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Toxicol Sci. 2009 Aug;110(2):363-75. doi: 10.1093/toxsci/kfp117. Epub 2009 Jun 18.

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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  • 1Laboratory of Research on Biologically Compatible Compounds, Faculty of Dentistry, Monastir 5000, Tunisia.

Abstract

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 O(2)(.-) 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.

PMID:
19541794
DOI:
10.1093/toxsci/kfp117
[PubMed - indexed for MEDLINE]
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