title: Metabolic Cooperation of Glucose and Glutamine Is Essential for the Lytic Cycle of Obligate Intracellular Parasite Toxoplasma gondii.
abstract: Toxoplasma gondii is a widespread protozoan parasite infecting nearly all warm-blooded organisms. Asexual reproduction of the parasite within its host cells is achieved by consecutive lytic cycles, which necessitates biogenesis of significant energy and biomass. Here we show that glucose and glutamine are the two major physiologically important nutrients used for the synthesis of macromolecules (ATP, nucleic acid, proteins, and lipids) in T. gondii, and either of them is sufficient to ensure the parasite survival. The parasite can counteract genetic ablation of its glucose transporter by increasing the flux of glutamine-derived carbon through the tricarboxylic acid cycle and by concurrently activating gluconeogenesis, which guarantee a continued biogenesis of ATP and biomass for host-cell invasion and parasite replication, respectively. In accord, a pharmacological inhibition of glutaminolysis or oxidative phosphorylation arrests the lytic cycle of the glycolysis-deficient mutant, which is primarily a consequence of impaired invasion due to depletion of ATP. Unexpectedly, however, intracellular parasites continue to proliferate, albeit slower, notwithstanding a simultaneous deprivation of glucose and glutamine. A growth defect in the glycolysis-impaired mutant is caused by a compromised synthesis of lipids, which cannot be counterbalanced by glutamine but can be restored by acetate. Consistently, supplementation of parasite cultures with exogenous acetate can amend the lytic cycle of the glucose transport mutant. Such plasticity in the parasite's carbon flux enables a growth-and-survival trade-off in assorted nutrient milieus, which may underlie the promiscuous survival of T. gondii tachyzoites in diverse host cells. Our results also indicate a convergence of parasite metabolism with cancer cells.
authors.affiliation: From the Department of Molecular Parasitology, Humboldt University, Berlin 10115, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Nitzsche
authors.affiliation: metaSysX GmbH, Potsdam-Golm 14476, Germany, and.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Zagoriy
authors.affiliation: From the Department of Molecular Parasitology, Humboldt University, Berlin 10115, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
authors.affiliation: From the Department of Molecular Parasitology, Humboldt University, Berlin 10115, Germany, Parasitology Unit, Max-Planck Institute for Infection Biology, Berlin 10117, Germany Gupta.Nishith@staff.hu-berlin.de.
authors.forename: Nishith
authors.identifier: http://orcid.org/0000-0003-1452-5126
authors.initials: N
authors.lastname: Gupta
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018533:Biomass; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002244:Carbon / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000469:parasitology; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000469:parasitology; D008018:Life Cycle Stages / Q000187:drug effects; D008055:Lipids / Q000737:chemistry; D008297:Male; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010271:Parasites / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D010641:Phenotype; D014176:Protein Biosynthesis / Q000187:drug effects; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D014122:Toxoplasma / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D014123:Toxoplasmosis / Q000378:metabolism / Q000469:parasitology
chemical_list: D000085:Acetates; D008055:Lipids; D005973:Glutamine; D002244:Carbon; D005947:Glucose
keywords: bioenergetics; energy metabolism; gluconeogenesis; glucose metabolism; glutamine; glycolysis; lipid synthesis; metabolic regulation; parasite metabolism; tricarboxylic acid cycle (TCA cycle) (Krebs cycle)