Mitochondrial involvement in Atuna racemosa induced toxicity

Our group has developed a system to extract information regarding potential novel pharmaceuticals from historic herbal texts. We have shown that one of the plants identified through this technique has the purported antibacterial properties suggested by the text. Here, the toxicity of this antibacterial extract was examined. Using a Jurkat cell model, a therapeutic window between the minimal inhibitory concentration for Gram-positive bacteria and the dose-dependent toxicity of the Atuna racemosa extract was established. Using cells with a mutated caspase 8, it was shown that the toxicity does not involve caspase 8. However, by transmission electron microscopy and a potentiometric dye, the toxicity was shown to involve the mitochondria. This toxicity also resulted in DNA cleavage and activation of caspase 3. This work suggests that the extract, originally reported as an antimicrobial therapeutic in a 400-year-old Dutch herbal text, may maintain a therapeutic window as an antibiotic. Furthermore, this work shows toxicity would occur in a mitochondrial dependent fashion.