Fig. 6. The model of our working hypothesis. Cr(vi) inhibited MRCC I, led to intracellular ROS accumulation and then caused cytotoxicity. ROS could induce a DNA damage response, which activated ATM kinase and its down-stream executor IGF-1, and resulted in up-regulation of CLU. High expression of CLU may activate the MRCC I subunit NDUFS3, which increased MRCC I activity, inhibited ROS production, and further alleviated cytotoxicity. CLU may help the hepatocytes to escape apoptosis and then undergo malignant transformation after Cr(vi) exposure.