Barbier-Torres, LucíaMurray, BenYang, Jin WonWang, JiaohongMatsuda, MichitakaRobinson, AaronBinek, AleksandraFan, WeiFernández-Ramos, DavidLopitz-Otsoa, FernandoLuque-Urbano, MariaMillet, OscarMavila, NirmalaPeng, HuiRamani, KomalGottlieb, RobertaSun, ZhaoliLiangpunsakul, SuthatSeki, EkihiroVan Eyk, Jennifer E.Mato, Jose M.Lu, Shelly C.2023-05-092023-05-092022-01-28Barbier-Torres L, Murray B, Yang JW, et al. Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease. Nat Commun. 2022;13(1):557. Published 2022 Jan 28. doi:10.1038/s41467-022-28201-2https://hdl.handle.net/1805/32857MATα1 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.en-USAttribution 4.0 InternationalAlcoholic liver diseaseMechanisms of diseaseMitochondrial proteinsArticle