Expression of the methionine sulfoxide reductase lost during evolution extends Drosophila lifespan in a methionine-dependent manner

Lee, Byeong Cheol; Lee, Hae Min; Kim, Sorah; Avanesov, Andrei; Lee, Aro; Chun, Bok Hwan; Vorbrüggen, Gerd; Gladyshev, Vadim N.

doi:10.1038/s41598-017-15090-5

Cited by 13 publications

(9 citation statements)

References 41 publications

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“…Interesting directions for future research include testing the hypothesis that microbial methionine metabolism influences organismal life span. We note that this idea is speculative, as it has not been supported by screens for bacterial influence on Caenorhabditis elegans longevity (79,80), and the manipulation of dietary methionine or methionine metabolism genes does not necessarily lead to tradeoffs between longevity and reproduction (58,81,82). Regardless, these data provide key hypotheses to pursue and support a previous assertion that future work investigating the relationship between Drosophila flies, the microbiota, and life history tradeoffs is of interest (83).…”

Section: Discussionmentioning

confidence: 63%

Bacterial Methionine Metabolism Genes Influence Drosophila melanogaster Starvation Resistance

Judd

Matthews

Hughes

et al. 2018

Appl Environ Microbiol

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Animal-associated microorganisms (microbiota) dramatically influence the nutritional and physiological traits of their hosts. To expand our understanding of such influences, we predicted bacterial genes that influence a quantitative animal trait by a comparative genomic approach, and we extended these predictions via mutant analysis. We focused on starvation resistance (SR). We first confirmed that SR responds to the microbiota by demonstrating that bacterium-free flies have greater SR than flies bearing a standard 5-species microbial community, and we extended this analysis by revealing the species-specific influences of 38 genome-sequenced bacterial species on SR. A subsequent metagenome-wide association analysis predicted bacterial genes with potential influence on SR, among which were significant enrichments in bacterial genes for the metabolism of sulfur-containing amino acids and B vitamins. Dietary supplementation experiments established that the addition of methionine, but not B vitamins, to the diets significantly lowered SR in a way that was additive, but not interactive, with the microbiota. A direct role for bacterial methionine metabolism genes in SR was subsequently confirmed by analysis of flies that were reared individually with distinct methionine cycle mutants. The correlated responses of SR to bacterial methionine metabolism mutants and dietary modification are consistent with the established finding that bacteria can influence fly phenotypes through dietary modification, although we do not provide explicit evidence of this conclusion. Taken together, this work reveals that SR is a microbiota-responsive trait, and specific bacterial genes underlie these influences. Extending descriptive studies of animal-associated microorganisms (microbiota) to define causal mechanistic bases for their influence on animal traits is an emerging imperative. In this study, we reveal that starvation resistance (SR), a model quantitative trait in animal genetics, responds to the presence and identity of the microbiota. Using a predictive analysis, we reveal that the amino acid methionine has a key influence on SR and show that bacterial methionine metabolism mutants alter normal patterns of SR in flies bearing the bacteria. Our data further suggest that these effects are additive, and we propose the untested hypothesis that, similar to bacterial effects on fruit fly triacylglyceride deposition, the bacterial influence may be through dietary modification. Together, these findings expand our understanding of the bacterial genetic basis for influence on a nutritionally relevant trait of a model animal host.

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Section: Discussionmentioning

confidence: 63%

Bacterial Methionine Metabolism Genes Influence Drosophila melanogaster Starvation Resistance

Judd

Matthews

Hughes

et al. 2018

Appl Environ Microbiol

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“…methionine-S-sulfoxide and methionine-R-sulfoxide. These are reduced back to methionine by distinct enzymes [38], although mammals do not encode an efficient free methionine-R-sulfoxide reductase [39].…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease

et al. 2018

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Cystic fibrosis (CF) lung disease progressively worsens from infancy to adulthood. Disease-driven changes in early CF airway fluid metabolites may identify therapeutic targets to curb progression.CF patients aged 12-38 months (n=24; three out of 24 later denoted as CF screen positive, inconclusive diagnosis) received chest computed tomography scans, scored by the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) method to quantify total lung disease (PRAGMA-%Dis) and components such as bronchiectasis (PRAGMA-%Bx). Small molecules in bronchoalveolar lavage fluid (BALF) were measured with high-resolution accurate-mass metabolomics. Myeloperoxidase (MPO) was quantified by ELISA and activity assays.Increased PRAGMA-%Dis was driven by bronchiectasis and correlated with airway neutrophils. PRAGMA-%Dis correlated with 104 metabolomic features (p<0.05, q<0.25). The most significant annotated feature was methionine sulfoxide (MetO), a product of methionine oxidation by MPO-derived oxidants. We confirmed the identity of MetO in BALF and used reference calibration to confirm correlation with PRAGMA-%Dis (Spearman's ρ=0.582, p=0.0029), extending to bronchiectasis (PRAGMA-%Bx; ρ=0.698, p=1.5×10), airway neutrophils (ρ=0.569, p=0.0046) and BALF MPO (ρ=0.803, p=3.9×10).BALF MetO associates with structural lung damage, airway neutrophils and MPO in early CF. Further studies are needed to establish whether methionine oxidation directly contributes to early CF lung disease and explore potential therapeutic targets indicated by these findings.

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“…There are two types of genes that encode isoforms of methione sulfoxide reductase, A and B, that each reduces one of the two isomers of methione sulfoxide. MSRA has been more closely linked with lifespan extension and uses both free methionine sulfoxide and the methionine sulfoxide present in proteins as substrates, while MSRB can only the use methionine-sulfoxide present in proteins [125]. MSRA is present in the cytoplasm, mitochondria and nucleus [126], while there are 3 genes in mammals encoding MSRBs, where the gene products localize to the cytoplasm, mitochondria, nucleus, and ER [126].…”

Section: The Nadph-thioredoxin Reductase Redox System and Agingmentioning

confidence: 99%

Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

Bradshaw

2019

Nutrients

115

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The reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) protects against redox stress by providing reducing equivalents to antioxidants such as glutathione and thioredoxin. NADPH levels decline with aging in several tissues, but whether this is a major driving force for the aging process has not been well established. Global or neural overexpression of several cytoplasmic enzymes that synthesize NADPH have been shown to extend lifespan in model organisms such as Drosophila suggesting a positive relationship between cytoplasmic NADPH levels and longevity. Mitochondrial NADPH plays an important role in the protection against redox stress and cell death and mitochondrial NADPH-utilizing thioredoxin reductase 2 levels correlate with species longevity in cells from rodents and primates. Mitochondrial NADPH shuttles allow for some NADPH flux between the cytoplasm and mitochondria. Since a decline of nicotinamide adenine dinucleotide (NAD+) is linked with aging and because NADP+ is exclusively synthesized from NAD+ by cytoplasmic and mitochondrial NAD+ kinases, a decline in the cytoplasmic or mitochondrial NADPH pool may also contribute to the aging process. Therefore pro-longevity therapies should aim to maintain the levels of both NAD+ and NADPH in aging tissues.

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Expression of the methionine sulfoxide reductase lost during evolution extends Drosophila lifespan in a methionine-dependent manner

Cited by 13 publications

References 41 publications

Bacterial Methionine Metabolism Genes Influence Drosophila melanogaster Starvation Resistance

Bacterial Methionine Metabolism Genes Influence Drosophila melanogaster Starvation Resistance

Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease

Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

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