دورية أكاديمية
Sumoylation of methionine adenosyltransferase alpha 1 promotes mitochondrial dysfunction in alcohol-associated liver disease.
| العنوان: | Sumoylation of methionine adenosyltransferase alpha 1 promotes mitochondrial dysfunction in alcohol-associated liver disease. |
|---|---|
| المؤلفون: | Floris A; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Chandla S; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Lim Y; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA., Barbier-Torres L; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Seth K; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Khangholi A; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Li TWH; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Robison A; Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA., Murray BJ; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Lee S; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Matsuda M; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Murali R; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA., Tomasi ML; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA., Lu SC; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA. |
| المصدر: | Hepatology (Baltimore, Md.) [Hepatology] 2024 Jul 01; Vol. 80 (1), pp. 102-118. Date of Electronic Publication: 2023 Dec 15. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 8302946 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1527-3350 (Electronic) Linking ISSN: 02709139 NLM ISO Abbreviation: Hepatology Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc. Original Publication: Baltimore, MD : Williams & Wilkins, [c1981]- |
| مواضيع طبية MeSH: | Methionine Adenosyltransferase*/metabolism , Methionine Adenosyltransferase*/genetics , Sumoylation* , Liver Diseases, Alcoholic*/metabolism , Liver Diseases, Alcoholic*/etiology , Liver Diseases, Alcoholic*/genetics, Animals ; Mice ; Humans ; Mitochondria, Liver/metabolism ; Male ; Hepatocytes/metabolism ; Liver/metabolism |
| مستخلص: | Background and Aims: Methionine adenosyltransferase alpha1 (MATα1) is responsible for the biosynthesis of S-adenosylmethionine in normal liver. Alcohol consumption enhances MATα1 interaction with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which blocks MATα1 mitochondrial targeting, resulting in lower mitochondrial MATα1 content and mitochondrial dysfunction in alcohol-associated liver disease (ALD) in part through upregulation of cytochrome P450 2E1. Conversely, alcohol intake enhances SUMOylation, which enhances cytochrome P450 2E1 expression. MATα1 has potential SUMOylation sites, but whether MATα1 is regulated by SUMOylation in ALD is unknown. Here, we investigated if MATα1 is regulated by SUMOylation and, if so, how it impacts mitochondrial function in ALD. Approach and Results: Proteomics profiling revealed hyper-SUMOylation of MATα1, and prediction software identified lysine 48 (K48) as the potential SUMOylation site in mice (K47 in humans). Experiments with primary hepatocytes, mouse, and human livers revealed that SUMOylation of MAT1α by SUMO2 depleted mitochondrial MATα1. Furthermore, mutation of MATα1 K48 prevented ethanol-induced mitochondrial membrane depolarization, MATα1 depletion, and triglyceride accumulation. Additionally, CRISPR/CRISPR associated protein 9 gene editing of MATα1 at K48 hindered ethanol-induced MATα1-PIN1 interaction, degradation, and phosphorylation of MATα1 in vitro. In vivo, CRISPR/CRISPR associated protein 9 MATα1 K48 gene-edited mice were protected from ethanol-induced fat accumulation, liver injury, MATα1-PIN1 interaction, mitochondrial MATα1 depletion, mitochondrial dysfunction, and low S-adenosylmethionine levels. Conclusions: Taken together, our findings demonstrate an essential role for SUMOylation of MATα1 K48 for interaction with PIN1 in ALD. Preventing MATα1 K48 SUMOylation may represent a potential treatment strategy for ALD. (Copyright © 2023 American Association for the Study of Liver Diseases.) |
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| معلومات مُعتمدة: | R01 AA026759 United States AA NIAAA NIH HHS; R01 AA029723 United States AA NIAAA NIH HHS |
| المشرفين على المادة: | EC 2.5.1.6 (Methionine Adenosyltransferase) EC 2.5.1.6 (Mat1a protein, mouse) EC 2.5.1.6 (MAT1A protein, human) |
| تواريخ الأحداث: | Date Created: 20231215 Date Completed: 20240619 Latest Revision: 20240709 |
| رمز التحديث: | 20240709 |
| مُعرف محوري في PubMed: | PMC11178676 |
| DOI: | 10.1097/HEP.0000000000000717 |
| PMID: | 38100286 |
| قاعدة البيانات: | MEDLINE |
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