Browsing by Author "Lopitz-Otsoa, Fernando"

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    Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease
    (Springer Nature, 2022-01-28) Barbier-Torres, Lucía; Murray, Ben; Yang, Jin Won; Wang, Jiaohong; Matsuda, Michitaka; Robinson, Aaron; Binek, Aleksandra; Fan, Wei; Fernández-Ramos, David; Lopitz-Otsoa, Fernando; Luque-Urbano, Maria; Millet, Oscar; Mavila, Nirmala; Peng, Hui; Ramani, Komal; Gottlieb, Roberta; Sun, Zhaoli; Liangpunsakul, Suthat; Seki, Ekihiro; Van Eyk, Jennifer E.; Mato, Jose M.; Lu, Shelly C.; Medicine, School of Medicine
    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.