Dataset Information

MiR449a/SIRT1/PGC-1? Is Necessary for Mitochondrial Biogenesis Induced by T-2 Toxin.

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-1? deacetylation. The accumulation of PGC-1? 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-1? axis plays an essential role in the ability of moderate concentrations of T-2 toxin to stimulate mitochondrial biogenesis and ROS production.

SUBMITTER: Ma S

PROVIDER: S-EPMC5760504 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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miR449a/SIRT1/PGC-1α Is Necessary for Mitochondrial Biogenesis Induced by T-2 Toxin.

Ma Shijie S Zhao Yurong Y Sun Jianwei J Mu Peiqiang P Deng Yiqun Y

Frontiers in pharmacology 20180105

T-2 toxin is one of the type A trichothecenes produced mainly by the <i>Fusarium</i> 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 re ...[more]

PMID: 29354057

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Project description:AimsPreventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, in vivo, remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocardial infarction.Main methodsRats were pre-treated with melatonin (10 mg/kg body weight (b.w.); intraperitoneally, i.p.) before isoproterenol bitartrate (ISO) administration (25 mg/kg body weight (b.w.) subcutaneously,s.c.) and their effect on rat heart mitochondrial structure and function was studied. Biochemical changes in activity of biomarkers of oxidative stress, antioxidant enzymes as well as Krebs' cycle enzymes were analyzed. Gene expression studies and Isothermal titration calorimetric studies with pure catalase and ISO were also carried out.Key findingsMelatonin was shown to reduce ISO induced oxidative stress, by stimulating superoxide dismutase activity and removing the inhibition of Krebs' cycle enzymes. Herein we report for the first time in rat model that melatonin activates the SIRT1-PGC-1α-SIRT3 signaling pathways after ISO administration, which ultimately induces mitochondrial biogenesis. Melatonin exhibited significant protection of mitochondrial architecture and topology along with increased calcium ion permeability and reactive oxygen species (ROS) generation induced by ISO. Isothermal calorimetric studies revealed that melatonin binds to ISO molecules and sequesters them from the reaction thereby limiting their interaction with catalase along with occupying the binding sites of catalase themselves.SignificanceActivation of SIRT1-PGC-1α-SIRT3 pathway by melatonin along with its biophysical properties prevents ISO induced mitochondrial injury in rat heart.

Dataset Information

MiR449a/SIRT1/PGC-1? Is Necessary for Mitochondrial Biogenesis Induced by T-2 Toxin.

Publications

miR449a/SIRT1/PGC-1α Is Necessary for Mitochondrial Biogenesis Induced by T-2 Toxin.

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