ToxSci Advance Access published online on June 18, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp117
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Fusarial toxin-induced toxicity in cultured cells and in isolated mitochondria involves PTPC-dependent activation of the mitochondrial pathway of apoptosis
1 Laboratory of Research on Biologically Compatible Compounds, Faculty of Dentistry, Rue Avicenne, Monastir 5000, Tunisia 2 Laboratoire de Génétique et Biologie Cellulaire, CNRS-UMR 8159,Université de Versailles/SQY, 45 Avenue des Etats-Unis, Versailles 78035, France
* Corresponding author: Tel: +216 73425550; Fax: +216 73461150. E-mail address: hassen.bacha{at}fmdm.rnu.tn
Received December 11, 2008; revision received April 30, 2009; accepted May 1, 2009
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Abstract |
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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 non-estrogenic trichotecenes 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 (PTPC), loss of mitochondrial transmembrane potential (
m), increase in O2.– production, mitochondrial relocalisation 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, while the inner membrane protein ANT could be the target of T-2 toxin, ZEN seems to target the outer membrane protein VDAC. Cells pre-treatment with the p53 inhibitor pifithrin-
(PFT) 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-XL 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.
Key Words: mitochondrial permeability transition, apoptosis; Carcinogenesis, cytotoxicity; In Vitro and Altenatives, natural products; Agents.