Depletion of mitochondrial methionine adenosyltransferase \u03b11 triggers mitochondrial dysfunction in alcohol-associated liver disease

Lucía Barbier-Torres,Ben Murray,Aaron Robinson,Jin Won Yang,Roberta A Gottlieb ,David Fernández‐Ramos ,Michitaka Matsuda,Zhaoli Sun,Komal Ramani,Ekihiro Seki,Nirmala Mavila,Jennifer E Van Eyk,Aleksandra Binek,Hui Peng,Fernando Lopitz‐Otsoa ,Suthat Liangpunsakul,Òscar Millet ,Maria Luque-Urbano,Wei Fan,Jiaohong Wang,José M Mato ,Shelly C Lu

doi:10.1038/s41467-022-28201-2

Abstract

MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function. Here, we show that mitochondrial MATα1 is selectively depleted in alcohol-associated liver disease through a mechanism that involves the isomerase PIN1 and the kinase CK2. Alcohol activates CK2, which phosphorylates MATα1 at Ser114 facilitating interaction with PIN1, thereby inhibiting its mitochondrial localization. Blocking PIN1-MATα1 interaction increased mitochondrial MATα1 levels and protected against alcohol-induced mitochondrial dysfunction and fat accumulation. Normally, MATα1 interacts with mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and fatty acid β-oxidation. Preserving mitochondrial MATα1 content correlates with higher methylation and expression of mitochondrial proteins. Our study demonstrates a role of CK2 and PIN1 in reducing mitochondrial MATα1 content leading to mitochondrial dysfunction in alcohol-associated liver disease.

Highlights

Methionine adenosyltransferase α1 (MATα1) catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor
We demonstrated that MATα1 normally interacts with mitochondrial proteins that participate in important mitochondrial metabolic pathways and that preserving mitochondrial MATα1 correlates with higher methylation and expression of mitochondrial proteins
To investigate whether an alteration in mitochondrial MATα1 could be involved in the pathogenesis of associated liver disease (ALD), we evaluated MATα1 levels in different ALD models

Summary

Introduction

MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. We show that mitochondrial MATα1 is selectively depleted in alcohol-associated liver disease through a mechanism that involves the isomerase PIN1 and the kinase CK2. Alcohol activates CK2, which phosphorylates MATα1 at Ser[114] facilitating interaction with PIN1, thereby inhibiting its mitochondrial localization. Our study demonstrates a role of CK2 and PIN1 in reducing mitochondrial MATα1 content leading to mitochondrial dysfunction in alcoholassociated liver disease. MATα1 is highly expressed in normal liver but its activity and SAMe levels are reduced in disease including ALD5. PIN1 can promote or inhibit the mitochondrial translocation of target proteins thereby regulating mitochondrial function[9], oxidative stress[9,10], and apoptosis[11,12]. CK2 has been implicated in many human diseases including NASH19 and HCC20 and was found upregulated in ethanol-treated hepatocytes[21]

Methods

Results

Conclusion