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

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.

Automated summary

The study shows that mitochondrial dysfunction and cellular senescence occur in A-T patient fibroblasts, ATM-deficient cells, and mice, and boosting intracellular NAD(+) levels can prevent senescence and senescence-associated secretory phenotype (SASP) by promoting mitophagy in a PINK1-dependent manner. This suggests a central role for mitochondrial dysfunction-induced senescence in A-T pathogenesis and highlights enhancing mitophagy as a potential therapeutic intervention.