title: Mitochondrial metabolism of sexual and asexual blood stages of the malaria parasite Plasmodium falciparum.
abstract: BACKGROUND
  The carbon metabolism of the blood stages of Plasmodium falciparum, comprising rapidly dividing asexual stages and non-dividing gametocytes, is thought to be highly streamlined, with glycolysis providing most of the cellular ATP. However, these parasitic stages express all the enzymes needed for a canonical mitochondrial tricarboxylic acid (TCA) cycle, and it was recently proposed that they may catabolize glutamine via an atypical branched TCA cycle. Whether these stages catabolize glucose in the TCA cycle and what is the functional significance of mitochondrial metabolism remains unresolved.
  
  
  RESULTS
  We reassessed the central carbon metabolism of P. falciparum asexual and sexual blood stages, by metabolically labeling each stage with 13C-glucose and 13C-glutamine, and analyzing isotopic enrichment in key pathways using mass spectrometry. In contrast to previous findings, we found that carbon skeletons derived from both glucose and glutamine are catabolized in a canonical oxidative TCA cycle in both the asexual and sexual blood stages. Flux of glucose carbon skeletons into the TCA cycle is low in the asexual blood stages, with glutamine providing most of the carbon skeletons, but increases dramatically in the gametocyte stages. Increased glucose catabolism in the gametocyte TCA cycle was associated with increased glucose uptake, suggesting that the energy requirements of this stage are high. Significantly, whereas chemical inhibition of the TCA cycle had little effect on the growth or viability of asexual stages, inhibition of the gametocyte TCA cycle led to arrested development and death.
  
  
  CONCLUSIONS
  Our metabolomics approach has allowed us to revise current models of P. falciparum carbon metabolism. In particular, we found that both asexual and sexual blood stages utilize a conventional TCA cycle to catabolize glucose and glutamine. Gametocyte differentiation is associated with a programmed remodeling of central carbon metabolism that may be required for parasite survival either before or after uptake by the mosquito vector. The increased sensitivity of gametocyte stages to TCA-cycle inhibitors provides a potential target for transmission-blocking drugs.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, VIC 3010, Australia.
authors.forename: James I
authors.initials: JI
authors.lastname: MacRae
authors.forename: Matthew Wa
authors.initials: MW
authors.lastname: Dixon
authors.forename: Megan K
authors.initials: MK
authors.lastname: Dearnley
authors.forename: Hwa H
authors.initials: HH
authors.lastname: Chua
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Chambers
authors.forename: Shannon
authors.initials: S
authors.lastname: Kenny
authors.forename: Iveta
authors.initials: I
authors.lastname: Bottova
authors.forename: Leann
authors.initials: L
authors.lastname: Tilley
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005463:Fluoroacetates / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D016778:Malaria, Falciparum / Q000469:parasitology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D010271:Parasites / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D012100:Reproduction, Asexual / Q000187:drug effects
chemical_list: D005463:Fluoroacetates; D005973:Glutamine; C014815:fluoroacetic acid; D005947:Glucose