scholarly journals Methionine sulfoxide reductase A (MsrA) restores α-crystallin chaperone activity lost upon methionine oxidation

2009 ◽  
Vol 1790 (12) ◽  
pp. 1665-1672 ◽  
Author(s):  
Lisa A. Brennan ◽  
Wanda Lee ◽  
Frank J. Giblin ◽  
Larry L. David ◽  
Marc Kantorow
Keyword(s):  
Methionine Sulfoxide ◽  
Chaperone Activity ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Oxidation ◽  
Methionine Sulfoxide Reductase A

scholarly journals Decreased Phosphorylation and Increased Methionine Oxidation of α-Synuclein in the Methionine Sulfoxide Reductase A Knockout Mouse

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Derek B. Oien ◽  
Gonzalo A. Carrasco ◽  
Jackob Moskovitz
Keyword(s):  
Knockout Mouse ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Yeast Cells ◽  
Mammalian Brain ◽  
Methionine Oxidation ◽  
Null Mutant ◽  
Supportive Evidence ◽  
Methionine Sulfoxide Reductase A ◽  
Protein Fibrillation

Previously, we have showed that overexpression of methionine-oxidized α-synuclein in methionine sulfoxide reductase A (MsrA) null mutant yeast cells inhibits α-synuclein phosphorylation and increases protein fibrillation. The current studies show that ablation of mouse MsrA gene caused enhanced methionine oxidation of α-synuclein while reducing its own phophorylation levels, especially in the hydrophobic cell-extracted fraction. These data provide supportive evidence that a compromised MsrA function in mammalian brain may cause enhanced pathologies associated with altered α-synuclein oxidation and phosphorylation levels.

Abstract 524: Deletion of Methionine Sulfoxide Reductase A in Mice Increases Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Paula J Klutho ◽  
Jason Scott ◽  
Litao Xie ◽  
Isabella M Grumbach
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Neointimal Hyperplasia ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Oxidation ◽  
Cyclin D ◽  
Mrna Levels ◽  
Neointima Formation ◽  
Methionine Sulfoxide Reductase A

Introduction: Neointima formation is the leading cause of restenosis after balloon angioplasty and surgical endarterectomy. ROS production promotes neointimal hyperplasia and causes methionine oxidation. Recent data suggest that oxidation of methionines can alter specific protein activity and induce cell signaling. Methionine Sulfoxide Reductase A (MsrA) reverses methionine oxidation. In humans, two independent genome-wide association studies have found MsrA polymorphisms to correlate with increased ischemic cardiovascular disease. Hypothesis: MsrA protects against neointimal formation. Methods: Immunofluorescence for MsrA was performed in autopsy specimen of arteries with and without neointimal hyperplasia. 12-week old WT and MsrA-/- mice underwent ligation of the left common carotid artery and received two injections of BrdU prior to sacrifice. Fourteen days after ligation, the neointimal area was determined using Image J. Cell proliferation and apoptosis in the neointima were quantified by BrdU and TUNEL staining. Proliferation of vascular smooth muscle cells (VSMC) from MsrA-/- and WT mice was determined by cell counts and FACS analysis. Levels of cell cycle proteins, pAkt, pGSK3β were analyzed by immunoblot in MsrA-/- and WT VSMC, mRNA levels by qrtPCR. Results: MsrA was detected in all layers of the vascular wall and in neointima in humans. Neointimal area was significantly increased in MsrA-/- compared to WT mice 14 days post-ligation (n=5-9, p<0.05). Additionally, neointimas from MsrA-/- mice contained a higher percentage of proliferating cells (0.92±1.42% vs 8.89±8.89%, p=0.007). MsrA-/- VSMC displayed significantly increased proliferation compared to WT VSMC (p<0.05). Moreover, the progression to S phase was accelerated and protein levels of the cell cycle regulators Cyclin D and CDK4 were upregulated in MsrA-/- VSMC. However, cyclin D mRNA levels are not increased (p=0.24). This implies that MsrA post-translationally regulates cyclin D. GSK3β, which is inhibited by Akt, promotes cyclin D degradation. An increase in pAkt and pGSK3β was identified in MsrA-/- VSMC. Conclusion: These data indicate that MsrA regulates neointima formation after vascular injury and support a role for MsrA in the regulation of Akt signaling.

