1. NAD + supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy.
- Author
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Yang B, Dan X, Hou Y, Lee JH, Wechter N, Krishnamurthy S, Kimura R, Babbar M, Demarest T, McDevitt R, Zhang S, Zhang Y, Mattson MP, Croteau DL, and Bohr VA
- Subjects
- Animals, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia Mutated Proteins metabolism, Case-Control Studies, Cell Line, Tumor, Disease Models, Animal, Female, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Male, Membrane Proteins genetics, Mice, Mice, Knockout, Mitochondria metabolism, Mitophagy genetics, Neurons drug effects, Neurons metabolism, Niacinamide administration & dosage, Rats, Rats, Sprague-Dawley, Signal Transduction genetics, Transfection, Treatment Outcome, Ataxia Telangiectasia diet therapy, Ataxia Telangiectasia metabolism, Dietary Supplements, Membrane Proteins metabolism, Mitophagy drug effects, NAD metabolism, Niacinamide analogs & derivatives, Pyridinium Compounds administration & dosage, Senescence-Associated Secretory Phenotype genetics, Signal Transduction drug effects
- Abstract
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., (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.)- Published
- 2021
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