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. / Yang, Beimeng; Dan, Xiuli; Hou, Yujun; Lee, Jong Hyuk; Wechter, Noah; Krishnamurthy, Sudarshan; Kimura, Risako; Babbar, Mansi; Demarest, Tyler; McDevitt, Ross; Zhang, Shiliang; Zhang, Yongqing; Mattson, Mark P.; Croteau, Deborah L.; Bohr, Vilhelm A.
In: Aging Cell, Vol. 20, No. 4, e13329, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy
AU - Yang, Beimeng
AU - Dan, Xiuli
AU - Hou, Yujun
AU - Lee, Jong Hyuk
AU - Wechter, Noah
AU - Krishnamurthy, Sudarshan
AU - Kimura, Risako
AU - Babbar, Mansi
AU - Demarest, Tyler
AU - McDevitt, Ross
AU - Zhang, Shiliang
AU - Zhang, Yongqing
AU - Mattson, Mark P.
AU - Croteau, Deborah L.
AU - Bohr, Vilhelm A.
N1 - 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.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Ataxia Telangiectasia
KW - mitophagy
KW - Nicotinamide riboside
KW - SASP
KW - senescence
U2 - 10.1111/acel.13329
DO - 10.1111/acel.13329
M3 - Journal article
C2 - 33734555
AN - SCOPUS:85102634978
VL - 20
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 4
M1 - e13329
ER -
ID: 276332375