ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2024; 20(4):1218-1237. doi:10.7150/ijbs.90104 This issue Cite
Research Paper
S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver
1. Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
2. Smidt Heart Institute and Advanced Clinical Biosystems Research Institute, Los Angeles, CA, USA.
3. Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
4. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
5. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA;
6. bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Basque Research and Technology Assembly (BRTA), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
Abstract
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.
Keywords: MCJ, MATα1, S-adenosylmethionine, protein methylation, alcohol-associated liver disease, mitochondrial dysfunction
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