Abstract: Monitoring Editor: Donald Newmeyer Metal ions are essential as well as toxic to the cell. Mechanism of metal-induced toxicity is not well established. Here, for the first time we studied two essential nutritional elements Cu- and Mn-induced cell death in yeast S. cerevisiae. We demonstrated that at moderate toxic levels both metals, while beneficial at subtoxic levels, induce extensive apoptosis in yeast cells. At even higher concentration, necrosis takes over. Further, we investigated molecular pathways mediating Cu- and Mn-mediated apoptotic action. Mitochondria-defective yeast exhibits much reduced apoptotic marker expression and better survival under Cu and Mn stress, indicating mitochondria are involved in both Cu- and Mn-induced apoptosis. ROS are generated greatly in Cu- but not in Mn-induced cell death, and Cu toxicity can be alleviated by overexpression of SOD2, suggesting ROS mediate Cu but not Mn toxicity. Yeast metacaspase Yca1p is not involved in Cu-induced apoptosis although it plays an important role in Mn-induced process. A genetic screen identified Cpr3p, a yeast cyclophilin D homologue, mediates the Cu-induced apoptotic program. Cpr3p mutant appears eliminating Cu-induced apoptosis without affecting ROS production, while leaving necrosis intact. These results may provide important insights into detailed understanding at molecular and cellular level of metal toxicity and metal-accumulation diseases.