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

Publication date: Available online 25 April 2017 Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Author(s): Chen Sun, Bing Zhou 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(2-8μM) of artemisinin(ART) and dihydro- artemisinin(DHA) partly depolarize the mitochondrial membranes, inhibiting yeast growth on non-fermentable media, only DHA at moderate levels(such as 40μM) 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(200-400μM) on fermentable medium is due to the presence of Sod1. While we expected this normally Sod1-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 Sod1-suppressible anti-mitochondrial action is hidden by its heme-mediated cytotoxicity, and becomes readily noticeable only when the heme-mediated action is compromised and Sod1 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 Sod1-indepe...
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research