Loss of methionine sulfoxide reductases increases resistance to oxidative stress.

Oxidation of methionine residues to methionine sulfoxide scavenges reactive species, thus protecting against oxidative stress. Reduction of the sulfoxide back to methionine by methionine sulfoxide reductases creates a cycle with catalytic efficiency. Protection by the methionine sulfoxide reductases is well documented in cultured cells, from microorganisms to mammals. However, knocking out one or two of the 4 mammalian reductases had little effect in mice that were not stressed. We hypothesized that the minimal effect is due to redundancy provided by the 4 reductases. We tested the hypothesis by creating a transgenic mouse line lacking all 4 reductases and predicted that this mouse would be exceptionally sensitive to oxidative stress. The mutant mice were phenotypically normal at birth, exhibited normal post-natal growth, and were fertile. Surprisingly, rather than being more sensitive to oxidative stress, they were more resistant to both cardiac ischemia-reperfusion injury and to parenteral paraquat, a redox-cycling agent. Resistance was not a result of hormetic induction of the antioxidant transcription factor Nrf2 nor activation of Akt. The mechanism of protection may be novel.