NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
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NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. / 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.
In: Nature Communications, Vol. 10, No. 1, 5284, 2019.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
AU - Fang, Evandro F
AU - Hou, Yujun
AU - Lautrup, Sofie
AU - Jensen, Martin Borch
AU - Yang, Beimeng
AU - SenGupta, Tanima
AU - Caponio, Domenica
AU - Khezri, Rojyar
AU - Demarest, Tyler G
AU - Aman, Yahyah
AU - Figueroa, David
AU - Morevati, Marya
AU - Lee, Ho-Joon
AU - Kato, Hisaya
AU - Kassahun, Henok
AU - Lee, Jong-Hyuk
AU - Filippelli, Deborah
AU - Okur, Mustafa Nazir
AU - Mangerich, Aswin
AU - Croteau, Deborah L
AU - Maezawa, Yoshiro
AU - Lyssiotis, Costas A
AU - Tao, Jun
AU - Yokote, Koutaro
AU - Rusten, Tor Erik
AU - Mattson, Mark P
AU - Jasper, Heinrich
AU - Nilsen, Hilde
AU - Bohr, Vilhelm A
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-13172-8
DO - 10.1038/s41467-019-13172-8
M3 - Journal article
C2 - 31754102
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5284
ER -
ID: 236986472