MassIVE MSV000085809

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MetaboLights MTBLS1223 - GNPS NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome (Intracellular UPLC-MS assay)

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Description

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 C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.


Intracellular UPLC-MS assay protocols and data are reported in the current study MTBLS1223.

Extracellular UPLC-MS assay protocols and data are reported in MTBLS1221.

[dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: GNPS Metabolomics MetaboLights

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Principal Investigators:
(in alphabetical order) 		Sofie Lautrup, Post doctoral fellow, Sykehusveien 25, Akershus University Hospital
Submitting User: caceves
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