Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation

Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (<i>WRN</i>) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD<sup>+</sup> causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD<sup>+</sup> changes in WS and the impact on WS pathologies were unknown. We show that loss of WRN increases senescence in mesenchymal stem cells (MSCs) likely related to dysregulation of metabolic and aging pathways. In line with this, NAD<sup>+</sup> augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with <i>WRN</i> knockout (<i>WRN<sup>-/-</sup></i>) and in primary fibroblasts derived from WS patients compared to controls. Moreover, <i>WRN</i> deficiency results in decreased mitochondrial NAD<sup>+</sup> (measured indirectly via mitochondrially-expressed PARP activity), and altered expression of key salvage pathway enzymes, including NMNAT1 and NAMPT; ChIP-seq data analysis unveils a potential co-regulatory axis between WRN and the NMNATs, likely important for chromatin stability and DNA metabolism. However, restoration of mitochondrial or cellular NAD<sup>+</sup> is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of <i>WRN</i>, highlighting an indispensable role of WRN in proliferation even in an NAD<sup>+</sup> affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.

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Publication Details

Journal
Aging
Published
2025-04-02
DOI
https://doi.org/10.18632/aging.206236
Citations
3
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
5.45

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article

Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation

Wai‐Yee Chan, Geir Selbæk, Shinichiro Funayama, Lisa Lirussi et al.
3 citations
Aging
Genetics and Neurodevelopmental Disorders
5.45
article

Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation

Wai‐Yee Chan, Geir Selbæk, Shinichiro Funayama, Lisa Lirussi, Hoi‐Hung Cheung, Per Nilsson, Tina Visnovska, Hisaya Kato, Yoshiro Maezawa, Sofie Lautrup, Mathias Ziegler, Marc Niere, Evandro Fei Fang, Janna Saarela, Hilde Nilsen, Koutaro Yokote, Yuyao Tian, Vilhelm A. Bohr, Shiqi Zhang
article en
3 citations

Abstract

Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (<i>WRN</i>) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD<sup>+</sup> causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD<sup>+</sup> changes in WS and the impact on WS pathologies were unknown. We show that loss of WRN increases senescence in mesenchymal stem cells (MSCs) likely related to dysregulation of metabolic and aging pathways. In line with this, NAD<sup>+</sup> augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with <i>WRN</i> knockout (<i>WRN<sup>-/-</sup></i>) and in primary fibroblasts derived from WS patients compared to controls. Moreover, <i>WRN</i> deficiency results in decreased mitochondrial NAD<sup>+</sup> (measured indirectly via mitochondrially-expressed PARP activity), and altered expression of key salvage pathway enzymes, including NMNAT1 and NAMPT; ChIP-seq data analysis unveils a potential co-regulatory axis between WRN and the NMNATs, likely important for chromatin stability and DNA metabolism. However, restoration of mitochondrial or cellular NAD<sup>+</sup> is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of <i>WRN</i>, highlighting an indispensable role of WRN in proliferation even in an NAD<sup>+</sup> affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.

AgingVol. 17(4)
University of Copenhagen (DK), Oslo University Hospital (NO), University of Helsinki (FI), Chiba University (JP), Chinese University of Hong Kong (HK), University of Oslo (NO), Akershus University Hospital (NO), Sykehuset i Vestfold (NO), Karolinska Institutet (SE), Massachusetts General Hospital (US), Chiba University Hospital (JP), Institute for Molecular Medicine Finland (FI), Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE), University of Bergen (NO)
Cure Alzheimer's Fund, Japan Agency for Medical Research and Development, European Commission, National Natural Science Foundation of China, Ministry of Health, Labour and Welfare, Novo Nordisk, NordForsk, Chinese University of Hong Kong, Norges Forskningsråd, Akershus Universitetssykehus, Nasjonalforeningen for Folkehelsen, Japan Society for the Promotion of Science
Zero hunger
Openalex Percentile: Top 5%
Genetics and Neurodevelopmental Disorders
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