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Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum


The origin of all mitochondria can be traced to the symbiotic arrangement that resulted in the emergence of eukaryotes in a world that was exclusively populated by prokaryotes1,2,3. This arrangement, however, has been in continuous genetic flux: the varying degrees of gene loss and transfer from the mitochondrial genome in different eukaryotic lineages seem to signify an ongoing ‘conflict’ between the host and the symbiont. Eukaryotic parasites belonging to the phylum Apicomplexa provide an excellent example to support this view. These organisms contain the smallest mitochondrial genomes known4,5, with an organization that differs among various genera; one genus, Cryptosporidium, seems to have lost the entire mitochondrial genome6,7. Here we show that erythrocytic stages of the human malaria parasite Plasmodium falciparum seem to maintain an active mitochondrial electron transport chain to serve just one metabolic function: regeneration of ubiquinone required as the electron acceptor for dihydroorotate dehydrogenase, an essential enzyme for pyrimidine biosynthesis. Transgenic P. falciparum parasites expressing Saccharomyces cerevisiae dihydroorotate dehydrogenase, which does not require ubiquinone as an electron acceptor8, were completely resistant to inhibitors of mitochondrial electron transport. Maintenance of mitochondrial membrane potential, however, was essential in these parasites, as indicated by their hypersensitivity to proguanil, a drug that collapsed the membrane potential in the presence of electron transport inhibitors. Thus, acquisition of just one enzyme can render mitochondrial electron transport nonessential in erythrocytic stages of P. falciparum.

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Figure 1: Transgenic P. falciparum expressing S. cerevisiae DHOD.
Figure 2: Transgenic parasites are resistant to atovaquone.
Figure 3: Extreme hypersensitivity of the transgenic parasites to atovaquone/proguanil combination.

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We thank our colleagues within the Center for Molecular Parasitology, especially J. Burns and B. Bergman, for discussions, advice, and general cheer; K. Henry for providing yeast strains; and B. A. Palfey (University of Michigan) for communicating that the Type 1A DHOD is not inhibited by proguanil. This work was supported by grants from the National Institute of Allergy and Infectious Diseases to A.B.V.

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Correspondence to Akhil B. Vaidya.

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Painter, H., Morrisey, J., Mather, M. et al. Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 446, 88–91 (2007).

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