Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals.
Oxidation of proteins by reactive oxygen species is associated with aging, oxidative stress, and many diseases. Although free and protein-bound methionine residues are particularly sensitive to oxidation to methionine sulfoxide derivatives, these oxidations are readily repaired by the action of methionine sulfoxide reductase (MsrA). To gain a better understanding of the biological roles of MsrA in metabolism, we have created a strain of mouse that lacks the MsrA gene. Compared with the wild type, this mutant: (i) exhibits enhanced sensitivity to oxidative stress (exposure to 100% oxygen); (ii) has a shorter lifespan under both normal and hyperoxic conditions; (iii) develops an atypical (tip-toe) walking pattern after 6 months of age; (iv) accumulates higher tissue levels of oxidized protein (carbonyl derivatives) under oxidative stress; and (v) is less able to up-regulate expression of thioredoxin reductase under oxidative stress. It thus seems that MsrA may play an important role in aging and neurological disorders.
Moskovitz
J
J
National Institutes of Health, National Heart Lung and Blood Institute, Laboratory of Biochemistry, Bethesda, MD 20892, USA. moskovij@nhlbi.nih.gov
Bar-Noy
S
S
Williams
W M
WM
Requena
J
J
Berlett
B S
BS
Stadtman
E R
ER
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D018390:Gene Targeting; D008017:Life Expectancy; D008715:Methionine / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors
D000975:Antioxidants; D008715:Methionine; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; C030542:sulfoxide reductase