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Transcriptome of a long-lived mutant nematode with severe mitochondrial deficiency

ABSTRACT: Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we analyze the transcriptome of a well established model for mitochondrial deficiency, gas-1(fc21) mutant nematodes, which when placed in a genetic context of IIS inhibition, undergo metabolic rewiring leading to a massive lifespan extension

OTHER RELATED OMICS DATASETS IN: PXD011851MTBLS794PXD011859

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE122902 | GEO | 2019/02/12

REPOSITORIES: GEO

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Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction

Project description:Aberrant mitochondrial function contributes to the pathogenesis of various metabolic and chronic disorders. Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Using an unbiased multi-omics approach, we report here that IIS inhibition reduces protein synthesis and favors catabolism in mitochondrial deficient Caenorhabditis elegans We unveil that the lifespan extension does not occur through the restoration of mitochondrial respiration, but as a consequence of an ATP-saving metabolic rewiring that is associated with an evolutionarily conserved phosphoproteome landscape. Furthermore, we identify xanthine accumulation as a prominent downstream metabolic output of IIS inhibition. We provide evidence that supplementation of FDA-approved xanthine derivatives is sufficient to promote fitness and survival of nematodes carrying mitochondrial lesions. Together, our data describe previously unknown molecular components of a metabolic network that can extend the lifespan of short-lived mitochondrial mutant animals.

2019-02-28 | MTBLS794 | MetaboLights

Mitochondrial mutant Caenorhabditis elegans phosphoproteome

Project description:Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we investigate the phosphoproteomic landscape of Caenorhabditis elegans with severe mitochondrial deficiency in the context of insulin signaling inhibition.

2019-02-13 | PXD011859 | Pride

Mitochondrial mutant Caenorhabditis elegans Proteome

Project description:Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we investigate the proteomic landscape of Caenorhabditis elegans with severe mitochondrial deficiency in the context of insulin signaling inhibition.

2019-02-13 | PXD011851 | Pride

CEST-2.2 stimulates lipid metabolism and promotes longevity in mitochondrial mutant animals (RNA-Seq)

Project description:Intestine-specific transcriptome of wild-type. gas-1(fc21) and gas-1(fc21); cest-2.2 OE Caenorhaditis elegans in order to gain insight into how cest-2.2 overexpression ameliorates Complex I deficiency

2021-10-01 | GSE168501 | GEO

Expression data from the complex I mutant gas-1 (fc21) C. elegans worms in comparison to wildtype N2 Bristol worm and under the inluence of antioxidant drug treatment

Project description:We studied genome-wide expression profiles of C. elegans young adult worms, complex I mutant gas-1(fc21) compare to the wild type N2 Bristol worm and the effect of different antioxidant drug treatment on the gene expression profile in gas-1(fc21).

2017-03-01 | GSE66680 | GEO

Expression data from the complex I mutant gas-1 (fc21) C. elegans worms in comparison to wildtype N2 Bristol worm and under the inluence combination drug therapy

Project description:We studied genome-wide expression profiles of C. elegans young adult worms, complex I mutant gas-1(fc21) compare to the wild type N2 Bristol worm and the effect of combination drug treatment on the gene expression profile in gas-1(fc21).

2021-07-01 | GSE134535 | GEO

NAD+ and PPAR-modifying drugs in a C. elegans model of respiratory chain complex I deficiency

2014-08-13 | GSE57626 | GEO

The Insulin/IGF Signaling Cascade Modulates SUMOylation to Regulate Aging and Proteostasis in C. elegans.

Project description:In this project we asked how reducing the activity of the insulin/IGF signaling (IIS) cascade by knocking down the expression of daf-2, affects global protein SUMOylation of C. elegans. We found that among other proteins, IIS reduction lowers the SUMOylation of CAR-1, a protein that negatively regulates the activity of the worm’s notch receptor, GLP-1. Thus, the knockdown of car-1 hyper-activates GLP-1, shortens lifespan and exposes the worm to toxic protein aggregation (proteotoxicity). In contrast, the expression of a SUMOylation resistant CAR-1 (K185R) promotes longevity and protects model nematodes from proteotoxicity.

2018-06-06 | PXD010011 | Pride

RNA sequencing analysis of DAF-16 target gene expression when math-33 function is genetically inactivated

Project description:In this study we have investigated the effect of loss of math-33 activity on DAF-16-mediated target gene regulation in C. elegans under conditions of reduced Insulin/IGF-1 signaling (IIS). Using whole nematode RNA sequencing experiments we found that the daf-2(e1370)-mediated induction and repression of DAF-16 target genes was decreased in daf-2(e1370); math-33(tm3561) mutant animals. Our data suggest that the downregulation of endogenous DAF-16 isoforms in the absence of a functional MATH-33 severely affects the global expression of DAF-16 targets when IIS activity is reduced. Therefore, MATH-33 is essential for DAF-16-mediated target gene activation and repression in the context of IIS. DAF-16 mediated target gene regulation was analyzed in daf-2(e1370) nematodes and compared to daf-2(e1370); math-33(tm3561) mutant animals. daf-16(mu86); daf-2(e1370); N2 (wild type) and math-33(tm3561) single mutant animals were used as controls.

2016-06-22 | E-GEOD-70117 | biostudies-arrayexpress

NAD+ and PPAR-modifying drugs in a C. elegans model of respiratory chain complex I deficiency

Project description:The gas-1(fc21) mutation affects the 49 kD subunit of complex I, decreasing the rate of complex I-dependent oxidative phosphorylation. This is a model for human mitochondrial respiratory chain disease. NAD+ and PPAR-modifying drugs may confer benefits with respect to lifespan in these short-lived mutant worms. Analysis of gas-1(fc21) electron transport chain complex I mutants treated either starting in development or in young adulthood only with nicotinic acid (1 mM), resveratrol (50 microM), rosiglitazone (5 mM) or fenofibrate (14 microM) is presented. The goal is to detect transcriptional changes in clusters of genes using gene set enrichment analysis to explain treament effects in these mutant worms. Four biological replicates were performed for each treatment condition (nicotinic acid, resveratrol, rosiglitazone, and fenofibrate) for each drug beginning either in development or in young adulthood for gas-1 mutant worms, i.e., 8 treated samples in total. At most one outlier was excluded from each analysis. Untreated N2 and gas-1 in each of the control solvents (S-basal, for nicotinic acid, and 1% DMSO, for resveratrol, rosiglitazone, and fenofibrate) were also analyzed; at least 3 replicates of each were included. These were used as sources of total RNA, each for hybridization to a single Affymetrix whole-genome microarray. Analysis was performed to reveal transcriptional changes related to mutantion and/or drug treatment effects.

2014-08-13 | E-GEOD-57626 | biostudies-arrayexpress

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