Augmentation of cellular NAD+ by NQO1 enzymatic action improves age-related hearing impairment
Augmentation of cellular NAD+ by NQO1 enzymatic action improves age-related hearing impairment
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DOI：
10.1111/acel.13016
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发表时间：
2019-07-28
期刊：
影响因子：
7.8
通讯作者：
So, Hong-Seob
中科院分区：
文献类型：
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作者：
Kim, Hyung-Jin;Cao, Wa;So, Hong-Seob
年龄相关性听力损失（ARHL）是一种主要的神经退行性疾病，也是老年人沟通障碍的主要原因，但在很大程度上仍未得到治疗。ARHL的发展是一个多因素的事件，包括内在因素和外在因素。最近的研究表明，NAD(+)/NADH比值可能通过调节sirtuins、PARP-1和PGC-1 α在细胞衰老中起关键作用。尽管如此，直接调节细胞NAD（+）水平对衰老和年龄相关疾病的有益作用尚未得到研究，其潜在机制仍不清楚。本文中，我们研究了β -拉帕酮（β -lap），一种已知的植物源代谢物，通过NADH：醌氧化还原酶1 （NQO1）对C57BL/6小鼠ARHL的酶促作用，通过将NADH转化为NAD（+）来调节细胞内的NAD（+）。我们发现衰老过程中细胞NAD（+）的减少是ARHL的重要因素；它通过调节改变各种信号通路的sirtuins，如NF-kappa B、p53和IDH2，促进耳蜗组织的氧化应激和促炎反应。然而，β -lap增加NAD（+）通过减少炎症和氧化应激，维持线粒体功能，促进线粒体生物发生，有效预防ARHL及其伴随的有害影响。这些结果表明，通过药物直接调节细胞NAD（+）水平可能是治疗包括ARHL在内的各种年龄相关疾病的切实可行的治疗选择。
Age-related hearing loss (ARHL) is a major neurodegenerative disorder and the leading cause of communication deficit in the elderly population, which remains largely untreated. The development of ARHL is a multifactorial event that includes both intrinsic and extrinsic factors. Recent studies suggest that NAD(+)/NADH ratio may play a critical role in cellular senescence by regulating sirtuins, PARP-1, and PGC-1 alpha. Nonetheless, the beneficial effect of direct modulation of cellular NAD(+) levels on aging and age-related diseases has not been studied, and the underlying mechanisms remain obscure. Herein, we investigated the effect of beta-lapachone (beta-lap), a known plant-derived metabolite that modulates cellular NAD(+) by conversion of NADH to NAD(+) via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD(+) during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro-inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF-kappa B, p53, and IDH2. However, augmentation of NAD(+) by beta-lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD(+) levels by pharmacological agents may be a tangible therapeutic option for treating various age-related diseases, including ARHL.