Effect of Kynurenic Acid on Development and Aging in Wild Type and Vermilion Mutants of Drosophila Melanogaster

Navrotskaya, Valeriya; Oxenkrug, Gregory F.

doi:10.15761/pddt.1000104

Cited by 11 publications

(5 citation statements)

References 23 publications

(27 reference statements)

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“…There is some information on role of tryptophan breakdown in regulating Drosophila life span. The vermilion gene encodes the Trp-2,3-dioxygenase (TDO) enzyme, which catalyzes tryptophan conversion into kynurenine, and in a Canton-S genetic background the vermilion mutation was reported to decrease male life span and have no effect on female life span ( Navrotskaya and Oxenkrug, 2016 ). In contrast, an inhibitor of TDO (alpha-methyl tryptophan) and an inhibitor of ABC transporters implicated in tryptophan import (5-methyl tryptophan) were reported to increase adult female life span ( Oxenkrug et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

et al. 2021

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Background: The synthetic steroid mifepristone is reported to have anti-obesity and anti-diabetic effects in mammals on normal and high-fat diets (HFD). We previously reported that mifepristone blocks the negative effect on life span caused by mating in female Drosophila melanogaster.Methods: Here we asked if mifepristone could protect virgin females from the life span-shortening effect of HFD. Mifepristone was assayed for effects on life span in virgin females, in repeated assays, on regular media and on media supplemented with coconut oil (HFD). The excrement quantification (EX-Q) assay was used to measure food intake of the flies after 12 days mifepristone treatment. In addition, experiments were conducted to compare the effects of mifepristone in virgin and mated females, and to identify candidate mifepristone targets and mechanisms.Results: Mifepristone increased life span of virgin females on regular media, as well as on media supplemented with either 2.5 or 5% coconut oil. Food intake was not reduced in any assay, and was significantly increased by mifepristone in half of the assays. To ask if mifepristone might rescue virgin females from all life span-shortening stresses, the oxidative stressor paraquat was tested, and mifepristone produced little to no rescue. Analysis of extant metabolomics and transcriptomics data suggested similarities between effects of mifepristone in virgin and mated females, including reduced tryptophan breakdown and similarities to dietary restriction. Bioinformatics analysis identified candidate mifepristone targets, including transcription factors Paired and Extra-extra. In addition to shortening life span, mating also causes midgut hypertrophy and activation of the lipid metabolism regulatory factor SREBP. Mifepristone blocked the increase in midgut size caused by mating, but did not detectably affect midgut size in virgins. Finally, mating increased activity of a SREBP reporter in abdominal tissues, as expected, but reporter activity was not detectably reduced by mifepristone in either mated or virgin females.Conclusion: Mifepristone increases life span of virgin females on regular and HFD without reducing food intake. Metabolomics and transcriptomics analyses suggest some similar effects of mifepristone between virgin and mated females, however reduced midgut size was observed only in mated females. The results are discussed regarding possible mifepristone mechanisms and targets.

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Section: Discussionmentioning

confidence: 99%

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

et al. 2021

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“…We observed a similar pattern in the interaction analysis, as immune-challenged workers activated molecular repair mechanisms ( base-excision repair, nucleotide-excision repair, telomere maintenance ), which indicate a physiological cost of the immune response. Indeed, an immune reaction is costly, generating reactive oxygen species and molecular damage that have to be compensated [ 34 , 57 ]. Moreover, an immune response is often accompanied by a proliferation of immune cells - haemocytes in insects [ 58 , 59 ] - which can shorten telomeres [ 60 ], and thus explain the activation of telomere maintenance.…”

