Abstract
T-2 toxin is one of the type A trichothecenes produced mainly by the Fusarium genus. Due to its broad distribution and highly toxic nature, it is of great concern as a threat to human health and animal breeding. In addition to its ribotoxic effects, T-2 toxin exposure leads to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and eventually cell apoptosis. We observed that mitochondrial biogenesis is highly activated in animal cells exposed to T-2 toxin, probably in response to the short-term toxic effects of T-2 toxin. However, the molecular mechanisms of T-2 toxin-induced mitochondrial biogenesis remain unclear. In this study, we investigated the regulatory mechanism of key factors in the ROS production and mitochondrial biogenesis that were elicited by T-2 toxin in HepG2 and HEK293T cells. Low dosages of T-2 toxin significantly increased the levels of both mitochondrial biogenesis and ROS. This increase was linked to the upregulation of SIRT1, which is controlled by miR-449a, whose expression was strongly inhibited by T-2 toxin treatment. In addition, we found that T-2 toxin-induced mitochondrial biogenesis resulted from SIRT1-dependent PGC-1α deacetylation. The accumulation of PGC-1α deacetylation, mediated by high SIRT1 levels in T-2 toxin-treated cells, activated the expression of many genes involved in mitochondrial biogenesis. Together, these data indicated that the miR449a/SIRT1/deacetylated PGC-1α axis plays an essential role in the ability of moderate concentrations of T-2 toxin to stimulate mitochondrial biogenesis and ROS production.
Highlights
T-2 toxin is one of the type A trichothecenes that are produced by different Fusarium species (McLachlan et al, 1992; Torp and Langseth, 1999)
The analysis revealed that T-2 toxin significantly decreased the acetylation level of PGC-1α, whereas, this upregulated deacetylation of PGC-1α could not be observed in the sirtuin 1 (SIRT1) knockdown cells with stably expressed shRNA for SIRT1, regardless of whether they were exposed to T-2 toxin or not (Figure 4C)
T-2 toxin led to the accumulation of reactive oxygen species (ROS) and was believed to disturb the biogenesis and functions of mitochondria
Summary
T-2 toxin is one of the type A trichothecenes that are produced by different Fusarium species (McLachlan et al, 1992; Torp and Langseth, 1999). It is well known that T-2 toxin strongly inhibits the synthesis of eukaryotic proteins, DNA and RNA (Suneja et al, 1983; Jeffery et al, 1984; Thompson and Wannemacher, 1990). It increases the intracellular level of reactive oxygen species (ROS) at an early stage after its entry into eukaryote cells (Bouaziz et al, 2008). T-2 toxin induces cell apoptosis, possibly mediated by a mitochondrial pathway, which has been considered an important mechanism of its toxic effects, the exact mechanism has still to be determined (Shinozuka et al, 1997; Islam et al, 1998).
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