Tumor hypoxia is known to promote the acquisition of more aggressive phenotypes in human transitional cell carcinoma (TCC), including drug resistance. Accumulating evidence suggests that mitochondria play a central role in the chemoresistance of TCC. However, the role of mitochondria in the hypoxia-induced drug resistance in TCC remains elusive. The present study investigated the function of mitochondria in the drug resistance using a TCC cell line under hypoxic conditions. In vitro hypoxia (0.1% O₂, 48 h) was achieved by incubating TCC cells in air chamber. Mitochondrial events involving hypoxia-induced drug resistance were assessed. Hypoxia significantly reduced the cisplatin-induced apoptosis of TCC cells. Additionally, hypoxia substantially decreased the level of mitochondrial reactive oxygen species (ROS) generated by cisplatin treatment. Analogously, elimination of mitochondrial ROS significantly rescued cells from cisplatin-induced apoptosis. Hypoxia enhanced mitochondrial hyperpolarization, which was not related to ATP production or the reversal of ATP synthase activity. The mitochondrial DNA (mtDNA) amplification efficiency data illustrated that hypoxia significantly prevented oxidative damage to the mitogenome. Moreover, transmission electron microscopy revealed that cisplatin-induced disruption of the mitochondrial ultrastructure was abated under hypoxic conditions. Notably, depletion of mtDNA by ethidium bromide abrogated hypoxia-induced resistance to cisplatin. Taken together, the present study demonstrated that TCC cells exposed to hypoxic conditions rendered mitochondria less sensitive to oxidative stress induced by cisplatin treatment, leading to enhanced drug resistance.

众所周知，肿瘤缺氧会促进人类移行细胞癌 (TCC) 中更具侵袭性的表型的获得，包括耐药性。越来越多的证据表明线粒体在 TCC 的化学抗性中起核心作用。然而，线粒体在TCC缺氧诱导的耐药中的作用仍然难以捉摸。本研究使用 TCC 细胞系在缺氧条件下研究线粒体在耐药性中的功能。体外缺氧（0.1% O ₂, 48 h) 是通过在气室中培养 TCC 细胞来实现的。评估了涉及缺氧诱导的耐药性的线粒体事件。缺氧显着降低了顺铂诱导的TCC细胞凋亡。此外，缺氧显着降低了顺铂治疗产生的线粒体活性氧 (ROS) 水平。类似地，线粒体 ROS 的消除显着使细胞免于顺铂诱导的细胞凋亡。缺氧增强了线粒体超极化，这与 ATP 产生或 ATP 合酶活性的逆转无关。线粒体 DNA (mtDNA) 扩增效率数据表明，缺氧显着防止了对有丝分裂基因组的氧化损伤。而且，透射电子显微镜显示，顺铂诱导的线粒体超微结构破坏在缺氧条件下得到缓解。值得注意的是，溴化乙锭对 mtDNA 的消耗消除了缺氧诱导的对顺铂的耐药性。总之，本研究表明，暴露于缺氧条件下的 TCC 细胞使线粒体对顺铂治疗诱导的氧化应激的敏感性降低，从而导致耐药性增强。