Overexpression of NMNAT3 improves mitochondrial function and enhances antioxidative stress capacity of bone marrow mesenchymal stem cells via the NAD+-Sirt3 pathway.
Overexpression of NMNAT3 improves mitochondrial function and enhances antioxidative stress capacity of bone marrow mesenchymal stem cells via the NAD+-Sirt3 pathway.
复制标题
NMNAT3过表达通过NAD-Sirt3途径改善线粒体功能并增强骨髓间充质干细胞的抗氧化应激能力
DOI：
10.1042/bsr20211005
复制
发表时间：
2022-01-28
影响因子：
4
通讯作者：
Gong Y
中科院分区：
文献类型：
--
作者：
Wang T;Zhang F;Peng W;Wang L;Zhang J;Dong W;Tian X;Ye C;Li Y;Gong Y
氧化应激损伤是骨髓间充质干细胞（BMSC）移植中常见的问题。在应激条件下，BMSCs的线粒体功能被破坏，加速BMSCs的衰老和凋亡，最终导致疗效不佳。因此，改善BMSCs线粒体功能、增强BMSCs抗氧化应激能力可能是提高BMSCs存活率和疗效的有效途径。在本研究中，我们证实烟酰胺单核苷酸腺苷酸转移酶 3 (NMNAT3) 的过表达可改善 BMSC 中的线粒体功能和对应激诱导的细胞凋亡的抵抗力。我们进一步揭示了 NMNAT3 介导的 BMSCs 抵抗应激诱导的细胞凋亡的机制。我们通过在BMSC中过表达NMNAT3来增加烟酰胺腺嘌呤二核苷酸（NAD+）的水平，发现它可以显着增加沉默交配型信息调节2同源物3（Sirt3）的活性，并显着降低Sirt3依赖性脱乙酰化相关蛋白异柠檬酸脱氢酶2（Idh2）和叉头盒蛋白O3a（FOXO3a）的乙酰化水平。这些发现表明，NMNAT3 可能通过增加 NAD+ 水平来增加 Sirt3 的活性。我们的结果证实，NMNAT3-NAD+-Sirt3 轴是改善线粒体功能和增强 BMSC 抗氧化应激能力的潜在机制。本研究利用NMNAT3抑制应激诱导的BMSCs凋亡的作用，为临床突破BMSCs移植疗效的瓶颈提供新的方法和思路。
Oxidative stress damage is a common problem in bone marrow mesenchymal stem cell (BMSC) transplantation. Under stress conditions, the mitochondrial function of BMSCs is disrupted, which accelerates senescence and apoptosis of BMSCs, ultimately leading to poor efficacy. Therefore, improving mitochondrial function and enhancing the antioxidative stress capacity of BMSCs may be an effective way of improving the survival rate and curative effect of BMSCs. In the present study, we have confirmed that overexpression of nicotinamide mononucleotide adenylyl transferase 3 (NMNAT3) improves mitochondrial function and resistance to stress-induced apoptosis in BMSCs. We further revealed the mechanism of NMNAT3-mediated resistance to stress-induced apoptosis in BMSCs. We increased the level of nicotinamide adenine dinucleotide (NAD+) by overexpressing NMNAT3 in BMSCs and found that it could significantly increase the activity of silent mating type information regulation 2 homolog 3 (Sirt3) and significantly decrease the acetylation levels of Sirt3-dependent deacetylation-related proteins isocitrate dehydrogenase 2 (Idh2) and Forkhead-box protein O3a (FOXO3a). These findings show that NMNAT3 may increase the activity of Sirt3 by increasing NAD+ levels. Our results confirm that the NMNAT3-NAD+-Sirt3 axis is a potential mechanism for improving mitochondrial function and enhancing antioxidative stress capacity of BMSCs. In the present study, we take advantage of the role of NMNAT3 in inhibiting stress-induced apoptosis of BMSCs and provide new methods and ideas for breaking through the bottleneck of transplantation efficacy of BMSCs in the clinic.