Oxidative stress impairs the Nur77-Sirt1 axis resulting in a decline in organism homeostasis during aging.
Oxidative stress impairs the Nur77-Sirt1 axis resulting in a decline in organism homeostasis during aging.
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作者：
Sirt 1是一种NAD+依赖性脱乙酰酶，可防止过早衰老和细胞衰老。衰老伴随着氧化应激导致Sirt1水平和活性下降，但连接这些事件的调节机制仍不清楚。在这里，我们报道了与Sirt1具有相似生物学途径的Nur77在多个器官中也随着年龄的增长而减少。我们的体内和体外结果显示，Nur77和Sirt1在衰老和氧化应激诱导的细胞衰老过程中减少。Nr4a1的缺失缩短了小鼠的寿命，加速了多个组织的衰老过程。Nr4a1的过表达通过E3连接酶MDM2的负转录调节保护Sirt1蛋白免于蛋白酶体降解。我们的研究结果表明，Nur77缺乏显著加重了衰老相关性肾病，并阐明了Nur77在肾脏衰老过程中稳定Sirt1稳态的关键作用。我们提出了一个模型，其中Nur77的减少响应于氧化应激促进Sirt1蛋白降解通过MDM2，这触发细胞衰老。这会产生额外的氧化应激，并通过进一步降低Nur77的表达为过早衰老提供正反馈。我们的研究结果揭示了氧化应激降低衰老过程中Sirt1表达的机制，并为靶向衰老和生物体内稳态提供了一种有吸引力的治疗策略。Nur77随着年龄的增长和对ROS刺激的反应而下降，这导致Sirt1通过MDM2介导的蛋白酶体降解而丢失。这些事件增加了p53的稳定性和激活，这反过来又进一步下调了Nur77和Sirt1的表达，加速了肾脏的衰老过程。
Sirt1 is an NAD+‐dependent deacetylase that protects against premature aging and cell senescence. Aging accompanied by oxidative stress leads to a decrease in Sirt1 levels and activity, but the regulatory mechanism that connects these events remains unclear. Here, we reported that Nur77, which shares similar biological pathways with Sirt1, was also decreased with age in multiple organs. Our in vivo and in vitro results revealed that Nur77 and Sirt1 decreased during aging and oxidative stress‐induced cell senescence. Deletion of Nr4a1 shortened the lifespan and accelerated the aging process in multiple mouse tissues. Overexpression of Nr4a1 protected the Sirt1 protein from proteasomal degradation through negative transcriptional regulation of the E3 ligase MDM2. Our results showed that Nur77 deficiency markedly aggravated aging‐related nephropathy and elucidated a key role for Nur77 in the stabilization of Sirt1 homeostasis during renal aging. We proposed a model wherein a reduction of Nur77 in response to oxidative stress promotes Sirt1 protein degradation through MDM2, which triggers cell senescence. This creates additional oxidative stress and provides positive feedback for premature aging by further decreasing Nur77 expression. Our findings reveal the mechanism by which oxidative stress reduces Sirt1 expression during aging and offers an attractive therapeutic strategy for targeting aging and homeostasis in organisms. Nur77 declines with aging and in response to ROS stimulation, which leads to the loss of Sirt1 via MDM2‐mediated proteasomal degradation. These events increase p53 stability and activation, which in turn further downregulate the expression of Nur77 and Sirt1 and accelerate the aging process in the kidney.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
雷公藤红素诱导的 Nur77 与 TRAF2 相互作用通过促进线粒体泛素化和自噬减轻炎症
影响因子：
16
作者：
Hu M;Luo Q;Alitongbieke G;Chong S;Xu C;Xie L;Chen X;Zhang D;Zhou Y;Wang Z;Ye X;Cai L;Zhang F;Chen H;Jiang F;Fang H;Yang S;Liu J;Diaz-Meco MT;Su Y;Zhou H;Moscat J;Lin X;Zhang XK
通讯作者：
Zhang XK
DOI：
10.1152/ajprenal.00255.2017
发表时间：
2017-09-01
影响因子：
4.2
作者：
Chuang, Peter Y.;Cai, Weijing;Lee, Kyung
通讯作者：
Lee, Kyung
JAML 升高通过调节足细胞脂质代谢促进糖尿病肾病。
影响因子：
29
作者：
Fu, Yi;Sun, Yu;Yi, Fan
通讯作者：
Yi, Fan
DOI：
10.1083/jcb.200512059
发表时间：
2006-05-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Knights CD;Catania J;Di Giovanni S;Muratoglu S;Perez R;Swartzbeck A;Quong AA;Zhang X;Beerman T;Pestell RG;Avantaggiati ML
通讯作者：
Avantaggiati ML