RRC ID 59487
Author Fang EF, Hou Y, Lautrup S, Jensen MB, Yang B, SenGupta T, Caponio D, Khezri R, Demarest TG, Aman Y, Figueroa D, Morevati M, Lee HJ, Kato H, Kassahun H, Lee JH, Filippelli D, Okur MN, Mangerich A, Croteau DL, Maezawa Y, Lyssiotis CA, Tao J, Yokote K, Rusten TE, Mattson MP, Jasper H, Nilsen H, Bohr VA.
Title NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome.
Journal Nat Commun
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.
Volume 10(1)
Pages 5284
Published 2019-11-21
DOI 10.1038/s41467-019-13172-8
PII 10.1038/s41467-019-13172-8
PMID 31754102
PMC PMC6872719
MeSH Aging, Premature / genetics Aging, Premature / metabolism* Animals Autophagy-Related Protein-1 Homolog / genetics Autophagy-Related Protein-1 Homolog / metabolism Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Cation Transport Proteins / genetics Cation Transport Proteins / metabolism Disease Models, Animal Drosophila melanogaster / genetics Drosophila melanogaster / metabolism Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism Mitophagy* Mutation NAD / metabolism* Nicotinamide-Nucleotide Adenylyltransferase / genetics Nicotinamide-Nucleotide Adenylyltransferase / metabolism Werner Syndrome / genetics Werner Syndrome / metabolism* Werner Syndrome Helicase / genetics Werner Syndrome Helicase / metabolism*
IF 11.878
Times Cited 10
C.elegans tm1145 tm1524