Browsing by Author "Ramani, Komal"

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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.
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    S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver
    (Ivyspring, 2024-01-27) Barbier-Torres, Lucía; Chhimwal, Jyoti; Kim, So Yeon; Ramani, Komal; Robinson, Aaron; Yang, Heping; Van Eyk, Jenny; Liangpunsakul, Suthat; Seki, Ekihiro; Mato, José M.; Lu, Shelly C.; Biochemistry and Molecular Biology, School of Medicine
    MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced MAT1A expression and SAMe levels along with mitochondrial injury. MCJ silencing protected against alcohol-induced mitochondrial dysfunction and lipid accumulation. Our study demonstrates a new role of MATα1 and SAMe in reducing hepatic MCJ expression.