Stock Amanda J, Liu Yie
Laboratory of Genomics and Genetics, Biomedical Research Center, National Institute on Aging/National Institutes of Health, Baltimore, MD, United States.
Front Aging. 2021 Oct 27;2:785171. doi: 10.3389/fragi.2021.785171. eCollection 2021.
Telomeres are specialized nucleoprotein structures that form protective caps at the ends of chromosomes. Short telomeres are a hallmark of aging and a principal defining feature of short telomere syndromes, including dyskeratosis congenita (DC). Emerging evidence suggests a crucial role for critically short telomere-induced DNA damage signaling and mitochondrial dysfunction in cellular dysfunction in DC. A prominent factor linking nuclear DNA damage and mitochondrial homeostasis is the nicotinamide adenine dinucleotide (NAD) metabolite. Recent studies have demonstrated that patients with DC and murine models with critically short telomeres exhibit lower NAD levels, and an imbalance in the NAD metabolome, including elevated CD38 NADase and reduced poly (ADP-ribose) polymerase and SIRT1 activities. CD38 inhibition and/or supplementation with NAD precursors reequilibrate imbalanced NAD metabolism and alleviate mitochondrial impairment, telomere DNA damage, telomere dysfunction-induced DNA damage signaling, and cellular growth retardation in primary fibroblasts derived from DC patients. Boosting NAD levels also ameliorate chemical-induced liver fibrosis in murine models of telomere dysfunction. These findings underscore the relevance of NAD dysregulation to telomeropathies and demonstrate how NAD interventions may prove to be effective in combating cellular and organismal defects that occur in short telomere syndromes.
端粒是一种特殊的核蛋白结构，在染色体末端形成保护帽。短端粒是衰老的标志，也是包括先天性角化不良（DC）在内的短端粒综合征的主要特征。新出现的证据表明，极短端粒诱导的DNA损伤信号和线粒体功能障碍在DC的细胞功能障碍中起关键作用。连接核DNA损伤和线粒体稳态的一个重要因素是烟酰胺腺嘌呤二核苷酸（NAD）代谢物。最近的研究表明，DC患者和端粒极短的小鼠模型的NAD水平较低，NAD代谢组失衡，包括CD38 NAD酶升高以及聚（ADP-核糖）聚合酶和SIRT1活性降低。抑制CD38和/或补充NAD前体可重新平衡失衡的NAD代谢，并减轻来自DC患者的原代成纤维细胞中的线粒体损伤、端粒DNA损伤、端粒功能障碍诱导的DNA损伤信号以及细胞生长迟缓。提高NAD水平还可改善端粒功能障碍小鼠模型中化学诱导的肝纤维化。这些发现强调了NAD失调与端粒病的相关性，并证明了NAD干预在对抗短端粒综合征中出现的细胞和机体缺陷方面可能是有效的。
