Decreased Mitochondrial Translation Suppresses 3,3′-Diindolylmethane-Induced Reactive Oxygen Species Generation in Schizosaccharomyces Pombe

Abstract

Broccoli-derived 3,3′-diindolylmethane (DIM) exhibits anticancer effects. The compound also inhibits the growth of fission yeast cells. Reduction of mitochondrial translation alleviates the growth defects caused by DIM in fission yeast; however, the underlying molecular mechanisms remain unclear. In this study, we show that DIM-induced reactive oxygen species (ROS) colocalized with mitochondria. Deletion of tsf1⁺, which leads to reduced mitochondrial translation, suppressed this colocalization. Deletions of stress response genes, such as sty1⁺, pap1⁺, and atf1⁺, increased DIM sensitivity. Growth defects in the wild-type and sty1, pap1, and atf1 disruptants in the presence of DIM were suppressed by the ROS scavenger N-acetylcysteine. Moreover, the ROS scavenger Sod1, which is suggested to function in the mitochondrial intermembrane space and cytoplasm, was important for survival in the presence of DIM. Collectively, the study results suggest that DIM increases ROS levels in mitochondria and suppression of ROS increase in mitochondria via inhibition of mitochondrial translation is the mechanism by which DIM-induced growth defects in wild-type cells are suppressed. Overall, the study highlights the potential use of DIM as an anticancer drug to increase ROS generation in mitochondria in cancer cells.