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000140583 041__ $$aEnglish
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000140583 1001_ $$0P:(DE-2719)2810464$$aGioran, Anna$$b0$$eFirst author$$udzne
000140583 245__ $$aMulti-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction.
000140583 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2019
000140583 264_1 $$2Crossref$$3online$$bEMBO$$c2019-02-22
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000140583 520__ $$aAberrant mitochondrial function contributes to the pathogenesis of various metabolic and chronic disorders. Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Using an unbiased multi-omics approach, we report here that IIS inhibition reduces protein synthesis and favors catabolism in mitochondrial deficient Caenorhabditis elegans We unveil that the lifespan extension does not occur through the restoration of mitochondrial respiration, but as a consequence of an ATP-saving metabolic rewiring that is associated with an evolutionarily conserved phosphoproteome landscape. Furthermore, we identify xanthine accumulation as a prominent downstream metabolic output of IIS inhibition. We provide evidence that supplementation of FDA-approved xanthine derivatives is sufficient to promote fitness and survival of nematodes carrying mitochondrial lesions. Together, our data describe previously unknown molecular components of a metabolic network that can extend the lifespan of short-lived mitochondrial mutant animals.
000140583 536__ $$0G:(DE-HGF)POF3-341$$a341 - Molecular Signaling (POF3-341)$$cPOF3-341$$fPOF III$$x0
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000140583 542__ $$2Crossref$$i2019-02-22$$uhttp://creativecommons.org/licenses/by/4.0/
000140583 542__ $$2Crossref$$i2019-02-22$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000140583 650_7 $$2NLM Chemicals$$aCaenorhabditis elegans Proteins
000140583 650_7 $$2NLM Chemicals$$aInsulin
000140583 650_7 $$2NLM Chemicals$$aProteome
000140583 650_7 $$01AVZ07U9S7$$2NLM Chemicals$$aXanthine
000140583 650_7 $$067763-96-6$$2NLM Chemicals$$aInsulin-Like Growth Factor I
000140583 650_7 $$08L70Q75FXE$$2NLM Chemicals$$aAdenosine Triphosphate
000140583 650_2 $$2MeSH$$aAdenosine Triphosphate: metabolism
000140583 650_2 $$2MeSH$$aAnimals
000140583 650_2 $$2MeSH$$aCaenorhabditis elegans: drug effects
000140583 650_2 $$2MeSH$$aCaenorhabditis elegans: growth & development
000140583 650_2 $$2MeSH$$aCaenorhabditis elegans: metabolism
000140583 650_2 $$2MeSH$$aCaenorhabditis elegans Proteins: genetics
000140583 650_2 $$2MeSH$$aCaenorhabditis elegans Proteins: metabolism
000140583 650_2 $$2MeSH$$aInsulin: chemistry
000140583 650_2 $$2MeSH$$aInsulin-Like Growth Factor I: antagonists & inhibitors
000140583 650_2 $$2MeSH$$aLongevity
000140583 650_2 $$2MeSH$$aMetabolome
000140583 650_2 $$2MeSH$$aMitochondria: drug effects
000140583 650_2 $$2MeSH$$aMitochondria: metabolism
000140583 650_2 $$2MeSH$$aMitochondria: pathology
000140583 650_2 $$2MeSH$$aMitochondrial Diseases: metabolism
000140583 650_2 $$2MeSH$$aMitochondrial Diseases: pathology
000140583 650_2 $$2MeSH$$aMitochondrial Diseases: prevention & control
000140583 650_2 $$2MeSH$$aProteome
000140583 650_2 $$2MeSH$$aTranscriptome
000140583 650_2 $$2MeSH$$aXanthine: administration & dosage
000140583 650_2 $$2MeSH$$aXanthine: metabolism
000140583 7001_ $$0P:(DE-2719)2811171$$aPiazzesi, Antonia$$b1$$udzne
000140583 7001_ $$0P:(DE-2719)2810664$$aBertan, Fabio$$b2$$udzne
000140583 7001_ $$0P:(DE-2719)2811395$$aSchroer, Jonas$$b3$$udzne
000140583 7001_ $$0P:(DE-2719)2811527$$aWischhof, Lena$$b4$$udzne
000140583 7001_ $$0P:(DE-2719)2010732$$aNicotera, Pierluigi$$b5$$udzne
000140583 7001_ $$0P:(DE-2719)2158358$$aBano, Daniele$$b6$$eLast author$$udzne
000140583 77318 $$2Crossref$$3journal-article$$a10.15252/embj.201899558$$b : EMBO, 2019-02-22$$n6$$tThe EMBO Journal$$v38$$x0261-4189$$y2019
000140583 773__ $$0PERI:(DE-600)1467419-1$$a10.15252/embj.201899558$$gVol. 38, no. 6$$n6$$pe99558$$q38:6$$tThe EMBO journal$$v38$$x0261-4189$$y2019
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000140583 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418696
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