Ochratoxin A causes mitochondrial dysfunction, apoptotic and autophagic cell death and also induces mitochondrial biogenesis in human gastric epithelium cells
Ochratoxin A causes mitochondrial dysfunction, apoptotic and autophagic cell death and also induces mitochondrial biogenesis in human gastric epithelium cells
复制标题
赭曲霉毒素 A 会导致线粒体功能障碍、细胞凋亡和自噬性细胞死亡，并诱导人胃上皮细胞中的线粒体生物合成
DOI：
10.1007/s00204-019-02433-6
复制
发表时间：
2019-04-01
影响因子：
6.1
通讯作者：
Cui, Hongjuan
中科院分区：
文献类型：
--
作者：
Li, Qian;Dong, Zhen;Cui, Hongjuan
赭曲霉毒素A（OTA）是一种常见的天然污染物，存在于世界各地的人类和动物食品中。我们的前期工作表明OTA可引起人胃上皮细胞（GES-1）DNA氧化损伤、G2期阻滞和恶性转化。线粒体被认为是许多细胞毒性剂作用的靶标。然而，线粒体在OTA的细胞毒性中的作用仍然未知。本研究的目的是通过分析线粒体在GES-1细胞中的变化来探讨线粒体在OTA细胞毒性中的作用。结果表明，OTA（5、10、20 μM）处理不同时间后，细胞内活性氧产生增加，线粒体膜电位降低，细胞内ATP浓度降低。随后，线粒体凋亡途径被激活，表现为凋亡率增加和凋亡蛋白的激活。自噬性细胞死亡也被触发，表现为轻链3B（LC 3B）-I转化为LC 3B-II和绿色荧光蛋白-LC 3（GFP-LC 3）斑点水平升高。此外，还通过MitoTracker与LysoTracker或GFP-LC 3点的共定位来激活Parkin依赖的线粒体自噬。通过抑制剂或siRNA抑制自噬和线粒体自噬，可减弱OTA对细胞生长的毒性作用。有趣的是，OTA处理还通过激活AMPK/PGC-1α/TFAM途径证实了线粒体生物合成的增强，并促进了细胞存活。总的来说，OTA对GES-1细胞线粒体的影响是复杂的。OTA可引起线粒体功能紊乱、凋亡和自噬性细胞死亡，并诱导线粒体生物合成。
Ochratoxin A (OTA) is a common natural contaminant found in human and animal food worldwide. Our previous work has shown that OTA can cause oxidative DNA damage, G2arrest and malignant transformation of human gastric epithelium (GES-1) cells. Mitochondria are considered to be target for the action of many cytotoxic agents. However, the role of mitochondria in the cytotoxicity of OTA remains unknown. The aim of this study is to explore the putative role of mitochondria on OTA cytotoxicity by analyzing mitochondrial changes in GES-1 cells. The results showed that OTA treatment (5, 10, 20 µM) for different times caused increases in the production of reactive oxygen species, and induced mitochondrial damage, shown by loss of mitochondrial membrane potential (ΔΨM), and decrease in cellular ATP concentration. Subsequently, the mitochondrial apoptotic pathway was activated, presented by increase of apoptotic rate and activation of apoptotic proteins. Autophagic cell death was also triggered, demonstrated by the conversion of light chain 3B (LC3B)-I to LC3B-II and elevated levels of green fluorescent protein-LC3 (GFP-LC3) puncta. Moreover, Parkin-dependent mitophagy was also activated presented by the colocalization of MitoTracker with LysoTracker or GFP-LC3 puncta. The inhibition of autophagy and mitophagy by inhibitors or siRNA attenuated the toxic effect of OTA on cell growth. Interestingly, OTA treatment also enhanced mitochondrial biogenesis confirmed by activation of AMPK/PGC-1α/TFAM pathway and promoted cell survival. Collectively, the effects of OTA on mitochondria of GES-1 cells are complex. OTA could cause mitochondrial function disturbance, apoptotic and autophagic cell death and also induce mitochondrial biogenesis.