Research Paper Advance Articles
Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation
- 1 Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway
- 2 Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba 260-0856, Japan
- 3 Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba 260-8677, Japan
- 4 Department of Microbiology, Oslo University Hospital, Oslo 0450, Norway
- 5 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
- 6 Department of Biomedicine, University of Bergen, Bergen 5009, Norway
- 7 Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
- 8 Institute of Clinical Medicine, University of Oslo, Oslo 0372, Norway
- 9 The Norwegian National Centre for Aging and Health, Vestfold Hospital Trust, Tønsberg 3103, Norway
- 10 Department of Geriatric Medicine, Oslo University Hospital, Oslo 0450, Norway
- 11 Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo 0372, Norway
- 12 Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
- 13 Department of Medical Genetics, Oslo University Hospital, Oslo 0450, Norway
- 14 Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna 17164, Sweden
- 15 Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena 07745, Germany
- 16 Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Copenhagen 1172, Denmark
- 17 The Norwegian Centre on Healthy Ageing (NO-Age) and The Norwegian National Anti-Alzheimer’s Disease (NO-AD) Networks, Oslo 0372, Norway
Received: May 30, 2024 Accepted: March 18, 2025 Published: April 2, 2025
https://doi.org/10.18632/aging.206236How to Cite
Copyright: © 2025 Lautrup et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (WRN) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD+ causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD+ 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+ augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with WRN knockout (WRN−/−) and in primary fibroblasts derived from WS patients compared to controls. Moreover, WRN deficiency results in decreased mitochondrial NAD+ (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+ is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of WRN, highlighting an indispensable role of WRN in proliferation even in an NAD+ affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.
Abbreviations
β-Gal: β-Galactosidase; ChIP-seq: chromatin immunoprecipitation sequencing; MSCs: mesenchymal stem cells; HEK293P: HEK293 Parental; KD: knock down; KO: knock out; NAAD: nicotinic acid adenine dinucleotide; NAM: nicotinamide; NAMPT: Nicotinamide phosphoribosyltransferase; NADSYN1: NAD Synthetase 1; NMN: nicotinamide mononucleotide; NMNAT1: Nicotinamide mononucleotide adenylyl transferase 1; NR: nicotinamide riboside; Veh: Vehicle; WS: Werner syndrome; WRN: WERNER; NAD+: Nicotinamide adenine dinucleotide.