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

Authors :
Tao Jun
Sofie Lautrup
Mustafa Nazir Okur
Tor Erik Rusten
Deborah L. Croteau
Beimeng Yang
Jong Hyuk Lee
Yoshiro Maezawa
Rojyar Khezri
Marya Morevati
Hilde Nilsen
Vilhelm A. Bohr
Costas A. Lyssiotis
David M. Figueroa
Evandro Fei Fang
Hisaya Kato
Yahyah Aman
Henok Kassahun
Tyler G Demarest
Domenica Caponio
Koutaro Yokote
Deborah Filippelli
Yujun Hou
Ho-Joon Lee
Aswin Mangerich
Mark P. Mattson
Martin Borch Jensen
Tanima SenGupta
Heinrich Jasper
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.

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