在 Keap1 功能丧失的背景下,Nrf2 枯竭导致线粒体细胞积累
Sharadha Dayalan Naidu1, Plamena R Angelova2, Elena V Knatko1
1Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, UK.
Free radical biology & medicine
|September 15, 2023
概括
核因子红色素2 p45相关因子2 (Nrf2) 调节肺癌中的线粒体健康. Nrf2 缺乏会损害线粒体呼吸,但会增强线粒体积累,这表明它在清除受损线粒体方面发挥了作用.
科学领域:
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
- 线粒体生物学 线粒体生物学
背景情况:
- 核因子红色素2 p45相关因子2 (Nrf2) 对于细胞氧化还原稳定和线粒体功能至关重要.
- 凯尔奇类ECH相关蛋白1 (Keap1) 通过向Nrf2进行降解来负面调节Nrf2.
- 功能丧失的Keap1突变在肺癌中很常见,导致构成性的Nrf2激活.
研究的目的:
- 研究Nrf2在肺癌细胞中的线粒体健康中的作用.
- 了解Nrf2缺乏如何影响线粒体呼吸,膜潜力,质量和动态.
主要方法:
- 使用了A549人类肺癌细胞及其CRISPR/Cas9生成的Nrf2-knockout (Nrf2-KO) 对应物.
- 使用siRNA (siNFE2L2) 创建Nrf2-knockdown (Nrf2-KD) 种群,证实了独立于克隆选择的结果.
- 评估了线粒体呼吸,膜潜力,质量,DNA含量和线粒体形成.
主要成果:
- Nrf2 缺乏导致线粒体呼吸能力下降.
- 相反,Nrf2缺乏增加了线粒体膜潜力,质量,DNA含量和线粒体酶体数量.
- 在Nrf2缺乏的基亚1突变细胞中,观察到ATG7和ATG3对LC3B的结合增加,而不会影响自细胞形成.
结论:
- 在功能丧失的Keap1突变的肺癌细胞中,Nrf2在促进线索细胞分解中发挥作用.
- 在这种情况下,Nrf2对于及时清除受损的线粒体至关重要.
- 这些发现突出了一个新的机制,Nrf2通过它影响肺癌中线粒体质量控制.
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