LAUSR

The hepatic methionine cycle comprises specific isoenzymes and proteins classically ascribed to the cytoplasm, with metabolites being putatively transported to other subcellular locations as required. This hypothesis was challenged by the identification of several enzymes in the nuclear compartment; hence new questions emerged regarding their nuclear role and the putative link between anomalous subcellular localization and disease. Using models of acute liver failure (D-galactosamine and acetaminophen intoxications) we have identified an opposite regulation for nuclear and cytoplasmic protein levels. Expression of liver-specific genes (Mat1a, Bhmt, Gnmt) decreases in hepatic intoxications, whereas the mRNA levels for the other genes of the cycle increase. Total AdoMet levels decrease in hepatic intoxications, while nuclear accumulation of MATα1 (encoded by Mat1a), BHMT, GNMT and SAHH is observed. These nucleo/cytoplasmic changes of localization correlate with specific epigenetic modifications and/or protein N-homocysteinylation. Subcellular distribution is controlled by the ratio of glutathione species, according to the data obtained using inhibitors or precusors of glutathione synthesis alone or in combination. Altogether, our results support the existence of a nuclear branch of the methionine cycle in order to provide or eliminate metabolites close to the nuclear machinery.