Chromium (Cr) compounds are markedly toxic and carcinogenic. Previously, we found that Cr (VI) induced autophagy in A549 cells. Here, the effect of mitochondrial dysfunction and endoplasmic reticulum (ER) stress on inducing mitophagy was investigated in both A549 and H1299 cells. Exposure to Cr (VI) for 6 h significantly enhanced reactive oxygen species (ROS) production and reduced mitochondrial membrane potential (MMP). Transmission electron microscopy showed that Cr (VI) induced mitochondrial morphological changes, such as, mitochondrial swelling and vacuolization. The elevated expression of GRP78 and p‐PERK suggested that Cr (VI) resulted in ER stress. Both mitochondrial dysfunction and ER stress played an important role in Cr (VI)‐induced mitophagy, as the mitochondrial function inhibitor, carbonyl cyanide 3‐chlorophenylhydrazone (CCCP) induced PINK1 and PARK2 and increased the expression of GRP78 and p‐PERK while the levels of Cr (VI)‐induced PINK1, PARK2, LC3‐II were reduced after ER stress inhibitor, phenylbutyric acid (4PBA) pretreatment. When A549 cells were treated with CCCP and 4‐PBA simultaneously, CCCP‐induced expressions of PINK1, PARK2 and LC3‐II decreased significantly compared with that of only CCCP‐treated cells, indicating that there was a crosstalk between mitochondria and ER in inducing mitophagy. Additionally, the crosstalk between mitochondrial dysfunction and ER stress modulated the expression of Cr (VI)‐induced ATF4, which resulted in mitophagy. Collectively, our data demonstrated that Cr (VI)‐induced mitophagy mediated by ATF4 via the crosstalk between ER stress and mitochondrial dysfunction.

中文翻译：

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线粒体功能障碍和内质网应激之间的串扰促进了六价铬诱导的ATF4介导的线粒体吞噬

铬（Cr）化合物具有明显的毒性和致癌性。以前，我们发现Cr（VI）诱导A549细胞自噬。在这里，在A549和H1299细胞中都研究了线粒体功能障碍和内质网（ER）应激对线粒体细胞的诱导作用。暴露于Cr（VI）6 h可以显着增强活性氧（ROS）的产生并降低线粒体膜电位（MMP）。透射电子显微镜显示Cr（VI）引起线粒体形态变化，例如线粒体肿胀和空泡化。GRP78和p-PERK的高表达表明Cr（VI）导致内质网应激。作为线粒体功能抑制剂，线粒体功能障碍和内质网应激都在Cr（VI）诱导的线粒体吞噬中起着重要作用，羰基氰化物3-氯苯基（（CCCP）诱导PINK1和PARK2并增加GRP78和p‐PERK的表达，而Cr（VI）诱导的PINK1，PARK2和LC3-II的水平在ER应力抑制剂，苯丁酸（4PBA ）预处理。当同时用CCCP和4-PBA处理A549细胞时，与仅用CCCP处理的细胞相比，CCCP诱导的PINK1，PARK2和LC3-II的表达显着降低，这表明线粒体和ER之间在诱导线粒体吞噬方面存在串扰。 。此外，线粒体功能障碍和内质网应激之间的串扰调节了Cr（VI）诱导的ATF4的表达，从而导致线粒体吞噬。总体而言，我们的数据表明Cr（VI）通过内质网应激与线粒体功能障碍之间的串扰，由ATF4介导的线粒体吞噬。