Maria Angeles Pajares
Spain
Title: New aspects on the regulation of the methionine cycle in liver injury
Biography
Biography: Maria Angeles Pajares
Abstract
The methionine cycle produces S-adenosylmethionine (AdoMet) the main methyl donor for cellular transmethylations, including several epigenetic modifications. Alterations in this pathway and specifically in the AdoMet synthesis by methionine adenosyltransferases (MATs) have been reported in a large variety of diseases, although most studies have been performed in liver. The enzymes involved, excluding methyltransferases, are oligomers that were classically consider cytoplasmic. Thus, the AdoMet synthesized in the cytoplasm was expected to be transported to other compartments as required, a hypothesis further sustained by identification of an AdoMet mitochondrial transporter. However, in the last decade several reports have shown that this is not the case for the cell nucleus, where most of these enzymes have been identified in very low quantities. Work of my laboratory has recently provided evidences showing nuclear accumulation of several proteins of the methionine cycle in two models of acute liver injury. Moreover, we demonstrated that the nucleocytoplasmic distribution is governed by the ratio between glutathione species (GSH/GSSG). In fact, the oxidative stress induced by D-galactosamine or acetaminophen produces opposite effects on MAT I/III isoenzymes according to the subcellular compartment examined. This opposite regulation leads to decreased AdoMet production in the cytoplasm, whereas the nuclear levels of active MAT I increase, as well as certain epigenetic methylations. Prevention by N-acetylcysteine administration did not avoid all the drug-induced changes. Hence, we propose that alterations in the subcellular localization pattern of several enzymes of this cycle show a potential as biomarkers of liver disease.