title: Phosphatidylethanolamine synthesis in the parasite mitochondrion is required for efficient growth but dispensable for survival of Toxoplasma gondii.
abstract: Toxoplasma gondii is a highly prevalent obligate intracellular parasite of the phylum Apicomplexa, which also includes other parasites of clinical and/or veterinary importance, such as Plasmodium, Cryptosporidium, and Eimeria. Acute infection by Toxoplasma is hallmarked by rapid proliferation in its host cells and requires a significant synthesis of parasite membranes. Phosphatidylethanolamine (PtdEtn) is the second major phospholipid class in T. gondii. Here, we reveal that PtdEtn is produced in the parasite mitochondrion and parasitophorous vacuole by decarboxylation of phosphatidylserine (PtdSer) and in the endoplasmic reticulum by fusion of CDP-ethanolamine and diacylglycerol. PtdEtn in the mitochondrion is synthesized by a phosphatidylserine decarboxylase (TgPSD1mt) of the type I class. TgPSD1mt harbors a targeting peptide at its N terminus that is required for the mitochondrial localization but not for the catalytic activity. Ablation of TgPSD1mt expression caused up to 45% growth impairment in the parasite mutant. The PtdEtn content of the mutant was unaffected, however, suggesting the presence of compensatory mechanisms. Indeed, metabolic labeling revealed an increased usage of ethanolamine for PtdEtn synthesis by the mutant. Likewise, depletion of nutrients exacerbated the growth defect (∼56%), which was partially restored by ethanolamine. Besides, the survival and residual growth of the TgPSD1mt mutant in the nutrient-depleted medium also indicated additional routes of PtdEtn biogenesis, such as acquisition of host-derived lipid. Collectively, the work demonstrates a metabolic cooperativity between the parasite organelles, which ensures a sustained lipid synthesis, survival and growth of T. gondii in varying nutritional milieus.
authors.affiliation: Department of Molecular Parasitology, Humboldt University, Philippstrasse 13, 10115 Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Molecular Parasitology, Humboldt University, Philippstrasse 13, 10115 Berlin, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Hellmund
authors.affiliation: Department of Molecular Parasitology, Humboldt University, Philippstrasse 13, 10115 Berlin, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado 80206.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Voelker
authors.affiliation: Department of Molecular Parasitology, Humboldt University, Philippstrasse 13, 10115 Berlin, Germany; Department of Parasitology, Max-Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: Gupta.Nishith@staff.hu-berlin.de.
authors.forename: Nishith
authors.initials: N
authors.lastname: Gupta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002262:Carboxy-Lyases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003565:Cytidine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D010714:Phosphatidylethanolamines / Q000096:biosynthesis*; D010802:Phylogeny; D015800:Protozoan Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D014122:Toxoplasma / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism
chemical_list: D004075:Diglycerides; D004983:Ethanolamines; D010714:Phosphatidylethanolamines; D015800:Protozoan Proteins; C006933:CDP ethanolamine; C483858:phosphatidylethanolamine; D003565:Cytidine Diphosphate; D002262:Carboxy-Lyases; C022353:phosphatidylserine decarboxylase
keywords: Host-Pathogen Interactions; Membrane Biogenesis; Microbiology; Parasite Metabolism; Parasitology; Phosphatidylethanolamine; Phosphatidylserine Decarboxylase