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The interplay between nucleo/cytoplasmic distribution of methionine cycle enzymes and disease

AuthorsPajares, María A. ; Garrido, Francisco ; Pérez-Miguelsanz, Juliana; Partearroyo, Teresa; González, M. Purificación; Varela-Moreiras, Gregorio; Pérez-Zuñiga, Francisco J. ; Martínez-Costa, Oscar H. ; Aragón, Juan J.
Issue Date2016
CitationFASEB Conference: (2016)
AbstractThe methionine cycle has been mainly studied in the liver, an organ that presents with specific isoenzymes and proteins of this pathway. Classical knowledge ascribed enzymes of this cycle to the cytoplasm and suggested that metabolites could be transported to other subcellular locations as required. This hypothesis was reinforced by the discovery of S-adenosylmethionine (AdoMet) transporters in the mitochondria, but later challenged by the identification of glycine N-methyltransferase (GNMT), S-adenosylhomocysteine hydrolase (SAHH) and methionine adenosyltransferases (MATs) in the nucleus. As a result, new questions emerged regarding their role in that compartment and the putative link between anomalous subcellular localization and disease. In the last years, we have used several approaches trying to provide evidences that answer these questions, first by analyzing models of acute liver failure (D-galactosamine and acetaminophen intoxications), and second by studying the impact of changes in nutrient concentrations (methionine). The results obtained to date indicate that there is an opposite regulation for nuclear and cytoplasmic protein levels, the later correlating with expression changes. Methionine restriction induces expression of the three Mat genes in several cell lines, and cytoplasmic protein levels follow this expression pattern. Liver-specific genes (Mat1a, Bhmt, Gnmt) decrease their expression in hepatic intoxications, whereas the mRNA steady-state levels of the rest increase, the result being the well-known Mat1a/Mat2a switch. Total AdoMet levels decrease in hepatic intoxications, while nuclear accumulation of MAT¿1 (encoded by Mat1a), GNMT and SAHH is observed. This nucleo/cytoplasmic change in MAT¿1 localization correlates with enhanced nuclear levels of the tetrameric isoenzyme (MAT I with intermediate Vmax) and of specific epigenetic modifications involved in repression. Subcellular distribution is controlled by the ratio of glutathione species, according to the data obtained using modulators/inhibitors of its synthesis/concentrations alone or in combination with cysteine suppliers. Altogether, our results support the hypothesis that the AdoMet required by the nuclear machinery to respond against an insult is synthesized close to the place where is needed, a process that involves alterations in subcellular localization.
DescriptionPóster presentado a la Conferencia de la Federation of American Societies for Experimental Biology (FASEB) titulada: Biological Methylation: Fundamental Mechanisms in Health and Diseases y celebrada en Lisboa (Portugal) del 19 al 24 de junio de 2016.
Appears in Collections:(IIBM) Comunicaciones congresos
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