeS]-binding proteins mediate electron relay from the hydrogenases to the ubiquinone pool. Under aerobic conditions, reduced ubiquinol transfers electrons to either cytochrome aa3 oxidase via cytochrome bc1 complex and cytochrome c4 or the alternate directly to cytochrome bd oxidase, resulting in proton efflux together with the reduction of molecular oxygen to water. Under anaerobic conditions, reduced ubiquinol transfers electrons to outer membrane cytochrome c (ferric iron reductase) via cytochrome bc1 complex and a cascade of electron transporters (cytochrome c4, cytochrome c552, rusticyanin, and high potential iron-sulfur protein), resulting in proton efflux together with the reduction of ferric iron to ferrous iron. The proton gradient generated by molecular hydrogen oxidation maintains the membrane potential and allows the generation of ATP via ATP synthase and NADH via NADH-ubiquinone oxidoreductase. To a lesser extent, NADH can also be generated by another bidirectional cytoplasmic hydrogenase. ATP and NADH are further utilized in the Calvin–Benson–Bassham cycle for inorganic carbon uptake and assimilation. These results further clarify the role of extremophiles in biogeochemical processes and their impact on the composition and features of the deep terrestrial subsurface from the distant past to the present.

Dataset Information

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

Publications

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

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