Details

Autor(en) / Beteiligte

• Lai, Lo
• Sun, Junhui
• Tarafdar, Sreya
• Liu, Chengyu
• Murphy, Elizabeth
• Kim, Geumsoo
• Levine, Rodney L.

Titel

Loss of methionine sulfoxide reductases increases resistance to oxidative stress

Ist Teil von

• Free radical biology & medicine, 2019-12, Vol.145, p.374-384

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Mammals have 4 methionine sulfoxide reductases thought to provide oxidative defense.•Knocking out one or two reductases in the mouse has little effect on phenotype.•We thus produced a mouse line lacking all 4 reductases.•This mouse line was predicted to be exquisitely sensitive to oxidative stress.•Instead, the quadruple knockout is notably resistant to oxidative stress.