Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage
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Zenodo
2024
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| author | González-Recio I Goikoetxea-Usandizaga N Rejano-Gordillo CM Conter C Rodríguez Agudo R Serrano-Maciá M Zapata-Pavas LE Peña-Sanfélix P Azkargorta M Elortza F Herranz JM Guillamon Thiery Á Guerra-Ruiz AR Jover R Galicia- Garcia U Martín C Schaeper U Delgado TC Díaz-Moreno I Díaz Quintana A Buccella D Nogueiras R Argemi J Ávila MA Gratacós-Ginès J Iruzubieta P Pose E Bataller R Crespo J Martínez-Cruz LA Martínez-Chantar ML |
| author_facet | González-Recio I Goikoetxea-Usandizaga N Rejano-Gordillo CM Conter C Rodríguez Agudo R Serrano-Maciá M Zapata-Pavas LE Peña-Sanfélix P Azkargorta M Elortza F Herranz JM Guillamon Thiery Á Guerra-Ruiz AR Jover R Galicia- Garcia U Martín C Schaeper U Delgado TC Díaz-Moreno I Díaz Quintana A Buccella D Nogueiras R Argemi J Ávila MA Gratacós-Ginès J Iruzubieta P Pose E Bataller R Crespo J Martínez-Cruz LA Martínez-Chantar ML |
| contents | <p><strong>Abstract</strong><br><strong>Background and Aims</strong>: Alcohol-associated liver disease (ALD) is a<br>leading cause of liver-related mortality worldwide, with limited treatment<br>options beyond abstinence and liver transplantation. Chronic alcohol<br>consumption has been linked to magnesium (Mg2+) deficiency, which can<br>influence liver disease progression. The mechanisms underlying Mg2+<br>homeostasis dysregulation in ALD remain elusive. This study aimed to<br>investigate the role of the Mg2+ transporter Cyclin M4 (CNNM4) in ALD by<br>analyzing its expression patterns in patients with ALD and preclinical<br>animal models.<br><strong>Approach and Results</strong>: In this study, CNNM4 is upregulated in the liver of<br>both patients with ALD and animal models. CNNM4 overexpression triggers<br>Mg2+ homeostasis dysregulation, linked to ALD progression. We<br>propose a novel therapeutic approach for ALD treatment using N-acetylgalactosamine<br>silencing RNA technology to specifically modulate<br>Cnnm4 expression in the liver, improving mitochondrial function and alleviating<br>endoplasmic reticulum stress. Notably, silencing Cnnm4 restores<br>protein isoaspartyl methyltransferase (PCMT1) activity, essential for<br>repairing ethanol-induced protein damage. Enhancing mitochondrial<br>activity through Cnnm4-dependent mechanisms increases S-adenosylmethionine<br>levels, crucial for PCMT1 function, highlighting the interconnected<br>roles of mitochondrial health and protein homeostasis in ALD<br>treatment.<br><strong>Conclusions</strong>: These findings shed light on the dysregulation of Mg2+<br>homeostasis in ALD, providing a promising therapeutic approach targeting<br>CNNM4. N-acetylgalactosamine siCnnm4 therapy boosts the repair processes<br>of ethanol-damaged proteins through the upregulation of PCMT1<br>activity.<br><strong>Keywords</strong>: alcohol, ALD, hepatotoxicity, magnesium</p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_1097_HEP_0000000000001156 |
| institution | Zenodo |
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| publishDate | 2024 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage González-Recio I Goikoetxea-Usandizaga N Rejano-Gordillo CM Conter C Rodríguez Agudo R Serrano-Maciá M Zapata-Pavas LE Peña-Sanfélix P Azkargorta M Elortza F Herranz JM Guillamon Thiery Á Guerra-Ruiz AR Jover R Galicia- Garcia U Martín C Schaeper U Delgado TC Díaz-Moreno I Díaz Quintana A Buccella D Nogueiras R Argemi J Ávila MA Gratacós-Ginès J Iruzubieta P Pose E Bataller R Crespo J Martínez-Cruz LA Martínez-Chantar ML <p><strong>Abstract</strong><br><strong>Background and Aims</strong>: Alcohol-associated liver disease (ALD) is a<br>leading cause of liver-related mortality worldwide, with limited treatment<br>options beyond abstinence and liver transplantation. Chronic alcohol<br>consumption has been linked to magnesium (Mg2+) deficiency, which can<br>influence liver disease progression. The mechanisms underlying Mg2+<br>homeostasis dysregulation in ALD remain elusive. This study aimed to<br>investigate the role of the Mg2+ transporter Cyclin M4 (CNNM4) in ALD by<br>analyzing its expression patterns in patients with ALD and preclinical<br>animal models.<br><strong>Approach and Results</strong>: In this study, CNNM4 is upregulated in the liver of<br>both patients with ALD and animal models. CNNM4 overexpression triggers<br>Mg2+ homeostasis dysregulation, linked to ALD progression. We<br>propose a novel therapeutic approach for ALD treatment using N-acetylgalactosamine<br>silencing RNA technology to specifically modulate<br>Cnnm4 expression in the liver, improving mitochondrial function and alleviating<br>endoplasmic reticulum stress. Notably, silencing Cnnm4 restores<br>protein isoaspartyl methyltransferase (PCMT1) activity, essential for<br>repairing ethanol-induced protein damage. Enhancing mitochondrial<br>activity through Cnnm4-dependent mechanisms increases S-adenosylmethionine<br>levels, crucial for PCMT1 function, highlighting the interconnected<br>roles of mitochondrial health and protein homeostasis in ALD<br>treatment.<br><strong>Conclusions</strong>: These findings shed light on the dysregulation of Mg2+<br>homeostasis in ALD, providing a promising therapeutic approach targeting<br>CNNM4. N-acetylgalactosamine siCnnm4 therapy boosts the repair processes<br>of ethanol-damaged proteins through the upregulation of PCMT1<br>activity.<br><strong>Keywords</strong>: alcohol, ALD, hepatotoxicity, magnesium</p> |
| title | Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage |
| url | https://doi.org/10.1097/HEP.0000000000001156 |