Acute Liver Injury Induces Nucleocytoplasmic Redistribution of Hepatic Methionine Metabolism Enzymes

Abstract

Aims: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. Results: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) a1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATa1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATa1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATa1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATa1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells. Innovation: Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. Conclusion: Altogether these results demonstrate galactosamine-and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of redox-dependent mechanisms in the control of MATa1 subcellular distribution. Antioxid. Redox Signal. 20, 2541-2554.

The Oncogene PDRG1 Is an Interaction Target of Methionine Adenosyltransferases

“…Effects at the cytosolic protein level follow the same trend with increases in MATα2 and MATβ and a reduction in MATα1, which also changes its preferred association state towards MAT III [16, 17]. Data regarding the MAT nuclear pool are limited, due to their recent identification in this compartment [6, 18].…”

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

“…Several enzymes of these pathways are susceptible to this condition given their need for cofactors and metals (20,41,58). Therefore, a reduction in folate levels, together with the cochlear oxidative stress detected, not only remodels expression and protein levels, but is expected to modify enzyme activities, subcellular distribution, and oligomerization as occur in several experimental settings (57,(70)(71)(72). Along this line, the increased p22phox levels in FD cochleae are expected to produce NOX activation and, hence, lead to elevated NADP + concentrations.…”

PDRG1at the interface between intermediary metabolism and oncogenesis

“…In contrast, the nuclear branch of the pathway involves a more reduced set of enzymes as follows (Figure 1 ): (1) MATs; (2) methyltransferases such as those involved in DNA and histone methylations, GNMT and GAMT; (3) AHCY[ 12 , 13 , 15 , 16 ]; and (4) BHMT[ 19 ]. Of note, levels of MATs, GNMT and AHCY are markedly higher in the cytoplasm than in the nucleus, but increases in the latter compartment can be observed as a consequence of pathological changes in glutathione concentrations and, precisely, decreases in the GSH/GSSG ratio[ 14 ]. More recently, PDRG1 [Consensus nomenclature for the human ( PDRG1 ) and mouse genes ( Pdrg1 ) is used throughout the text.…”