Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease

Lucía Barbier-Torres, Ben Murray, Jin Won Yang, Jiaohong Wang, Michitaka Matsuda, Aaron Robinson, Aleksandra Binek, Wei Fan, David Fernández-Ramos, Fernando Lopitz-Otsoa, Maria Luque-Urbano, Oscar Millet, Nirmala Mavila, Hui Peng, Komal Ramani, Roberta Gottlieb, Zhaoli Sun, Suthat Liangpunsakul, Ekihiro Seki, Jennifer E. Eyk, Jose M. Mato and Shelly C. Lu ()
Additional contact information
Lucía Barbier-Torres: Cedars-Sinai Medical Center
Ben Murray: Cedars-Sinai Medical Center
Jin Won Yang: Cedars-Sinai Medical Center
Jiaohong Wang: Cedars-Sinai Medical Center
Michitaka Matsuda: Cedars-Sinai Medical Center
Aaron Robinson: Cedars-Sinai Medical Center
Aleksandra Binek: Cedars-Sinai Medical Center
Wei Fan: Cedars-Sinai Medical Center
David Fernández-Ramos: CIC bioGUNE, BRTA, CIBERehd
Fernando Lopitz-Otsoa: CIC bioGUNE, BRTA, CIBERehd
Maria Luque-Urbano: CIC bioGUNE, BRTA, CIBERehd
Oscar Millet: CIC bioGUNE, BRTA, CIBERehd
Nirmala Mavila: Cedars-Sinai Medical Center
Hui Peng: Cedars-Sinai Medical Center
Komal Ramani: Cedars-Sinai Medical Center
Roberta Gottlieb: Cedars-Sinai Medical Center
Zhaoli Sun: Johns Hopkins University School of Medicine
Suthat Liangpunsakul: Indiana University School of Medicine
Ekihiro Seki: Cedars-Sinai Medical Center
Jennifer E. Eyk: Cedars-Sinai Medical Center
Jose M. Mato: CIC bioGUNE, BRTA, CIBERehd
Shelly C. Lu: Cedars-Sinai Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28201-2

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DOI: 10.1038/s41467-022-28201-2

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