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Fang, E.F., Hou, Y., Lautrup, S., Jensen, M.B., Yang, B., SenGupta, T., Caponio, D., Khezri, R., Demarest, T.G., Aman, Y., Figueroa, D., Morevati, M., Lee, H.J., Kato, H., Kassahun, H., Lee, J.H., Filippelli, D., Okur, M.N., Mangerich, A., Croteau, D.L., Maezawa, Y., Lyssiotis, C.A., Tao, J., Yokote, K., Rusten, T.E., Mattson, M.P., Jasper, H., Nilsen, H., Bohr, V.A. (2019). NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome.  Nat. Commun. 10(1): 5284.
FlyBase ID
FBrf0244134
Publication Type
Research paper
Abstract

Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

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PubMed Central ID
PMC6872719 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nat. Commun.
    Title
    Nature communications
    ISBN/ISSN
    2041-1723
    Data From Reference
    Alleles (3)
    Genes (2)
    Human Disease Models (1)
    Insertions (1)
    Transgenic Constructs (1)