Researchers at Cedars-Sinai have discovered a novel mechanism that explains how excessive drinking damages the liver, especially mitochondrial dysfunction in alcohol-related liver disease.
In addition to a novel therapeutic method, the finding was published in the peer-reviewed journal Nature Communications.
Alcohol-related liver disease is one of the primary causes of alcohol-related mortality in the peer-reviewed journal Nature Communications. The condition ranges from hepatitis to cirrhosis and liver cancer. Cirrhosis kills 1.6 million people worldwide, with alcohol being the leading cause. There are presently no viable treatments for the condition outside abstinence.
Mitochondria are found in abundance in the liver and serve as a crucial component in the liver's overall functioning. Alcohol, on the other hand, may affect the mitochondria's structure and function, resulting in liver damage.
Researchers studied the function of an enzyme called MATα1 in providing the liver with essential nutrients for life to understand better the causes underlying mitochondrial damage in alcohol-associated liver disease.
Researchers found that this enzyme was explicitly decreased in the mitochondria of liver tissues from patients with alcohol-associated liver disease and preclinical models.
The researchers discovered that alcohol stimulates the casein kinase 2 (CK2) protein, resulting in the phosphorylation of MATα1 at a particular amino acid position. In their investigations, the researchers discovered that this pathway allows MATα1 to connect with another protein called PIN1 and stops MATα1 from entering the mitochondria.
Using this insight, the scientists opted to mutate MATα1 to prevent phosphorylation from taking place, therefore inhibiting this interaction. Mitochondria were shielded from alcohol-induced damage because the two proteins did not interact, protecting mitochondrial MATα1 position and function in the mitochondria. When MATα1 phosphorylation was decreased by reducing CK2 expression, the same level of protection was seen.
Researchers' next step is to create small molecule therapies that may disrupt the link between MAT-1/PIN1 and therefore protect the mitochondria from alcohol-induced damage.
Barbier-Torres, L., Murray, B., Yang, J.W. et al. Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease. Nat Commun 13, 557 (2022). https://doi.org/10.1038/s41467-022-28201-2