The antimalarial drug artemisinin induces an additional, Sod1-supressible anti-mitochondrial action in yeast

The molecular action of artemisinins (ARTs) is not well understood. To determine the molecular and cellular basis that might underlie their differential effects observed in anti-malarial and anti-cancer studies, we utilized the yeast Saccharomyces cerevisiae to examine their toxicity profiles and properties. Previously we reported that while both low levels (2-8 mu M) of artemisinin (ART) and dihydroartemisinin (DHA) partly depolarize the mitochondrial membranes, inhibiting yeast growth on non-fermentable media, only DHA at moderate levels (such as 40 mu M) potently represses yeast growth on fermentable media via a heme-mediated pathway. Here we show that the lack of toxicity of ART even at high levels (200-400 mu M) on fermentable medium is due to the presence of Sodl. While we expected this normally Sodl-supressed action to be heme-mediated like DHA, surprisingly, this toxicity of ART is due to further depolarization of the mitochondrial membrane. We also found that for DHA, the Sodl-suppressible anti-mitochondrial action is hidden by its heme-mediated cytotoxicity, and becomes readily noticeable only when the heme-mediated action is compromised and Sodl is inactivated. Based on these findings, we propose that depending on the cell type and particular compound, ARTs work via one or more of the three types of activities: a Sodl-independent, partial mitochondria-depolarizing action; a Sodl-suppressible, more severe mitochondria-depolarizing action; and a heme-mediated general cytotoxicity. These action properties may underlie the disparities seen in the efficacy and toxicity of various ARTs, and additionally suggest it is important for researchers to clearly detail the particular compound when reporting on the effects of ARTs.