Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-08, Vol.112 (33), p.10216-10223
• Main Authors: Sturm, Angelika, Vanessa Mollard, Anton Cozijnsen, Christopher D. Goodman, Geoffrey I. McFadden
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - chemistry; Adenosine triphosphatase; adenosine triphosphate; Adenosine Triphosphate - chemistry; aerobic respiration; Animals; Anopheles stephensi; ATP synthase; Bacterial Proteins - metabolism; Biological Sciences; blood; Computational Biology; Crosses, Genetic; Culicidae; disease control; Female; females; Gene Expression Regulation, Enzymologic; genes; germ cells; Glycolysis; H+/K+-exchanging ATPase; H-transporting ATP synthase; insect vectors; Luminescent Proteins - metabolism; Malaria; Malaria - parasitology; Male; Mice; midgut; Mitochondria; Mitochondria - enzymology; mitochondrial endosymbiosis; Mitochondrial Proton-Translocating ATPases - metabolism; oocysts; Oocysts - enzymology; ookinetes; oxidation; Oxygen - chemistry; Parasites; Phenotype; Plasmodium berghei; Plasmodium berghei - enzymology; Plasmodium berghei - pathogenicity; proton-motive force; pyruvic acid; Rodents; sexual reproduction; sporozoites; Sporozoites - enzymology; Symbioses Becoming Permanent: The Origins and Evolutionary Trajectories of Organelles Sackler; Transgenes; viability
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1423959112

Mitochondrial ATP synthase is driven by chemiosmotic oxidation of pyruvate derived from glycolysis. Blood-stage malaria parasites eschew chemiosmosis, instead relying almost solely on glycolysis for their ATP generation, which begs the question of whether mitochondrial ATP synthase is necessary during the blood stage of the parasite life cycle. We knocked out the mitochondrial ATP synthase β subunit gene in the rodent malaria parasite, Plasmodium berghei , ablating the protein that converts ADP to ATP. Disruption of the β subunit gene of the ATP synthase only marginally reduced asexual blood-stage parasite growth but completely blocked mouse-to-mouse transmission via Anopheles stephensi mosquitoes. Parasites lacking the β subunit gene of the ATP synthase generated viable gametes that fuse and form ookinetes but cannot progress beyond this stage. Ookinetes lacking the β subunit gene of the ATP synthase had normal motility but were not viable in the mosquito midgut and never made oocysts or sporozoites, thereby abrogating transmission to naive mice via mosquito bite. We crossed the self-infertile ATP synthase β subunit knockout parasites with a male-deficient, self-infertile strain of P. berghei , which restored fertility and production of oocysts and sporozoites, which demonstrates that mitochondrial ATP synthase is essential for ongoing viability through the female, mitochondrion-carrying line of sexual reproduction in P. berghei malaria. Perturbation of ATP synthase completely blocks transmission to the mosquito vector and could potentially be targeted for disease control.