Section: Discussionmentioning

confidence: 99%

Immune challenge reduces gut microbial diversity and triggers fertility-dependent gene expression changes in a social insect

et al. 2020

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Background The gut microbiome can influence life history traits associated with host fitness such as fecundity and longevity. In most organisms, these two life history traits are traded-off, while they are positively linked in social insects. In ants, highly fecund queens can live for decades, while their non-reproducing workers exhibit much shorter lifespans. Yet, when fertility is induced in workers by death or removal of the queen, worker lifespan can increase. It is unclear how this positive link between fecundity and longevity is achieved and what role the gut microbiome and the immune system play in this. To gain insights into the molecular regulation of lifespan in social insects, we investigated fat body gene expression and gut microbiome composition in workers of the ant Temnothorax rugatulus in response to an experimental induction of fertility and an immune challenge. Results Fertile workers upregulated several molecular repair mechanisms, which could explain their extended lifespan. The immune challenge altered the expression of several thousand genes in the fat body, including many immune genes, and, interestingly, this transcriptomic response depended on worker fertility. For example, only fertile, immune-challenged workers upregulated genes involved in the synthesis of alpha-ketoglutarate, an immune system regulator, which extends the lifespan in Caenorhabditis elegans by down-regulating the TOR pathway and reducing oxidant production. Additionally, we observed a dramatic loss in bacterial diversity in the guts of the ants within a day of the immune challenge. Yet, bacterial density did not change, so that the gut microbiomes of many immune challenged workers consisted of only a single or a few bacterial strains. Moreover, the expression of immune genes was linked to the gut microbiome composition, suggesting that the ant host can regulate the microbiome in its gut. Conclusions Immune system flare-ups can have negative consequence on gut microbiome diversity, pointing to a previously underrated cost of immunity. Moreover, our results provide important insights into shifts in the molecular regulation of fertility and longevity associated with insect sociality.

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“…In mammalian cells, the AP-3 complex is required for the formation of LROs, organelles known to accumulate zinc (Kantheti et al, 1998;Salazar et al, 2004;McAllister and Dyck, 2017). Furthermore, and despite the generally held idea that w mutants lack pigment because of defective transport of 3-hydroxy-kynurenine and 6-pyruvoyl tetrahydropterin into pigment granules (Sullivan et al, 1979;Evans et al, 2008;Green et al, 2012;Hersh, 2016;Navrotskaya and Oxenkrug, 2016), earlier studies had demonstrated physical absence of these organelles in the w mutants (Nolte, 1961;Shoup, 1966;Nickla, 1972). Could it be that all Drosophila mutants in the LRO-biogenesis pathway (Lloyd et al, 1998; Krämer, 2002; Dell 'Angelica, 2009;Cheli et al, 2010;Harris et al, 2011), including w, lacked zinc storage?…”

Section: Mapping the Mutant That Caused Threefold Reduction In Total mentioning

confidence: 99%

Biogenesis of zinc storage granules inDrosophila melanogaster

Tejeda-Guzmán

Rosas‐Arellano

Kröll

et al. 2018

Journal of Experimental Biology

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Membrane transporters and sequestration mechanisms concentrate metal ions differentially into discrete subcellular microenvironments for use in protein cofactors, signalling, storage or excretion. Here we identify zinc storage granules as the insect's major zinc reservoir in principal Malpighian tubule epithelial cells of The concerted action of Adaptor Protein-3, Rab32, HOPS and BLOC complexes as well as of the white-scarlet (ABCG2-like) and ZnT35C (ZnT2/ZnT3/ZnT8-like) transporters is required for zinc storage granule biogenesis. Due to lysosome-related organelle defects caused by mutations in the homologous human genes, patients with Hermansky-Pudlak syndrome may lack zinc granules in beta pancreatic cells, intestinal paneth cells and presynaptic vesicles of hippocampal mossy fibers.

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Effect of Kynurenic Acid on Development and Aging in Wild Type and Vermilion Mutants of Drosophila Melanogaster

Cited by 11 publications

References 23 publications

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

Immune challenge reduces gut microbial diversity and triggers fertility-dependent gene expression changes in a social insect

Biogenesis of zinc storage granules inDrosophila melanogaster

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