Metabolomics

Dataset Information

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NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome (Extracellular UPLC-MS assay)


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 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.


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

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

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse phase, Liquid Chromatography MS - negative - hilic

SUBMITTER: Ho-Joon Lee 

PROVIDER: MTBLS1221 | MetaboLights | 2019-10-17

REPOSITORIES: MetaboLights

Dataset's files

Source:
Action DRS
MTBLS1221 Other
FILES Other
a_MTBLS1221_LC-MS_negative_hilic_metabolite_profiling.txt Txt
a_MTBLS1221_LC-MS_positive_reverse-phase_metabolite_profiling.txt Txt
i_Investigation.txt Txt
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