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NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
- Source :
- Nature Communications, Vol 10, Iss 1, Pp 1-18 (2019), Fang, E F, Hou, Y, Lautrup, S, Jensen, M B, Yang, B, SenGupta, T, Caponio, D, Khezri, R, Demarest, T G, Aman, Y, Figueroa, D, Morevati, M, Lee, H-J, Kato, H, Kassahun, H, Lee, J-H, Filippelli, D, Okur, M N, Mangerich, A, Croteau, D L, Maezawa, Y, Lyssiotis, C A, Tao, J, Yokote, K, Rusten, T E, Mattson, M P, Jasper, H, Nilsen, H & Bohr, V A 2019, ' NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome ', Nature Communications, vol. 10, no. 1, 5284 . https://doi.org/10.1038/s41467-019-13172-8
- Publication Year :
- 2019
-
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 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.
- Subjects :
- 0301 basic medicine
Premature aging
Science
General Physics and Astronomy
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
NMNAT1
ddc:570
Mitophagy
medicine
lcsh:Science
Caenorhabditis elegans
Werner syndrome
Multidisciplinary
biology
Nicotinamide-nucleotide adenylyltransferase
Chemistry
General Chemistry
biology.organism_classification
medicine.disease
3. Good health
Cell biology
030104 developmental biology
lcsh:Q
NAD+ kinase
Drosophila melanogaster
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications, Vol 10, Iss 1, Pp 1-18 (2019), Fang, E F, Hou, Y, Lautrup, S, Jensen, M B, Yang, B, SenGupta, T, Caponio, D, Khezri, R, Demarest, T G, Aman, Y, Figueroa, D, Morevati, M, Lee, H-J, Kato, H, Kassahun, H, Lee, J-H, Filippelli, D, Okur, M N, Mangerich, A, Croteau, D L, Maezawa, Y, Lyssiotis, C A, Tao, J, Yokote, K, Rusten, T E, Mattson, M P, Jasper, H, Nilsen, H & Bohr, V A 2019, ' NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome ', Nature Communications, vol. 10, no. 1, 5284 . https://doi.org/10.1038/s41467-019-13172-8
- Accession number :
- edsair.doi.dedup.....4d3a125e60965f3d4db8951fff678286
- Full Text :
- https://doi.org/10.1038/s41467-019-13172-8