Glycolysis is important for optimal asexual growth and formation of mature tissue cysts by Toxoplasma gondii. Issue 12 (October 2018)

• Record Type: Journal Article
• Authors: Shukla, Anurag; Olszewski, Kellen L.; Llinás, Manuel; Rommereim, Leah M.; Fox, Barbara A.; Bzik, David J.; Xia, Dong; Wastling, Jonathan; Beiting, Daniel; Roos, David S.; Shanmugam, Dhanasekaran
• Is Part Of: International journal for parasitology. Volume 48:Issue 12(2018)
• Page Start: 955
• Page End: 968
• Publication Date: 2018-10
• Subjects: Toxoplasma gondii -- Glycolysis -- Gluconeogenesis -- Metabolomics -- Hexokinase -- ATP synthesis; Parasitology -- Periodicals; Parasitology -- Periodicals; Parasitologie -- Périodiques; Parasitology; Periodicals; Electronic journals; 571.999
• DOI: 10.1016/j.ijpara.2018.05.013
• Languages: English
• ISSNs: 0020-7519

Abstract

Graphical abstract: Highlights: Hexokinase gene is dispensable for tachyzoite stage Toxoplasma gondii. Glycolysis is essential only for tissue cyst formation by T. gondii . 13 C metabolic labelling studies highlight metabolic adaptation. Toxoplasma gondii can obtain ATP from either glycolysis or oxidative phosphorylation. Abstract: Toxoplasma gondii can grow and replicate using either glucose or glutamine as the major carbon source. Here, we have studied the essentiality of glycolysis in the tachyzoite and bradyzoite stages of T. gondii, using transgenic parasites that lack a functional hexokinase gene ( Δhk ) in RH (Type-1) and Prugniaud (Type-II) strain parasites. Tachyzoite stage Δhk parasites exhibit a fitness defect similar to that reported previously for the major glucose transporter mutant, and remain virulent in mice. However, although Prugniaud strain Δhk tachyzoites were capable of transforming into bradyzoites in vitro, they were severely compromised in their ability to make mature bradyzoite cysts in the brain tissue of mice. Isotopic labelling studies reveal that glucose-deprived tacyzoites utilise glutamine to replenish glycolytic and pentose phosphate pathway intermediates via gluconeogenesis. Interestingly, while glutamine-deprived intracellular Δhk tachyzoites continued to replicate, extracellular parasites were unable to efficiently invade host cells. Further, studies on mutant tachyzoites lacking a functional phosphoenolpyruvate carboxykinase ( Δpepck1 ) revealed that glutaminolysis is the sole source of gluconeogenic flux in glucose-deprived parasites. In addition, glutaminolysis is essential for sustaining oxidative phosphorylation in Δhk parasites, while wild type ( wt ) and Δpepck1 parasites can obtain ATP from either glycolysis or oxidative phosphorylation. This study provides insights into the role of nutrient metabolism during asexual propagation and development of T. gondii, and validates the versatile nature of central carbon and energy metabolism in this parasite.