ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal.
ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal.
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DOI：
10.1073/pnas.2216310120
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发表时间：
2023-06-13
影响因子：
11.1
通讯作者：
Duan, Cunming
中科院分区：
文献类型：
--
作者：
Li, Yingxiang;Liu, Chengdong;Rolling, Luke;Sikora, Veronica;Chen, Zhimin;Gurwin, Jack;Barabell, Caroline;Lin, Jiandie;Duan, Cunming
关键词：
细胞更新对于组织稳态和再生至关重要。使用斑马鱼模型，我们表明线粒体膜电位和 TCA 循环/OXPHOS 的增加是细胞周期重新进入所必需的且足够的。线粒体活性升高导致 ATP 合成和 ROS 产生增加。线粒体 ROS 升高会诱导 Sgk1 的线粒体表达。 Sgk1 通过调节 F1Fo-ATP 合酶磷酸化状态和 ATP 合成来改变细胞命运。该信号环路还介导人类乳腺癌细胞线粒体代谢依赖性进入 S 期，表明这是一种进化上保守的机制。许多类型的分化细胞在受伤或应激时可以重新进入细胞周期。其基本机制仍知之甚少。在这里，我们研究了如何使用斑马鱼模型重新激活静止细胞，其中一群分化的上皮细胞在生理背景下重新激活。在重新激活的细胞中观察到线粒体膜电位强劲且持续的增加。遗传和药理学扰动表明，线粒体代谢和 ATP 合成的升高对于细胞重新激活至关重要。进一步的分析表明，线粒体代谢升高会增加线粒体 ROS 水平，从而诱导线粒体中 Sgk1 的表达。斑马鱼中 Sgk1 的基因缺失和抑制消除了上皮细胞的再激活。同样，SGK1 的 ROS 依赖性线粒体表达促进人乳腺癌细胞进入 S 期。从机制上讲，SGK1 通过磷酸化 F1Fo-ATP 合酶来协调线粒体活性与 ATP 合成。这些发现表明保守的线粒体内信号环路调节上皮细胞更新。
Cell renewal is critical for tissue homeostasis and regeneration. Using a zebrafish model, we show that an increase in mitochondrial membrane potential and TCA cycle/OXPHOS are required and sufficient for the cell cycle reentry. The elevated mitochondrial activity leads to increased ATP synthesis and ROS production. Elevated mitochondrial ROS induces the mitochondrial expression of Sgk1. Sgk1 alters cell fate by modulating F1Fo-ATP synthase phosphorylation state and ATP synthesis. This signaling loop also mediates mitochondrial metabolism–dependent S phase entry of human breast cancer cells, suggesting that it is an evolutionarily conserved mechanism. Many types of differentiated cells can reenter the cell cycle upon injury or stress. The underlying mechanisms are still poorly understood. Here, we investigated how quiescent cells are reactivated using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. A robust and sustained increase in mitochondrial membrane potential was observed in the reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Further analyses showed that elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Genetic deletion and inhibition of Sgk1 in zebrafish abolished epithelial cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, SGK1 coordinates mitochondrial activity with ATP synthesis by phosphorylating F1Fo-ATP synthase. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal.
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影响因子：
50.3
作者：
Castel P;Ellis H;Bago R;Toska E;Razavi P;Carmona FJ;Kannan S;Verma CS;Dickler M;Chandarlapaty S;Brogi E;Alessi DR;Baselga J;Scaltriti M
通讯作者：
Scaltriti M
DOI：
10.1084/jem.20081297
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen C;Liu Y;Liu R;Ikenoue T;Guan KL;Liu Y;Zheng P
通讯作者：
Zheng P
影响因子：
--
作者：
Jiang, Daofang;Fu, Chensheng;Zhang, Xiaoli
通讯作者：
Zhang, Xiaoli
影响因子：
4.6
作者：
Kim, Yeji;Lee, Yong-Soo;Kweon, Mi-Na
通讯作者：
Kweon, Mi-Na
影响因子：
2.9
作者：
Del Prete, E;Lutz, TA;Scharrer, E
通讯作者：
Scharrer, E