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Differential Responses of Methionine Sulfoxide Reductases A and B to Anoxia and Oxidative Stress in the Freshwater Turtle Trachemys scripta.

ABSTRACT: Oxidative stress has been acknowledged as a major factor in aging, senescence and neurodegenerative conditions. Mammalian models are susceptible to these stresses following the restoration of oxygen after anoxia; however, some organisms including the freshwater turtle Trachemys scripta can withstand repeated anoxia and reoxygenation without apparent pathology. T. scripta thus provides us with an alternate vertebrate model to investigate physiological mechanisms of neuroprotection. The objective of this study was to investigate the antioxidant methionine sulfoxide reductase system (Msr) in turtle neuronal tissue. We examined brain transcript and protein levels of MsrA and MsrB and examined the potential for the transcription factor FOXO3a to regulate the oxygen-responsive changes in Msr in vitro. We found that Msr mRNA and protein levels are differentially upregulated during anoxia and reoxygenation, and when cells were exposed to chemical oxidative stress. However, while MsrA and MsrB3 levels increased when cell cultures were exposed to chemical oxidative stress, this induction was not enhanced by treatment with epigallocatechin gallate (EGCG), which has previously been shown to enhance FOXO3a levels in the turtle. These results suggest that FOXO3a and Msr protect the cells from oxidative stress through different molecular pathways, and that both the Msr pathway and EGCG may be therapeutic targets to treat diseases related to oxidative damage.

SUBMITTER: Reiterer M

PROVIDER: S-EPMC8304764 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Methionine residues in proteins are susceptible to oxidation by reactive oxygen species, but can be repaired via reduction of the resulting methionine sulfoxides by methionine-S-sulfoxide reductase (MsrA) and methionine-R-sulfoxide reductase (MsrB). However, the identity of all methionine sulfoxide reductases involved, their cellular locations and relative contributions to the overall pathway are poorly understood. Here, we describe a methionine-R-sulfoxide reduction system in mammals, in which two MsrB homologues were previously described. We found that human and mouse genomes possess three MsrB genes and characterized their protein products, designated MsrB1, MsrB2, and MsrB3. MsrB1 (Selenoprotein R) was present in the cytosol and nucleus and exhibited the highest methionine-R-sulfoxide reductase activity because of the presence of selenocysteine (Sec) in its active site. Other mammalian MsrBs contained cysteine in place of Sec and were less catalytically efficient. MsrB2 (CBS-1) resided in mitochondria. It had high affinity for methionine-R-sulfoxide, but was inhibited by higher concentrations of the substrate. The human MsrB3 gene gave rise to two protein forms, MsrB3A and MsrB3B. These were generated by alternative splicing that introduced contrasting N-terminal and C-terminal signals, such that MsrB3A was targeted to the endoplasmic reticulum and MsrB3B to mitochondria. We found that only mitochondrial forms of mammalian MsrBs (MsrB2 and MsrB3B) could compensate for MsrA and MsrB deficiency in yeast. All mammalian MsrBs belonged to a group of zinc-containing proteins. The multiplicity of MsrBs contrasted with the presence of a single mammalian MsrA gene as well as with the occurrence of single MsrA and MsrB genes in yeast, fruit flies, and nematodes. The data suggested that different cellular compartments in mammals maintain a system for repair of oxidized methionine residues and that this function is tuned in enzyme- and stereo-specific manner.

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Differential Responses of Methionine Sulfoxide Reductases A and B to Anoxia and Oxidative Stress in the Freshwater Turtle Trachemys scripta.

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