|Copper and manganese induce yeast apoptosis via different pathways [MANUSCRIPT]|
Liang Q, Zhou B
Molecular Biology of the Cell (2007)
Category: apoptosis, ions ¤ Added: Sep 24, 2007 ¤ Rating: ◊◊
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 Saccharomyces cerevisiae. We demonstrated that at moderate toxic levels both metals, while beneficial at sub-toxic 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.