Modulatory effects of CNNM4 on Protein-L-Isoaspartyl-O-Methyltransferase repair function during Alcohol-Induced hepatic damage.

Autor:	González-Recio I; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Goikoetxea-Usandizaga N; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain., Rejano-Gordillo CM; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.; Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, University Institute of Biosanitary Research of Extremadura (INUBE), 06071 Badajoz, Spain.; Biofisika Institute, Consejo Superior de Investigaciones Científicas (CSIC), Departamento Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Leioa, Spain., Conter C; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Rodríguez Agudo R; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Serrano-Maciá M; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Zapata-Pavas LE; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Peña-Sanfélix P; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Azkargorta M; Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Elortza F; Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Herranz JM; Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, 31008 Pamplona, Spain., Guillamon Thiery Á; Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain., Guerra-Ruiz AR; Clinical Biochemistry Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain., Jover R; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain.; Experimental Hepatology Joint Research Unit, IIS Hospital La Fe & Dep. Biochemistry, University of Valencia, Spain., Galicia-Garcia U; Biofisika Institute, Consejo Superior de Investigaciones Científicas (CSIC), Departamento Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Leioa, Spain., Martín C; Biofisika Institute, Consejo Superior de Investigaciones Científicas (CSIC), Departamento Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Leioa, Spain., Schaeper U; Silence Therapeutics GmbH, Berlin, Robert Rössle Strasse 10, 13125, Berlin, Germany., Delgado TC; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Díaz-Moreno I; Institute for Chemical Research (IIQ), Scientific Research Centre 'Isla de la Cartuja' (cicCartuja), University of Seville - CSIC, Avda. Américo Vespucio 49, 41092 Seville, Spain., Díaz Quintana A; Departamento de Bioquímica Vegetal y Biologia Molecular, Facultad de Biología, Universidad de Sevilla, C. San Fernando 4, 41004 Sevilla (Spain)., Buccella D; Department of Chemistry, New York University, New York, New York 10003, United States., Nogueiras R; Molecular Metabolism Lab, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Av. Barcelona, Campus Vida, Santiago de Compostela University, 15782 Santiago de Compostela, Spain., Argemi J; Hepatology Program, Centro de Investigación Médica Aplicada (CIMA), Liver Unit, Clinica Universidad de Navarra (CUN), Instituto de Investigación de Navarra (IdisNA), University of Navarra, Pamplona, Spain.; Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA., Ávila MA; Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, 31008 Pamplona, Spain., Gratacós-Ginès J; Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain., Iruzubieta P; Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain., Pose E; Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain., Bataller R; Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA., Crespo J; Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain., Martínez-Cruz LA; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain., Martínez-Chantar ML; Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Hepatology (Baltimore, Md.) [Hepatology] 2024 Dec 06. Date of Electronic Publication: 2024 Dec 06.
DOI:	10.1097/HEP.0000000000001156
Abstrakt:	Background and Aims: Alcohol-related liver disease (ALD) is a leading cause of liver-related mortality worldwide, with limited treatment options beyond abstinence and liver transplantation. Chronic alcohol consumption has been linked to magnesium (Mg2+) deficiency, which can influence the liver disease progression. The mechanisms underlying Mg2+ homeostasis dysregulation in ALD remain elusive. This study aimed to investigate the role of the Mg2+ transporter Cyclin M4 (CNNM4) in ALD by analyzing its expression patterns in ALD patients and preclinical animal models. Approach and Results: In this study, CNNM4 is upregulated in the liver of both ALD patients and animal models. CNNM4 overexpression triggers Mg²⁺ homeostasis dysregulation, linked to ALD progression. We propose a novel therapeutic approach for ALD treatment using N-acetylgalactosamine (GalNAc) silencing RNA (siRNA) technology to specifically modulate Cnnm4 expression in the liver, improving mitochondrial function and alleviating ER stress. Notably, silencing Cnnm4 restores protein isoaspartyl methyltransferase (PCMT1) activity, essential for repairing ethanol-induced protein damage. Enhancing mitochondrial activity through Cnnm4-dependent mechanisms increases SAMe levels, crucial for PCMT1 function, highlighting the interconnected roles of mitochondrial health and protein homeostasis in ALD treatment. Conclusions: These findings shed light on the dysregulation of Mg2+ homeostasis in ALD, providing a promising therapeutic approach targeting CNNM4. GalNAc siCnnm4 therapy boost the repair processes of ethanol damaged proteins through the upregulation of PCMT1 activity. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
Databáze:	MEDLINE
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