Fusarial Toxin-Induced Toxicity in Cultured Cells and in Isolated Mitochondria Involves PTPC-Dependent Activation of the Mitochondrial Pathway of Apoptosis
Fusarial Toxin-Induced Toxicity in Cultured Cells and in Isolated Mitochondria Involves PTPC-Dependent Activation of the Mitochondrial Pathway of Apoptosis
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DOI：
10.1093/toxsci/kfp117
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发表时间：
2009-08-01
影响因子：
3.8
通讯作者：
Bacha, Hassen
中科院分区：
文献类型：
--
作者：
Bouaziz, Chayma;Martel, Cecile;Bacha, Hassen
镰刀菌产生的霉菌毒素可引起多种人类疾病和牲畜的经济损失。镰刀菌属主要产生两种类型的真菌毒素：非雌激素类的真菌毒素，包括T-2毒素和真菌雌激素类，如玉米赤霉烯酮（ZEN）。在以前的报告中，我们证明了这些真菌毒素的肝毒性涉及线粒体凋亡途径。在此，我们观察到两种镰刀菌毒素通过线粒体依赖性凋亡过程诱导细胞死亡，所述凋亡过程包括线粒体渗透性转换孔复合物（PTPC）的打开、线粒体跨膜电位的丧失、O2中心点产生的增加、Bax的线粒体重新定位、细胞色素c释放和半胱天冬酶活化。对分离的小鼠肝线粒体进行的研究表明，ZEN和T-2毒素都可以直接作用于线粒体，诱导线粒体膜的PTC依赖性透化。此外，他们可能针对PTPC的不同成员。事实上，虽然内膜蛋白腺嘌呤核苷酸移位酶可能是T-2毒素的靶点，但ZEN似乎靶向外膜蛋白电压依赖性阴离子通道。用p53抑制剂pifithrin-alpha预处理细胞表明ZEN而不是T-2毒素触发了p53依赖的线粒体凋亡途径。最后，由ZEN和T-2毒素诱导的线粒体改变由Bcl-2家族蛋白（如Bax）介导，并由Bcl-x（L）和Bcl-2在较小程度上阻止。总之，这些数据表明，线粒体在ZEN和T-2毒素诱导的细胞凋亡中起着关键作用，并且Bcl-2家族的PTPC成员和蛋白质应该是克服镰孢毒素毒性的有趣靶点。
Mycotoxins produced by the Fusarium molds can cause a variety of human diseases and economic losses in livestock. Fusaria produce predominantly two types of mycotoxins: the nonestrogenic trichothecenes including T-2 toxin and the mycoestrogens such as zearalenone (ZEN). In a previous report, we demonstrated that the hepatotoxicity of these mycotoxins involves the mitochondrial pathway of apoptosis. Here, we observed that both fusarotoxins induced cell death by a mitochondria-dependent apoptotic process which includes opening of the mitochondrial permeability transition pore complex (PTPC), loss of mitochondrial transmembrane potential, increase in O2 center dot- production, mitochondrial relocalization of Bax, cytochrome c release, and caspase activation. Studies performed on isolated mouse liver mitochondria showed that both ZEN and T-2 toxin might act directly on mitochondria to induce a PTPC-dependent permeabilization of mitochondrial membranes. Moreover, they may target different members of PTPC. Indeed, although the inner membrane protein adenine nucleotide translocase could be the target of T-2 toxin, ZEN seems to target the outer membrane protein voltage-dependent anion channel. Cells pretreatment with the p53 inhibitor pifithrin-alpha suggested that ZEN but not T-2 toxin triggered a p53-dependent mitochondrial apoptotic pathway. Finally, mitochondrial alterations induced by ZEN and T-2 toxin are mediated by Bcl-2 family proteins, such as Bax, and prevented by Bcl-x(L) and to a lesser extent by Bcl-2. Taken together, these data indicate that mitochondria play a pivotal role in both ZEN- and T-2 toxin-induced apoptosis and that PTPC members and proteins of Bcl-2 family should be interesting targets to overcome fusarotoxin toxicity.