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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.

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Hexavalent chromium [Cr (VI)] is a well‐established carcinogen. Cr (VI)‐treated cells are phenotypically characterized by aberrant levels of growth and migration. Curcumin, a polyphenolic compound from the plant turmeric, has been found to possess antiproliferation, anti‐inflammation, and antioxidant properties. In this study, the effect of curcumin on Cr (VI)‐induced cell survival and migration and the underlying mechanism were investigated. Cell viability assay on A549 and human embryonic lung fibroblast cells showed that curcumin at the concentration of 10 µM could significantly attenuate Cr (VI)‐induced viability in both cell lines. Following Western blot assay and metabolomics assays, cotreatment with curcumin and Cr (VI) resulted in the suppression of Cr (VI)‐induced glycolysis‐, autophagy‐, and migration‐related proteins. Meanwhile, curcumin increased Cr (VI)‐reduced oxidative phosphorylation (OXPHOS)‐related proteins, COXIV and ND1. Moreover, curcumin suppressed Cr (VI)‐induced mitochondrial dysfunction, mitochondrial mass decrease, and mitochondrial membrane potential loss. Treatment with curcumin for 24 h significantly attenuated pcATG4B‐induced autophagy and the subsequent expression of glucose transporter 1, hexokinase II, and pyruvate kinase M2. Wound healing and transwell assay demonstrated that curcumin reduced Cr (VI)‐induced cell migration. Taken together, these results showed that curcumin was able to attenuate Cr (VI)‐induced cell viability and migration by targeting autophagy‐dependent reprogrammed metabolism from OXPHOS to glycolysis.

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