The mitochondrion in the life and death of Plasmodium falciparum

Heather Jill Painter

doi:10.17918/00010274

Plasmodium falciparum is the causative protozoan parasite of the most severe form of malaria. This disease is still a major problem throughout many regions of the world and eradication efforts have fallen short. Although effective anti-malaria chemotherapies have been developed, we don't know why these drugs work and whether their effects on the parasite are static or cidal. Mitochondrial electron transport chain is a well established anti-malarial drug target, molecular details underlying the parasite demise have not been elucidated. However, the mitochondrion remains a validated drug target in the malaria parasite. Disruption of the mitochondrial electron transport leads to parasite death. Here we show that the blood-stages of the parasite seem to maintain an active electron transport chain to serve one function; de novo pyrimidine synthesis. By supplying P. falciparum with the Saccharomyces cerevisiae dihydroorotate dehydrogenase (DHOD), which does not require ubiquinone to function, the transgenic parasites become resistant to electron transport inhibitors. Surprisingly, disrupting the flow of electrons does not abolish the mitochondrial membrane potential in P. falciparum and these parasites have established an alternate mode of generating this potential. Subsequently, we explored the effects of atovaquone, alone as well as in combination with its synergistic partner, proguanil, on mitochondrial physiology and the stage specific static or cidal effects of the inhibition of mitochondrial electron transport. Our results suggest that, in P. falciparum, the in vitro effects of atovaquone and atovaquone/proguanil are dependent upon the erythrocytic stage of the parasites exposed to the drugs. We found a large proportion of ring-stage parasites are most resilient to drug treatment and seem to survive for up to 48 hours, with a small fraction remaining viable even after 96 hours of treatment. The survival of the parasites depends on their ability to exist in a 'static' phase; once treatment ceases, the parasites re-enter the erythrocytic development cycle as seen by parasite morphology. To further elucidate the mechanism of resistance development, we have analyzed the response of drug selected parasites to a subsequent drug treatment. These studies begin to provide information on the physiological state of the drug-inhibited parasites when mutations in mitochondrial DNA could arise that lead to drug resistance.

The mitochondrion in the life and death of Plasmodium falciparum

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The mitochondrion in the life and death of Plasmodium falciparum

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