Department of Health Toxicology, School of Public Health, Central South University, Changsha 410008, China.
Department of Physiology and Pathology, Health Sciences Center, Federal University of Paraíba, João Pessoa 58059-900, Brazil.
Int J Mol Sci. 2017 Sep 14;18(9):1877. doi: 10.3390/ijms18091877.
Hexavalent chromium (Cr(VI)) is a ubiquitous environmental pollutant, which poses a threat to human public health. Recent studies have shown that mitochondrial biogenesis can be activated by inflammatory and oxidative stress. However, whether mitochondrial biogenesis is involved in Cr(VI)-induced hepatotoxicity is unclear. Here, we demonstrated the induction of inflammatory response and oxidative stress, as indicated by upregulation of inflammatory factors and reactive oxygen species (ROS). Subsequently, we demonstrated that mitochondrial biogenesis, comprising the mitochondrial DNA copy number and mitochondrial mass, was significantly increased in HepG2 cells exposed to low concentrations of Cr(VI). Expression of genes related to mitochondrial function complex I and complex V was upregulated at low concentrations of Cr(VI). mRNA levels of antioxidant enzymes, including superoxide dismutase 1 and 2 ( and , respectively), kech like ECH associate protein 1 () and nuclear respiratory factor 2 (), were also upregulated. Consistent with the above results, mRNA and protein levels of key transcriptional regulators of mitochondrial biogenesis such as the peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α), NRF-1 and mitochondrial transcription factor A (TFAM) were increased by low concentrations of Cr(VI) in HepG2 cells. Moreover, we found that PGC-1α and NRF-1 tended to translocate into the nucleus. The expression of genes potentially involved in mitochondrial biogenesis pathways, including mRNA level of silent information regulator-1 (), forkhead box class-O (), threonine kinase 1 (), and cAMP response element-binding protein (), was also upregulated. In contrast, mitochondrial biogenesis was inhibited and the expression of its regulatory factors and antioxidants was downregulated at high and cytotoxic concentrations of Cr(VI) in HepG2 cells. It is believed that pretreatment with α-tocopherol could be acting against the mitochondrial biogenesis imbalance induced by Cr(VI). In conclusion, our study suggests that the homeostasis of mitochondrial biogenesis may be an important cellular compensatory mechanism against Cr(VI)-induced toxicity and a promising detoxification target.
六价铬（Cr(VI)）是一种普遍存在的环境污染物，对人类公共健康构成威胁。最近的研究表明，线粒体生物发生可以被炎症和氧化应激激活。然而，线粒体生物发生是否参与 Cr(VI)诱导的肝毒性尚不清楚。在这里，我们证明了炎症反应和氧化应激的诱导，表现为炎症因子和活性氧（ROS）的上调。随后，我们证明了在暴露于低浓度 Cr(VI)的 HepG2 细胞中，线粒体生物发生，包括线粒体 DNA 拷贝数和线粒体质量，显著增加。与线粒体功能复合物 I 和复合物 V 相关的基因表达在低浓度 Cr(VI)下上调。抗氧化酶的 mRNA 水平，包括超氧化物歧化酶 1 和 2（和 ，分别）、kech 样 ECH 相关蛋白 1（）和核呼吸因子 2（），也上调。与上述结果一致，低浓度 Cr(VI)也增加了 HepG2 细胞中线粒体生物发生关键转录调节因子的 mRNA 和蛋白水平，如过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）、NRF-1 和线粒体转录因子 A（TFAM）。此外，我们发现 PGC-1α 和 NRF-1 倾向于转位到核内。参与线粒体生物发生途径的基因的表达，包括沉默信息调节因子-1（）、叉头框类-O（）、苏氨酸激酶 1（）和 cAMP 反应元件结合蛋白（）的 mRNA 水平，也上调。相反，在 HepG2 细胞中，高浓度和细胞毒性浓度的 Cr(VI)抑制了线粒体生物发生，并下调了其调节因子和抗氧化剂的表达。据信，α-生育酚的预处理可以对抗 Cr(VI)诱导的线粒体生物发生失衡。总之，我们的研究表明，线粒体生物发生的平衡可能是细胞对抗 Cr(VI)毒性的重要补偿机制，也是有前途的解毒靶标。
