Dissertation
Dual function of mitochondrial Complex III in Plasmodium falciparum
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2026
DOI:
https://doi.org/10.17918/00011332
Abstract
Complex III of the malaria parasite mitochondrial electron transport chain (mtETC) has been validated as an attractive target for currently used antimalarials. We previously showed that the main function of mtETC in blood-stage Plasmodium falciparum is to regenerate ubiquinone, an obligatory co-substrate for dihydroorotate dehydrogenase (DHOD), an essential mitochondrial enzyme in pyrimidine biosynthesis. P. falciparum can be rendered resistant to all mtETC inhibitors by provision of a bypass mediated by cytosolic yeast DHOD, a fumarate-reducing enzyme. Malaria parasite mitochondrial DNA (mtDNA) encodes only 3 proteins, each of which is a component of the mtETC. However, attempts to eliminate mtDNA in transgenic parasites expressing yDHOD have been unsuccessful, suggesting the possibility that essential function(s) other than the canonical redox reactions of the mtETC also require mtDNA maintenance. Here, we tested the hypothesis that Complex III serves dual functions: processing imported mitochondrial proteins and regenerating ubiquinone. We have generated transgenic lines that conditionally express mitochondrial processing peptidase [alpha] (MPP[alpha]), which is also a component of Complex III. Using these parasites, we have determined that MPPα is essential even when mitochondrial electron transport is bypassed. MPP[alpha] knockdown also resulted in hypersensitivity of the parasites to proguanil, a drug that synergizes with mtETC inhibitors such as atovaquone. Pulldown with MPP[alpha] followed by proteomics revealed the association of multiple mitochondrially targeted proteins, in addition to all components of Complex III. MPP[alpha] parasites that are selected with DSM1, a dihydroorotate dehydrogenase inhibitor, demonstrate a smaller than 720kDA Complex III structure. Interestingly, treatment with Atovaquone re-establishes the 720kDa complex. These parasites still synthesize Rieske protein, an additional component of Complex III. DSM1-selected parasites did not demonstrate a hypersensitivity to proguanil. These results are consistent with the suggestion that Complex III in P. falciparum serves both mtETC and protein processing functions in mitochondrial physiology, and that prolonged DSM1 selection of mtETC independent parasites causes a dissociation of Mitochondrial Processing Peptidase subunits from additional Complex III subunits.
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Details
- Title
- Dual function of mitochondrial Complex III in Plasmodium falciparum
- Creators
- River S. Rell
- Contributors
- Akhil B. Vaidya (Advisor)Patrick J. Loll (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- xiii, 118 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022173173404721