ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis.
ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis.
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DOI：
10.1111/acel.12720
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发表时间：
2018-04
期刊：
影响因子：
7.8
通讯作者：
Mora AL
中科院分区：
文献类型：
--
作者：
Bueno M;Brands J;Voltz L;Fiedler K;Mays B;St Croix C;Sembrat J;Mallampalli RK;Rojas M;Mora AL
PINK1 （PTEN诱导的推定激酶1）是线粒体稳态的关键调节因子，在特发性肺纤维化（IPF）患者的衰老肺部和肺上皮细胞中相对减少。纤维化肺上皮细胞中PINK1表达受损和受损线粒体的积累与内质网应激的存在有关。在这里，我们发现ATF3（激活转录因子3）是综合应激反应（ISR）的一个成员，负调控PINK1基因的转录。人类PINK1启动子内的ATF3结合位点位于转录起始位点上游的前150bp。内质网应激的诱导或ATF3的过表达抑制了PINK1启动子的活性。重要的是，ATF3的过表达导致去极化线粒体的积累，线粒体ROS的产生增加，以及细胞活力的丧失。此外，II型肺上皮细胞中ATF3的条件缺失可以保护小鼠免受博来霉素诱导的肺纤维化。最后，我们观察到ATF3在肺中的表达随着年龄的增长而增加，特别是在来自IPF肺的肺上皮细胞中。这些数据提供了ATF3和PINK1表达之间的独特联系，表明由ATF3驱动的持续应激可以通过抑制PINK1 mRNA合成来失调线粒体稳态。
PINK1 (PTEN‐induced putative kinase 1) is a key regulator of mitochondrial homeostasis that is relatively depleted in aging lungs and in lung epithelial cells from patients with idiopathic pulmonary fibrosis (IPF), a disease linked with aging. Impaired PINK1 expression and accumulation of damaged mitochondria in lung epithelial cells from fibrotic lungs were associated with the presence of ER stress. Here, we show that ATF3 (activating transcription factor 3), a member of the integrated stress response (ISR), negatively regulates transcription of the PINK1 gene. An ATF3 binding site within the human PINK1 promoter is located in the first 150 bp upstream of the transcription start site. Induction of ER stress or overexpression of ATF3 inhibited the activity of the PINK1 promoter. Importantly, overexpression of ATF3 causes accumulation of depolarized mitochondria, increased production of mitochondrial ROS, and loss of cell viability. Furthermore, conditional deletion of ATF3 in type II lung epithelial cells protects mice from bleomycin‐induced lung fibrosis. Finally, we observed that ATF3 expression increases in the lung with age and, specially, in lung epithelial cells from IPF lungs. These data provide a unique link between ATF3 and PINK1 expression suggesting that persistent stress, driven by ATF3, can dysregulate mitochondrial homeostasis by repression of PINK1 mRNA synthesis.
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