NAD⁺ augmentation restores mitophagy and limits accelerated aging in Werner syndrome.

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 mito

SUBMITTER: Fang EF 

PROVIDER: S-EPMC6872719 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature