ArticleThe Journal of biological chemistry2015
Ambient Light Promotes Selective Subcellular Proteotoxicity after Endogenous and Exogenous Porphyrinogenic Stress.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- Animal Models of Porphyria with Hepatic Involvement.Seminars in liver disease · 2025Review
- Porphyrias: Pathophysiology and clinical management recommendations for hepatologists.Hepatology communications · 2025Review
- Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches.World journal of hepatology · 2025Review
- Scavenger endothelial cells alleviate tissue damage by engulfing toxic molecules derived from hemolysis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Surface Acoustic Wave-Enhanced Multi-View Acoustofluidic Rotation Cytometry (MARC) for Pre-Cytopathological Screening.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- BALB.NCT-Molecular genetics and metabolism reports · 2023Article
- Analysis of Renal Cell Carcinoma Cell Response to the Enhancement of 5-aminolevulinic Acid-mediated Protoporphyrin IX Fluorescence by Iron Chelator DeferoxaminePhotochemistry and photobiology · 2023Article
- Significance of Singlet Oxygen Molecule in Pathologies.International journal of molecular sciences · 2023Review
- Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications.Diagnostics (Basel, Switzerland) · 2021Review
- Chimeric Mouse With Humanized Liver Is an Appropriate Animal Model to Investigate Mode of Action for Porphyria-Mediated Hepatocytotoxicity.Toxicologic pathology · 2021Article
- Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models.Scientific reports · 2021Article
- Geographic prevalence variation and phenotype penetrance in porphyria: insights from a Chinese population database.Blood advances · 2021Article
- Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations.Frontiers in neuroscience · 2021Review
- A Novel Mechanism for NF-κB-activation via IκB-aggregation: Implications for Hepatic Mallory-Denk-Body Induced Inflammation.Molecular & cellular proteomics : MCP · 2020Article
- Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury.Cellular and molecular gastroenterology and hepatology · 2019Review
- Oxygen and Conformation Dependent Protein Oxidation and Aggregation by Porphyrins in Hepatocytes and Light-Exposed Cells.Cellular and molecular gastroenterology and hepatology · 2019Article
- Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury.Journal of hepatology · 2019Article
- Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease.Gastroenterology · 2018Review
- Intermediate filament proteins of digestive organs: physiology and pathophysiology.American journal of physiology. Gastrointestinal and liver physiology · 2017Review
- A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Hepatic accumulation of protoporphyrin-IX (PP-IX) in erythropoietic protoporphyria (EPP) or X-linked-dominant protoporphyria (XLP) cause liver damage. Hepatocyte nuclear lamin aggregation is a sensitive marker for PP-IX-mediated liver injury. We tested the hypothesis that extracellular or intracellular protoporphyria cause damage to different subcellular compartments, in a light-triggered manner. Three hepatoma cell lines (HepG2, Hepa-1, and Huh-7) were treated with exogenous PP-IX (mimicking XLP extrahepatic protoporphyria) or with the iron chelator deferoxamine and the porphyrin precursor 5-aminolevulinic acid (ALA) (mimicking intracellular protoporphyrin accumulation in EPP). Exogenous PP-IX accumulated predominantly in the nuclear fraction and caused nuclear shape deformation and cytoplasmic vacuoles containing electron-dense particles, whereas ALA+deferoxamine treatment resulted in higher PP-IX in the cytoplasmic fraction. Protein aggregation in the nuclear and cytoplasmic fractions paralleled PP-IX levels and, in cell culture, the effects were exclusively ambient light-mediated. PP-IX and ALA caused proteasomal inhibition, whereas endoplasmic reticulum protein aggregation was more prominent in ALA-treated cells. The enhanced ALA-related toxicity is likely due to generation of additional porphyrin intermediates including uroporphyrin and coproporphyrin, based on HPLC analysis of cell lysates and the culture medium, as well as cell-free experiments with uroporphyrin/coproporphyrin. Mouse livers from drug-induced porphyria phenocopied the in vitro findings, and mass spectrometry of liver proteins isolated in light/dark conditions showed diminished (as compared with light-harvested) but detectable aggregation under dark-harvested conditions. Therefore, PP-IX leads to endoplasmic reticulum stress and proteasome inhibition in a manner that depends on the source of porphyrin buildup and light exposure. Porphyrin-mediated selective protein aggregation provides a potential mechanism for porphyria-associated tissue injury.
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Registered trials
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