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.
Original language | English |
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Article number | e13329 |
Journal | Aging Cell |
Volume | 20 |
Issue number | 4 |
Number of pages | 14 |
ISSN | 1474-9718 |
DOIs | |
Publication status | Published - 2021 |
Bibliographical note
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.
- Ataxia Telangiectasia, mitophagy, Nicotinamide riboside, SASP, senescence
Research areas
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