NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy
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- NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy
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Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A-T). Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in A-T patient fibroblasts, and in ATM-deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1-dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm−/− mice. Our findings suggest a central role for mitochondrial dysfunction-induced senescence in A-T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention.
Originalsprog | Engelsk |
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Artikelnummer | e13329 |
Tidsskrift | Aging Cell |
Vol/bind | 20 |
Udgave nummer | 4 |
Antal sider | 14 |
ISSN | 1474-9718 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This research was supported by the Intramural Research Program of the NIH, the National Institute on Aging (V.A.B.). We thank Drs. Elin Lehrmann and Kevin Becker for performing microarray experiments and data analysis. We thank Drs. Aiwu Cheng, and Peisu Zhang for technical support. We thank Drs. Bindu Paul, Vinod Tiwari, and Nima Borhan Fakouri for reading the paper.
Publisher Copyright:
Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
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