In summary, this study indicates that the inability of cancer cells to downregulate mitochondrial respiration and excessive ROS production upon NAC1 silenced correlates with increased cell apoptosis in hypoxia, and demonstrates that this previously unrecognized function of NAC1 involved in depressing mitochondrial respiration in hypoxia is mediated through the HIF-1α-PDK3 axis. Here, PDK3 is linked to cancer.