Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency

Robinson, Aaron; Binek, Aleksandra; Ramani, Komal; Sundararaman, Niveda; Barbier-Torres, Lucía; Murray, Ben; Venkatraman, Vidya; Kreimer, Simion; Ardle, Angela Mc; Noureddin, Mazen; Fernández‐Ramos, David; Lopitz‐Otsoa, Fernando; Juan, Virginia Gutiérrez de; Millet, Óscar; Mato, José M.; Lu, Shelly C.; Eyk, Jennifer E. Van

doi:10.1016/j.isci.2023.105987

Cited by 2 publications

(2 citation statements)

References 66 publications

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“…Since SAMe and MAT1A deficiency can lead to mitochondrial changes 8 , 10 , 19 , 20 , we evaluated whether SAMe treatment could have affected the overall content of mitochondria in our experiments. Using a cocktail antibody that detects different oxidative phosphorylation (OXPHOS) system subunits of the electron transport chain, we evaluated the mitochondrial content in livers of WT mice treated with SAMe, and Huh-7 and HepG2 cells treated with SAMe.…”

Section: Resultsmentioning

confidence: 99%

“…We did not see any difference as compared to WT MCJ, suggesting that the mechanism by which SAMe regulates MCJ might involve more than just methylation at a single lysine residue. It is possible that 1) multiple methylation sites are involved in MCJ, 2) other post-translational modifications (PTMs) are involved such as phosphorylation and sumoylation, both of which are inhibited by SAMe 20 , 21 , 38 , 3) an indirect effect on another protein to enhance that protein's ability to degrade MCJ. Although the outcome has not been studied, multiple phosphorylation and glycosylation sites in MCJ have been identified in high-throughput studies and we found several SUMO interaction motifs predicted in its sequence.…”

Section: Discussionmentioning

confidence: 99%

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S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver

Barbier-Torres,

Chhimwal,

Kim

et al. 2024

Int. J. Biol. Sci.

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver

Barbier-Torres,

Chhimwal,

Kim

et al. 2024

Int. J. Biol. Sci.

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Non-Alcoholic Fatty Liver Disease in Proceedings of Congress Easl – 2023

Pinsky

2023

Med. Sci. of Ukr.

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Background. The significant increase in the prevalence of type 2 diabetes has led to an increase in the incidence of its hepatic manifestations, in particular non-alcoholic fatty liver disease. A complication of this disease is the asymptomatic progression of fibrosis, the development of liver cirrhosis and hepatocellular carcinoma. Aim. To analyze the results of studies on non-alcoholic fatty liver disease that were reviewed at the Congress of the European Association for the Study of the Liver (EASL - 2023). Materials and methods. Analysis of current data presented in the materials of the Congress of the European Association for the Study of the Liver (EASL - 2023) on the prevalence, pathogenesis and treatment of non-alcoholic fatty liver disease. Conclution. Non-alcoholic fatty liver disease and the new term metabolic associated steatohepatitis (MASH) are the hepatic manifestations of type 2 diabetes mellitus, the prevalence of which is rapidly increasing with the increasing incidence of uncontrolled hyperglycemia. The new term MASH, which replaced the diagnosis of NAFLD, emphasizes that the main etiopathogenetic factor in the development of this liver pathology is type 2 diabetes mellitus. The progression of liver fibrosis and the development of hepatocellular carcinoma in MASH can be caused not only by a high level of glycated hemoglobin, but also by multiple comorbid factors, in particular, autoimmune hepatitis, alcoholic and drug-induced liver damage, hemochromatosis, etc.

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Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency

Cited by 2 publications

References 66 publications

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver

Non-Alcoholic Fatty Liver Disease in Proceedings of Congress Easl – 2023

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