An international team of researchers led by Cedars-Sinai Medical Centre in Los Angeles has uncovered a new pathway that helps explain how consuming too much alcohol causes damage to the liver, specifically mitochondrial dysfunction in alcohol-associated liver disease. The discovery could help lead to a new treatment approach.
The study was recently published in the peer-reviewed journal Nature Communications.
Cases of alcohol-associated liver disease continue to rise and is one of the leading causes of alcohol-related deaths, according to material published by Cedars-Sinai – a respected non-profit academic healthcare provider – on 14 February 2022.
The spectrum of the disease includes hepatitis, fibrosis to cirrhosis and liver cancer. Cirrhosis alone causes 1.6 million deaths worldwide and over 50% of cases are due to alcohol abuse. Besides abstinence, there currently are no effective therapies for treating people with the disease.
“Alcohol-associated liver disease is a major problem in the world,” said Dr Shelly C Lu, director of the Karsh Division of Gastroenterology and Hepatology in Department of Medicine and senior author of the study.
“We’ve known for a long time that alcohol somehow damages mitochondria, but until now, it’s not been clear as to what the mechanisms are for this damage to occur.”
The liver is very rich in mitochondria, known as the powerhouse of all cells, and plays a critical role in liver function. Alcohol, however, can alter the structure and function of the mitochondria, leading to liver injury.
To better understand the mechanisms for mitochondrial damage in alcohol-associated liver disease, Lu and her team looked at the role of an enzyme called MATα1 that’s responsible for providing the liver vital nutrients for survival.
Using liver tissues from patients with alcohol-associated liver disease and preclinical models, the team found levels of this enzyme were selectively reduced in the mitochondria.
“Once we saw the depletion of MATα1, we needed to figure out what was making that happen,” said Dr Lucia Barbier-Torres, a postdoctoral scientist in the Lu laboratory and first author of the study.
The team found alcohol activates the casein kinase 2 (CK2) protein, which triggers a process called phosphorylation of MATα1 at a specific amino acid residue. In their experiments, the team found this process facilitates an interaction between MATα1 with another protein called PIN1 and prevents MATα1 from transporting into the mitochondria.
“Once this interaction happens, MATα1 cannot get into the mitochondria to provide the essential nutrient and instead gets degraded,” Barbier-Torres said.
With this information, the team decided to block this interaction by muting MATα1, therefore preventing phosphorylation from occurring. This prevented the interaction of the two proteins, preserving mitochondrial MATα1 location and function in the mitochondria and thus protected the mitochondria from being damaged by alcohol consumption. They observed the same protection when they reduced CK2 expression to lower MATα1 phosphorylation.
“Our results support a novel and targetable mechanism to help treat alcohol-associated liver disease,” said Lu, who is also a professor of medicine and the Women's Guild Chair in Gastroenterology.
The next steps in this line of research for Lu and her team include developing small molecule therapeutics that can interfere with the interaction between MATα1 and PIN1, which should protect the mitochondria from alcohol-mediated damage.
Study details
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, Nirmala Mavila, Hui Peng, Komal Ramani, Roberta Gottlieb, Zhaoli Sun, Suthat Liangpunsakul, Ekihiro Seki, Jennifer Van Eyk, Jose M Mato and Shelly C Lu.
Author affiliations: Cedars-Sinai Medical Center in Los Angeles; Woosuk University in South Korea; Precision Medicine and Metabolism of Bizkaia in Spain; Johns Hopkins University School of Medicine; Indiana University; and the Roudebush Veterans Administration Medical Center in Indianapolis in the United States.
First published in Nature Communications, volume 13, Article number: 557 (2022), on 28 January 2022.
Abstract
MATα1 catalyses 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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