title: Mitochondrial electron transport inhibition and viability of intraerythrocytic Plasmodium falciparum.
abstract: Although mitochondrial electron transport is a validated target of the antimalarial drug atovaquone, the molecular details underlying parasite demise are unclear. We have shown that a critical function of mitochondrial electron transport in blood-stage Plasmodium falciparum is to support pyrimidine biosynthesis. Here, we explore the effects of atovaquone, alone and in combination with proguanil, on P. falciparum viability. Our results suggest that the effects of inhibition depend upon the erythrocytic stage of the parasites and the duration of exposure. Ring- and schizont-stage parasites are most resilient to drug treatment and can survive for 48 h, with a fraction remaining viable even after 96 h. Survival of parasites does not appear to require nutrient uptake. Thus, intraerythrocytic parasites with inhibited mitochondrial electron transport and collapsed mitochondrial membrane potential do not undergo apoptosis but enter an apparent static state. These results have significant implications for desirable properties of antimalarials under development that target mitochondrial functions.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Painter
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Morrisey
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053626:Atovaquone / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects*; D004912:Erythrocytes / Q000469:parasitology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D053626:Atovaquone