Role of mitochondrial respiration in sensitization of copper-deficient yeast to cisplatin-induced cytotoxicity

Abstract

Copper-depleted cells are more sensitive to cisplatin-induced cytotoxicity due to upregulation of Ctr1, and enhanced accumulation of cis-diamminedichloroplatinum(II) (CDDP). Here we investigated the specific role of mitochondria in enhanced CDDP cytotoxicity under copper-depleted conditions. BY4741 Saccharomyces cerevisiae grown in yeast peptone and glycerol media were subjected to copper-sufficient or-deficient conditions. These cells were then treated with cisplatin to study the changes in cytochrome c oxidase activity, mitochondrial respiration, production of reactive oxygen species, cytosolic pH, translocation of cytochrome c from mitochondria to cytosol and mitochondrial membrane potential. Copper deprivation resulted in decreased cytochrome c oxidase activity and impaired respiration, which were further augmented by cisplatin. Cisplatin caused the release of mitochondrial cytochrome c and a dramatic drop in the mitochondrial membrane potential (ψ m). Also, cisplatin reduced the intracellular cytosolic pH in the copper-deficient cells. Copper-deficiency induced decrease in cytochrome c oxidase activity alters mitochondrial respiration which is further worsened by cisplatin, resulting in enhanced apoptosis.