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

• Published in: Nature communications Vol. 10; no. 1; pp. 5284 - 18
• Main Authors: Fang, Evandro F., Hou, Yujun, Lautrup, Sofie, Jensen, Martin Borch, Yang, Beimeng, SenGupta, Tanima, Caponio, Domenica, Khezri, Rojyar, Demarest, Tyler G., Aman, Yahyah, Figueroa, David, Morevati, Marya, Lee, Ho-Joon, Kato, Hisaya, Kassahun, Henok, Lee, Jong-Hyuk, Filippelli, Deborah, Okur, Mustafa Nazir, Mangerich, Aswin, Croteau, Deborah L., Maezawa, Yoshiro, Lyssiotis, Costas A., Tao, Jun, Yokote, Koutaro, Rusten, Tor Erik, Mattson, Mark P., Jasper, Heinrich, Nilsen, Hilde, Bohr, Vilhelm A.
• Format: Journal Article
• Language: English; Norwegian
• Published: London Nature Publishing Group UK 21.11.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 631/80/39/2348; 692/699/2743/137/138; 96; Aging; 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; Deoxyribonucleic acid; Depletion; Disease Models, Animal; DNA; DNA helicase; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Fruit flies; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Invertebrates; Life span; Metabolism; Mitochondria; Mitophagy; multidisciplinary; Mutation; NAD; NAD - metabolism; Nicotinamide; Nicotinamide-Nucleotide Adenylyltransferase - genetics; Nicotinamide-Nucleotide Adenylyltransferase - metabolism; Nucleotides; Phenotypes; Science; Science (multidisciplinary); Stem cells; Transcription; Werner Syndrome - genetics; Werner Syndrome - metabolism; Werner Syndrome Helicase - genetics; Werner Syndrome Helicase - metabolism; Werner's syndrome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13172-8

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. The molecular mechanisms of mitochondrial dysfunction in the premature ageing Werner syndrome were elusive. Here the authors show that NAD + depletion-induced impaired mitophagy contributes to this phenomenon, shedding light on potential therapeutics.