ArticleCellular and molecular gastroenterology and hepatology2019
Oxygen and Conformation Dependent Protein Oxidation and Aggregation by Porphyrins in Hepatocytes and Light-Exposed Cells.
Article in Cellular and molecular gastroenterology and hepatology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
- 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
- Practical Recommendations in the Treatment of Acute and Chronic Life-Threatening Infectious Diseases in Patients with Acute Hepatic Porphyria.Metabolites · 2025Review
- Causal effect of porphyria biomarkers on alcohol-related hepatocellular carcinoma through Mendelian Randomization.PloS one · 2024Article
- Protoporphyrin IX-induced phototoxicity: Mechanisms and therapeutics.Pharmacology & therapeutics · 2023Review
- BALB.NCT-Molecular genetics and metabolism reports · 2023Article
- Significance of Singlet Oxygen Molecule in Pathologies.International journal of molecular sciences · 2023Review
- Mechanisms of Phototoxic Effects of Cationic Porphyrins on Human Cells In Vitro.Molecules (Basel, Switzerland) · 2023Article
- Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria.Diagnostics (Basel, Switzerland) · 2022Review
- 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
- 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
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsPorphyrias are caused by porphyrin accumulation resulting from defects in the heme biosynthetic pathway that typically lead to photosensitivity and possible end-stage liver disease with an increased risk of hepatocellular carcinoma. Our aims were to study the mechanism of porphyrin-induced cell damage and protein aggregation, including liver injury, where light exposure is absent.
methodsPorphyria was induced in vivo in mice using 3,5-diethoxycarbonyl-1,4-dihydrocollidine or in vitro by exposing human liver Huh7 cells and keratinocytes, or their lysates, to protoporphyrin-IX, other porphyrins, or to δ-aminolevulinic acid plus deferoxamine. The livers, cultured cells, or porphyrin exposed purified proteins were analyzed for protein aggregation and oxidation using immunoblotting, mass spectrometry, and electron paramagnetic resonance spectroscopy. Consequences on cell-cycle progression were assessed.
resultsPorphyrin-mediated protein aggregation required porphyrin-photosensitized singlet oxygen and porphyrin carboxylate side-chain deprotonation, and occurred with site-selective native protein methionine oxidation. Noncovalent interaction of protoporphyrin-IX with oxidized proteins led to protein aggregation that was reversed by incubation with acidified n-butanol or high-salt buffer. Phototoxicity and the ensuing proteotoxicity, mimicking porphyria photosensitivity conditions, were validated in cultured keratinocytes. Protoporphyrin-IX inhibited proteasome function by aggregating several proteasomal subunits, and caused cell growth arrest and aggregation of key cell proliferation proteins. Light-independent synergy of protein aggregation was observed when porphyrin was applied together with glucose oxidase as a secondary peroxide source.
conclusionsPhoto-excitable porphyrins with deprotonated carboxylates mediate protein aggregation. Porphyrin-mediated proteotoxicity in the absence of light, as in the liver, requires porphyrin accumulation coupled with a second tissue oxidative injury. These findings provide a potential mechanism for internal organ damage and photosensitivity in porphyrias.
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