title: Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle.
abstract: New antimalarial drugs are urgently needed to control drug-resistant forms of the malaria parasite Plasmodium falciparum. Mitochondrial electron transport is the target of both existing and new antimalarials. Herein, we describe 11 genetic knockout (KO) lines that delete six of the eight mitochondrial tricarboxylic acid (TCA) cycle enzymes. Although all TCA KOs grew normally in asexual blood stages, these metabolic deficiencies halted life-cycle progression in later stages. Specifically, aconitase KO parasites arrested as late gametocytes, whereas α-ketoglutarate-dehydrogenase-deficient parasites failed to develop oocysts in the mosquitoes. Mass spectrometry analysis of (13)C-isotope-labeled TCA mutant parasites showed that P. falciparum has significant flexibility in TCA metabolism. This flexibility manifested itself through changes in pathway fluxes and through altered exchange of substrates between cytosolic and mitochondrial pools. Our findings suggest that mitochondrial metabolic plasticity is essential for parasite development.
authors.affiliation: Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Hangjun
authors.initials: H
authors.lastname: Ke
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Lewis
authors.affiliation: Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Morrisey
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: McLean
authors.affiliation: Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Suresh M
authors.initials: SM
authors.lastname: Ganesan
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Painter
authors.affiliation: Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Mather
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Jacobs-Lorena
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Llinás
authors.affiliation: Center for Molecular Parasitology, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address: avaidya@drexelmed.edu.
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D002952:Citric Acid Cycle / Q000235:genetics; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D008018:Life Cycle Stages; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000469:parasitology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D014233:Tricarboxylic Acids / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D004798:Enzymes; D014233:Tricarboxylic Acids
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