Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage

Irene González-Recio ¹, Naroa Goikoetxea-Usandizaga ^1,2, Claudia M Rejano-Gordillo ^1,3,4

¹Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.
²Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain.
³Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, University Institute of Biosanitary Research of Extremadura (INUBE), Badajoz, Spain.
⁴Biofisika Institute (UPV/EHU, CSIC), UPV/EHU Science Park, and Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa, Spain.
⁵Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.
⁶Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Pamplona, Spain.
⁷Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain.
⁸Clinical Biochemistry, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
⁹Experimental Hepatology Joint Research Unit, IIS Hospital La Fe & Dep. Biochemistry, University of Valencia, Valencia, Spain.
¹⁰Silence Therapeutics GmbH, Berlin, Berlin, Germany.
¹¹Institute for Chemical Research (IIQ), Scientific Research Centre "Isla de la Cartuja" (cicCartuja), University of Seville-CSIC, Seville, Spain.
¹²Departamento de Bioquímica Vegetal y Biologia Molecular, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
¹³Department of Chemistry, New York University, New York, New York, USA.
¹⁴Molecular Metabolism Lab, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Av. Barcelona, Campus Vida, Santiago de Compostela University, Santiago de Compostela, Spain.
¹⁵Hepatology 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.
¹⁶Division of Gastroenterology, Hepatology, and Nutrition, Center for Liver Diseases, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
¹⁷Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain.

⁰Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.

Hepatology Forum +

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December 6, 2024

View abstract on PubMed

Summary

This study reveals that Cyclin M4 (CNNM4) is upregulated in alcohol-associated liver disease (ALD), disrupting magnesium (Mg2+) balance. Targeting CNNM4 with N-acetylgalactosamine siRNA offers a novel therapeutic strategy for ALD by restoring protein repair mechanisms.

Area Of Science

Hepatology
Molecular Biology
Biochemistry

Background

Alcohol-associated liver disease (ALD) is a major cause of liver mortality with few treatment options.
Chronic alcohol use is linked to magnesium (Mg2+) deficiency, impacting liver disease progression.
Mechanisms of Mg2+ homeostasis disruption in ALD are not fully understood.

Purpose Of The Study

Investigate the role of the Mg2+ transporter CNNM4 in ALD.
Analyze CNNM4 expression in ALD patients and animal models.
Explore CNNM4 as a therapeutic target for ALD.

Main Methods

Expression analysis of CNNM4 in liver tissues from ALD patients and animal models.
Utilized N-acetylgalactosamine silencing RNA (siRNA) technology to modulate Cnnm4 expression.
Assessed Mg2+ homeostasis, mitochondrial function, endoplasmic reticulum stress, and PCMT1 activity.

Main Results

CNNM4 expression is upregulated in the livers of ALD patients and animal models.
CNNM4 overexpression exacerbates Mg2+ dysregulation and ALD progression.
N-acetylgalactosamine siRNA targeting Cnnm4 improved mitochondrial function, reduced ER stress, and restored PCMT1 activity.
Silencing Cnnm4 enhanced S-adenosylmethionine levels, supporting PCMT1 function in repairing ethanol-induced protein damage.

Conclusions

Mg2+ homeostasis dysregulation is implicated in ALD, with CNNM4 playing a key role.
Targeting CNNM4 with N-acetylgalactosamine siRNA presents a promising therapeutic strategy for ALD.
This therapy enhances protein repair pathways, specifically PCMT1 activity, offering a novel treatment avenue.

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