Copper and cisplatin share copper transporter 1 (Ctr1) for cellular import. Copper depletion increases sensitivity of wild type yeast to cisplatin, whereas mitochondrial DNA-deficient rho0 cells are resistant to cisplatin. In the current study, we sought to determine whether copper deprivation modulates sensitivity of rho0 yeast to cisplatin. Yeast cultures grown in low copper medium and exposed to bathocuproine disulfonic acid resulted in significant reduction of intracellular copper. We report here that low copper medium rendered wild type hypersensitive to cisplatin, but failed to sensitize rho0 yeast to cisplatin. Wild type yeast grown in low copper medium exhibited ~2.0 fold enhanced cytotoxicity in survival and colony-forming ability compared to copper adequate wild type cells. The effect of copper restriction on cisplatin sensitivity was associated with upregulation of copper transporter 1 mRNA as well as protein, facilitating enhanced uptake and accumulation of cisplatin. Rho0 yeast also showed increased copper transporter 1 mRNA upon copper restriction, but failed to increase corresponding protein. Loss of synthesis of cytochrome c oxidase 1 protein (Sco1) in rho0 cells deregulated copper transporter 1, impaired Pt uptake and lowered cytotoxicity, despite lowered glutathione levels. Sco1Δ mutants exhibited low copper transporter 1, reduced Pt accumulation suggesting that Sco1 mediated regulation of copper transporter 1 is responsible for altered sensitivity to cisplatin. Rho0 cells demonstrated loss of Sco1, resulting in copper deficiency by lowering copper transporter 1 abundance, via mechanism involving increased turnover due to ubiquitination. These findings reveal that a Sco1-dependent mitochondrial signal regulates cellular cisplatin import and cytotoxicity.

铜和顺铂共享用于细胞导入的铜转运蛋白1（Ctr1）。铜耗竭可增加野生型酵母对顺铂的敏感性，而线粒体DNA缺失的rho0细胞则对顺铂具有抗性。在当前的研究中，我们试图确定铜的剥夺是否调节rho0酵母对顺铂的敏感性。酵母培养物在低铜​​培养基中生长并暴露于浴嘌呤二磺酸中会导致细胞内铜的显着减少。我们在这里报告低铜培养基使野生型对顺铂过敏，但未能使rho0酵母对顺铂敏感。与铜充足的野生型细胞相比，在低铜培养基中生长的野生型酵母在存活和集落形成能力方面显示出约2.0倍的细胞毒性增强。铜限制对顺铂敏感性的影响与铜转运蛋白1 mRNA和蛋白质的上调有关，从而促进顺铂的摄取和积累。Rho0酵母还显示在铜限制下增加了铜转运蛋白1 mRNA，但未能增加相应的蛋白质。的损失小号的ynthesis Ç ytochrome Ç ö xidase 1个解除管制的铜转运体1 rho0细胞蛋白（SCO1），受损的Pt摄取和降低的细胞毒性，尽管降低谷胱甘肽水平。Sco1Δ突变体表现出低铜转运蛋白1，减少Pt积累，这表明Sco1介导的铜转运蛋白1的调节是改变对顺铂的敏感性的原因。Rho0细胞表现出Sco1的丢失，并通过涉及泛素化导致营业额增加的机制，通过降低铜转运蛋白1的丰度而导致铜缺乏。这些发现表明，Sco1依赖的线粒体信号调节细胞顺铂的导入和细胞毒性。