NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy

被引：79

作者：

Yang, Beimeng ^{[1
]}

Dan, Xiuli ^{[1
]}

Hou, Yujun ^{[1
]}

Lee, Jong-Hyuk ^{[1
]}

Wechter, Noah ^{[1
]}

Krishnamurthy, Sudarshan ^{[1
]}

Kimura, Risako ^{[1
]}

Babbar, Mansi ^{[1
]}

Demarest, Tyler ^{[1
]}

McDevitt, Ross ^{[2
]}

Zhang, Shiliang ^{[3
]}

Zhang, Yongqing ^{[4
]}

Mattson, Mark P. ^{[5
]}

Croteau, Deborah L. ^{[1
]}

Bohr, Vilhelm A. ^{[1
,6
]}

机构：

[1] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA

[2] NIA, Mouse Phenotyping Unit, NIH, Baltimore, MD 21224 USA

[3] Natl Inst Drug Abuse Intramural Res Program, Electron Microscopy Core, NIH, Baltimore, MD USA

[4] NIA, Lab Genet & Genom, NIH, Baltimore, MD 21224 USA

[5] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA

[6] Univ Copenhagen, Danish Ctr Hlth Aging, Copenhagen, Denmark

来源：

AGING CELL | 2021年 / 20卷 / 04期

关键词：

Ataxia Telangiectasia; mitophagy; Nicotinamide riboside; SASP; senescence;

D O I：

10.1111/acel.13329

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：14

共 42 条

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