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Variation among Plasmodium falciparum strains in their reliance on mitochondrial electron transport chain function
Journal article   Open access

Variation among Plasmodium falciparum strains in their reliance on mitochondrial electron transport chain function

Hangjun Ke, Joanne M Morrisey, Suresh M Ganesan, Heather J Painter, Michael W Mather and Akhil B Vaidya
Eukaryotic cell, v 10(8), pp 1053-1061
Aug 2011
DOI: https://doi.org/10.1128/EC.05049-11
PMID: 21685321
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1128/EC.05049-11View
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Abstract

Recombinant Proteins - metabolism Mitochondria - enzymology Electron Transport Recombinant Proteins - antagonists & inhibitors Humans Ubiquinone - analogs & derivatives Cells, Cultured Fungal Proteins - antagonists & inhibitors Mitochondria - metabolism Recombinant Proteins - genetics Fungal Proteins - genetics Plasmodium falciparum - drug effects Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors Antimalarials - pharmacology Ubiquinone - pharmacology Oxidoreductases Acting on CH-CH Group Donors - metabolism Atovaquone - pharmacology Plasmodium falciparum - genetics Parasitemia - parasitology Oxidoreductases Acting on CH-CH Group Donors - genetics Organisms, Genetically Modified Plasmodium falciparum - physiology Drug Resistance Fungal Proteins - metabolism
Previous studies demonstrated that Plasmodium falciparum strain D10 became highly resistant to the mitochondrial electron transport chain (mtETC) inhibitor atovaquone when the mtETC was decoupled from the pyrimidine biosynthesis pathway by expressing the fumarate-dependent (ubiquinone-independent) yeast dihydroorotate dehydrogenase (yDHODH) in parasites. To investigate the requirement for decoupled mtETC activity in P. falciparum with different genetic backgrounds, we integrated a single copy of the yDHODH gene into the genomes of D10attB, 3D7attB, Dd2attB, and HB3attB strains of the parasite. The yDHODH gene was equally expressed in all of the transgenic lines. All four yDHODH transgenic lines showed strong resistance to atovaquone in standard short-term growth inhibition assays. During longer term growth with atovaquone, D10attB-yDHODH and 3D7attB-yDHODH parasites remained fully resistant, but Dd2attB-yDHODH and HB3attB-yDHODH parasites lost their tolerance to the drug after 3 to 4 days of exposure. No differences were found, however, in growth responses among all of these strains to the Plasmodium-specific DHODH inhibitor DSM1 in either short- or long-term exposures. Thus, DSM1 works well as a selective agent in all parasite lines transfected with the yDHODH gene, whereas atovaquone works for some lines. We found that the ubiquinone analog decylubiquinone substantially reversed the atovaquone inhibition of Dd2attB-yDHODH and HB3attB-yDHODH transgenic parasites during extended growth. Thus, we conclude that there are strain-specific differences in the requirement for mtETC activity among P. falciparum strains, suggesting that, in erythrocytic stages of the parasite, ubiquinone-dependent dehydrogenase activities other than those of DHODH are dispensable in some strains but are essential in others.

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Web of Science research areas
Microbiology
Mycology
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