Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes
Deficiency in Cardiolipin Reduces Doxorubicin-Induced Oxidative Stress and Mitochondrial Damage in Human B-Lymphocytes
复制标题
DOI：
10.1371/journal.pone.0158376
复制
发表时间：
2016-07-19
期刊：
影响因子：
3.7
通讯作者：
Rao, V. Ashutosh
中科院分区：
文献类型：
--
作者：
Aryal, Baikuntha;Rao, V. Ashutosh
心磷脂（CL）是一种线粒体内膜磷脂，在线粒体功能中发挥重要作用。 CL 生物合成的扰动会改变线粒体生物能量学，导致严重的遗传性疾病，通常称为巴特综合征。众所周知，巴斯综合征患者的 CL 浓度降低且成分发生改变。众所周知，心磷脂对化疗药物阿霉素 (Dox) 具有高亲和力，导致该药物在线粒体中大量积聚。我们的结果表明，与 Barth 综合征的 B 淋巴细胞相比，健康个体的 B 淋巴细胞对 Dox 诱导的氧化应激和细胞毒性更敏感，Dox 治疗后细胞死亡更多，裂解的 caspase-3 水平更高。与健康淋巴细胞相比，巴斯淋巴细胞显示出较高的线粒体活性氧 (mito-ROS) 基础水平，但响应 Dox 的诱导线粒体 -ROS 产生水平较低。与 Dox 处理后的 Barth 细胞相比，健康细胞中的 ATP 含量显着降低，而 OXPHOS 蛋白水平略高。与更高的线粒体 ROS 一致，与 Barth 淋巴细胞相比，Dox 治疗在健康淋巴细胞中诱导了更高水平的脂质过氧化和蛋白质羰基化。 CL 合成过程中 CL 的最终重塑是由 tafazzin 蛋白催化的。使用 siRNA 敲低 H9c2 心肌细胞中的 tafazzin 基因，显示氧化剂诱导的损伤减少，正如在 Barth 淋巴细胞中观察到的那样。我们的研究结果表明，CL 的缺乏可能会提供有利于氧化剂诱导的抗癌活性的治疗优势。
Cardiolipin (CL) is an inner mitochondrial membrane phospholipid which plays an important role in mitochondrial function. Perturbation in CL biosynthesis alters mitochondrial bioenergetics causing a severe genetic disorder commonly known as Barth syndrome. Barth syndrome patients are known to have a reduced concentration and altered composition of CL. Cardiolipin is also known to have a high affinity for the chemotherapeutic agent doxorubicin (Dox), resulting in an extensive mitochondrial accumulation of the drug. Our results indicate that B-lymphocytes from healthy individuals are more sensitive to Dox-induced oxidative stress and cellular toxicity compared to the B-lymphocytes from Barth syndrome as indicated by greater cell death and greater level of cleaved caspase-3 following Dox treatment. Barth lymphocytes, when compared to healthy lymphocytes, showed a greater basal level of mitochondrial reactive oxygen species (mito-ROS), yet exhibited a lower level of induced mito-ROS production in response to Dox. Significantly less ATP content and slightly greater OXPHOS protein levels were detected in healthy cells compared to Barth cells after Dox treatment. Consistent with greater mitochondrial ROS, treatment with Dox induced a higher level of lipid peroxidation and protein carbonylation in healthy lymphocytes compared to Barth lymphocytes. The final remodeling of CL during CL synthesis is catalyzed by the tafazzin protein. Knockdown of tafazzin gene in H9c2 cardiomyocytes using siRNA showed decreased oxidant-induced damage, as observed in Barth lymphocytes. Our findings demonstrate that a deficiency in CL might provide a therapeutic advantage in favor of oxidant-induced anticancer activities.