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Malaria parasites utilize pyrophosphate to fuel an essential proton pump in the ring stage and the transition to trophozoite stage
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Malaria parasites utilize pyrophosphate to fuel an essential proton pump in the ring stage and the transition to trophozoite stage

Omobukola Solebo, Liqin Ling, Jing Zhou, Fu Tian-Min and Hangjun Ke
bioRxiv
19 Dec 2021
DOI: https://doi.org/10.1101/2021.10.25.465524
url
https://doi.org/10.1101/2021.10.25.465524View
SubmittedOpen Access (License Unspecified),  Open

Abstract

Developmental stages Glycolysis Malaria Membrane potential Parasites Protein transport Protons Pyrophosphatase Transcription
The malaria parasite relies on anaerobic glycolysis for energy supply when growing inside RBCs as its mitochondrion does not produce ATP. The ring stage lasts ~ 22 hours and is traditionally thought to be metabolically quiescent. However, recent studies show that the ring stage is active for several energy-costly processes including gene transcription/translation, protein export, and movement inside the RBC. It has remained unclear if a low glycolytic flux can meet the energy demand of the ring stage. Here we show that the metabolic by-product, pyrophosphate, is a critical energy source for the development of the ring stage and its transition to the trophozoite stage. During early phases of the asexual development, the parasite utilizes Plasmodium falciparum vacuolar pyrophosphatase 1 (PfVP1), an ancient pyrophosphate-driven proton pump, to pump protons across the parasite plasma membrane to maintain the membrane potential and cytosolic pH. Conditional deletion of PfVP1 leads to delayed ring stage development and a complete blockage of the ring-to-trophozoite transition, which can be partially rescued by Arabidopsis thaliana vacuolar pyrophosphatase 1, but not by the soluble pyrophosphatase from Saccharomyces cerevisiae. Proton-pumping pyrophosphatases are absent in humans, which highlights the possibility of developing highly selective VP1 inhibitors against the malaria parasite. Competing Interest Statement The authors have declared no competing interest. Footnotes * Hello, this version of the manuscript has been revised to the title, the abstract, and some data figures. Thank you! Happy holidays!

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