Mitochondria plays a key role in regulating cell death process under stress conditions and it has been indicated that NAMPT overexpression promotes cell survival under genotoxic stress by maintaining mitochondrial NAD+ level. NAMPT is a rate-limiting enzyme for NAD+ production in mammalian cells and it was suggested that NAMPT and NMNAT3 are responsible for mitochondrial NAD+ production to maintain mitochondrial NAD+ pool. However, subsequent studies suggested mitochondrial may lack the NAMPT-NMANT3 pathway to maintain NAD+ level. Therefore, how NAMPT overexpression rescues mitochondrial NAD+ content to promote cell survival in response to genotoxic stress remains elusive. Here, we show that NAMPT promotes cell survival under oxidative stress via both SIRT1 dependent p53-CD38 pathway and SIRT1 independent NRF2-PPARα/AMPKα pathway, and the NRF2-PPARα/AMPKα pathway plays a more profound role in facilitating cell survival than the SIRT1-p53-CD38 pathway does. Mitochondrial content and membrane potential were significantly reduced in response to H2O2 treatment, whereas activated NRF2-PPARα/AMPKα pathway by NAMPT overexpression rescued the mitochondrial membrane potential and content, suggesting that maintained mitochondrial content and integrity by NAMPT overexpression might be one of the key mechanisms to maintain mitochondrial NAD+ level and subsequently dictate cell survival under oxidative stress. Our results indicated that NRF2 is a novel down-stream target of NAMPT, which mediates anti-apoptosis function of NAMPT via maintaining mitochondrial content and membrane potential.

中文翻译：

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NAMPT通过NRF2-PPARα/AMPKα途径维持线粒体含量，从而促进细胞在氧化应激下的存活。

线粒体在应激条件下调节细胞死亡过程中起着关键作用，并且已经表明，NAMPT的过表达通过保持线粒体NAD +水平而在遗传毒性应激下促进细胞存活。NAMPT是哺乳动物细胞中产生NAD +的限速酶，提示NAMPT和NMNAT3负责线粒体NAD +的产生，以维持线粒体NAD +库。然而，随后的研究表明线粒体可能缺乏维持NAD +水平的NAMPT-NMANT3途径。因此，NAMPT过表达如何挽救线粒体NAD +含量以响应遗传毒性应激而促进细胞存活尚不清楚。在这里，我们显示NAMPT通过SIRT1依赖的p53-CD38途径和SIRT1独立的NRF2-PPARα/AMPKα途径促进细胞在氧化应激下的存活，NRF2-PPARα/AMPKα通路在促进细胞存活方面比SIRT1-p53-CD38通路起着更重要的作用。H2O2处理后线粒体含量和膜电位显着降低，而NAMPT过量表达激活的NRF2-PPARα/AMPKα途径挽救了线粒体膜电位和含量，表明通过NAMPT过量表达保持线粒体含量和完整性可能是关键机制之一维持线粒体NAD +的水平，并随后决定细胞在氧化应激下的存活率。我们的结果表明，NRF2是NAMPT的新型下游靶标，它通过维持线粒体含量和膜电位来介导NAMPT的抗凋亡功能。