Possible Role of the Ca/Mn P-Type ATPase Pmr1p on Artemisinin Toxicity through an Induction of Intracellular Oxidative Stress.

Artemisinins are widely used to treat infections due to their high clinical efficacy; however, the antimalarial mechanism of artemisinin remains unresolved. Mutations in ATPase6 (PfATP6), a sarcoplasmic endoplasmic reticulum Ca-transporting ATPase, are associated with increased tolerance to artemisinin. We utilized as a model to examine the involvement of Pmr1p, a functional homolog of PfATP6, on the toxicity of artemisinin. Our analysis demonstrated that cells lacking Pmr1p are less susceptible to growth inhibition from artemisinin and its derivatives. No association between sensitivity to artemisinin and altered trafficking of the drug efflux pump Pdr5p, calcium homeostasis, or protein glycosylation was found in ∆ yeast. Basal ROS levels are elevated in ∆ yeast and artemisinin exposure does not enhance ROS accumulation. This is in contrast to WT cells that exhibit a significant increase in ROS production following treatment with artemisinin. Yeast deleted for are known to accumulate excess manganese ions that can function as ROS-scavenging molecules, but no correlation between manganese content and artemisinin resistance was observed. We propose that loss of function mutations in Pmr1p in yeast cells and PfATP6 in are protective against artemisinin toxicity due to reduced intracellular oxidative damage.