scholarly journals An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

2021 ◽  
Vol 78 (7) ◽  
pp. 3673-3689
Author(s):  
David Leitsch ◽  
Alvie Loufouma Mbouaka ◽  
Martina Köhsler ◽  
Norbert Müller ◽  
Julia Walochnik
Keyword(s):  
Oxidative Stress ◽  
Stop Codon ◽  
Acanthamoeba Castellanii ◽  
Methionine Sulfoxide ◽  
Redox System ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Sulfoxide Reductase A ◽  
Protein Levels ◽  
Thioredoxin System ◽  
Facultative Parasite

AbstractThe free-living amoeba Acanthamoeba castellanii occurs worldwide in soil and water and feeds on bacteria and other microorganisms. It is, however, also a facultative parasite and can cause serious infections in humans. The annotated genome of A. castellanii (strain Neff) suggests the presence of two different thioredoxin reductases (TrxR), of which one is of the small bacterial type and the other of the large vertebrate type. This combination is highly unusual. Similar to vertebrate TrxRases, the gene coding for the large TrxR in A. castellanii contains a UGA stop codon at the C-terminal active site, suggesting the presence of selenocysteine. We characterized the thioredoxin system in A. castellanii in conjunction with glutathione reductase (GR), to obtain a more complete understanding of the redox system in A. castellanii and the roles of its components in the response to oxidative stress. Both TrxRases localize to the cytoplasm, whereas GR localizes to the cytoplasm and the large organelle fraction. We could only identify one thioredoxin (Trx-1) to be indeed reduced by one of the TrxRases, i.e., by the small TrxR. This thioredoxin, in turn, could reduce one of the two peroxiredoxins tested and also methionine sulfoxide reductase A (MsrA). Upon exposure to hydrogen peroxide and diamide, only the small TrxR was upregulated in expression at the mRNA and protein levels, but not the large TrxR. Our results show that the small TrxR is involved in the A. castellanii’s response to oxidative stress. The role of the large TrxR, however, remains elusive.

scholarly journals METABOLIC CONSEQUENCES OF METHIONINE REDOX IN METHIONINE RESTRICTION

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S106-S107
Author(s):  
Kevin Thyne ◽  
Yuhong Liu ◽  
Adam B Salmon
Keyword(s):  
Protein Function ◽  
Methionine Sulfoxide ◽  
Redox Status ◽  
Significant Loss ◽  
Methionine Sulfoxide Reductase ◽  
Wild Type ◽  
Entire Family ◽  
Methionine Sulfoxide Reductase A ◽  
Methionine Restriction

Abstract While caloric restriction (CR) provides highly robust improvements to longevity and health, dietary restriction of the essential amino acid methionine can provide similar benefits including improved metabolic function and increased longevity. Despite these similarities between CR and methionine restriction (MR), there is growing evidence to suggest they may be mediated by different mechanisms that require further elucidation. The sulfur side-chain of methionine is highly prone to oxidation, even in vivo, with redox changes of these residues potentially altering protein function and interfering with its use as a substrate. An entire family of enzymes, methionine sulfoxide reductases, have evolved in aerobic organisms to regulate the redox status of methionine. We tested the role of methionine sulfoxide reductase A (MsrA) in the physiological and metabolic benefits of MR. After three months of MR, mice lacking MsrA (MsrA KO) showed significant loss of weight, including both fat and lean mass, in comparison to wild-type mice under MR. Both MsrA KO and wild-type mice responded to MR with improvements to both glucose and insulin tolerance. However, MR MsrA KO mice showed lower HbA1c and reduced leptin compared to MR wild-type mice. Overall, our results show mice lacking MsrA have a stronger response to MR suggesting that methionine redox may play an important role in some of the mechanisms responsible for these metabolic outcomes. Further studies clarify whether MsrA could also be a potential regulator of the longevity benefits of MR.

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