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

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2019
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Fang, Evandro F.
Hou, Yujun
Lautrup, Sofie
Jensen, Martin Borch
Yang, Beimeng
SenGupta, Tanima
Caponio, Domenica
Bohr, Vilhelm A.
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Nature Communications. 2019, 10(1), 5284. eISSN 2041-1723. Available under: doi: 10.1038/s41467-019-13172-8
Zusammenfassung

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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ISO 690FANG, Evandro F., Yujun HOU, Sofie LAUTRUP, Martin Borch JENSEN, Beimeng YANG, Tanima SENGUPTA, Domenica CAPONIO, Deborah FILIPPELLI, Aswin MANGERICH, Vilhelm A. BOHR, 2019. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. In: Nature Communications. 2019, 10(1), 5284. eISSN 2041-1723. Available under: doi: 10.1038/s41467-019-13172-8
BibTex
@article{Fang2019-12augme-48233,
  year={2019},
  doi={10.1038/s41467-019-13172-8},
  title={NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome},
  number={1},
  volume={10},
  journal={Nature Communications},
  author={Fang, Evandro F. and Hou, Yujun and Lautrup, Sofie and Jensen, Martin Borch and Yang, Beimeng and SenGupta, Tanima and Caponio, Domenica and Filippelli, Deborah and Mangerich, Aswin and Bohr, Vilhelm A.},
  note={Article Number: 5284}
}
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