title: Mitochondrial Membrane Potential in a Small Subset of Artemisinin-Induced Dormant Plasmodium falciparum Parasites In Vitro.
abstract: Artemisinin-induced dormancy is a proposed mechanism for failures of monotherapy and is linked with artemisinin resistance in Plasmodium falciparum. The biological characterization and dynamics of dormant parasites are not well understood. Here we report that after dihydroartemisinin treatment in vitro, a small subset of morphologically dormant parasites was stained with rhodamine 123 (RH), a mitochondrial membrane potential marker, and persisted to recovery. RH-positive parasites sorted with fluorescence-activated cell sorting resumed growth at 10,000/well whereas RH-negative parasites failed to recover at 5 million/well. Furthermore, transcriptional activity for mitochondrial enzymes was detected only in RH-positive dormant parasites. Importantly, after treatment of dormant parasites with different concentrations of atovaquone, a mitochondrial inhibitor, the recovery of dormant parasites was delayed or stopped. This demonstrates that mitochondrial activity is critical for survival and regrowth of dormant parasites and that RH staining provides a means of identifying these parasites. These findings provide novel paths for studying and eradicating this dormant stage.
authors: Drug Resistance and Diagnostics, Australian Army Malaria Institute Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute.
authors: Christopher L
authors: CL
authors: Peatey
authors: Drug Resistance and Diagnostics, Australian Army Malaria Institute.
authors: Marina
authors: M
authors: Chavchich
authors: Drug Resistance and Diagnostics, Australian Army Malaria Institute.
authors: Nanhua
authors: N
authors: Chen
authors: Drug Resistance and Diagnostics, Australian Army Malaria Institute Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute.
authors: Karryn J
authors: KJ
authors: Gresty
authors: Drug Resistance and Diagnostics, Australian Army Malaria Institute Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute.
authors: Karen-Ann
authors: KA
authors: Gray
authors: School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia.
authors: Michelle L
authors: ML
authors: Gatton
authors: Walter Reed Army Institute of Research, Malaria Vaccine Branch, Military Malaria Research Program, Silver Spring, Maryland.
authors: Norman C
authors: NC
authors: Waters
authors: Drug Resistance and Diagnostics, Australian Army Malaria Institute Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute.
authors: Qin
authors: Q
authors: Cheng
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000032:analysis; D050259:Genes, Mitochondrial; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects* / Q000502:physiology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology*; D020112:Rhodamine 123 / Q000032:analysis
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D005456:Fluorescent Dyes; D020112:Rhodamine 123; C039060:artenimol; D053626:Atovaquone
keywords: P. falciparum; artemisinin; dihydroartemisinin (DHA); dormancy; mitochondrial membrane potential