Journal Article

DZNE-2020-06905

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multi-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction.

Gioran, A. (First author)DZNE* ; Piazzesi, A.DZNE* ; Bertan, F.DZNE* ; Schroer, J.DZNE* ; Wischhof, L.DZNE* ; Nicotera, P.DZNE* ; Bano, D. (Last author)DZNE*

2019
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embj.201899558

Abstract: 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.

Keyword(s): Adenosine Triphosphate: metabolism (MeSH) ; Animals (MeSH) ; Caenorhabditis elegans: drug effects (MeSH) ; Caenorhabditis elegans: growth & development (MeSH) ; Caenorhabditis elegans: metabolism (MeSH) ; Caenorhabditis elegans Proteins: genetics (MeSH) ; Caenorhabditis elegans Proteins: metabolism (MeSH) ; Insulin: chemistry (MeSH) ; Insulin-Like Growth Factor I: antagonists & inhibitors (MeSH) ; Longevity (MeSH) ; Metabolome (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: metabolism (MeSH) ; Mitochondria: pathology (MeSH) ; Mitochondrial Diseases: metabolism (MeSH) ; Mitochondrial Diseases: pathology (MeSH) ; Mitochondrial Diseases: prevention & control (MeSH) ; Proteome (MeSH) ; Transcriptome (MeSH) ; Xanthine: administration & dosage (MeSH) ; Xanthine: metabolism (MeSH) ; Caenorhabditis elegans Proteins ; Insulin ; Proteome ; Xanthine ; Insulin-Like Growth Factor I ; Adenosine Triphosphate

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Contributing Institute(s):

1. Aging and Neurodegeneration (AG Bano)
2. Synaptic Connectivity and Neurodegeneration (AG Nicotera)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)
2. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; SCOPUS ; Web of Science Core Collection

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