title: BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei.
abstract: While the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are thought to primarily depend on glycolysis for ATP synthesis, recent studies have shown that they can fully catabolize glucose in a canonical TCA cycle. However, these parasites lack a mitochondrial isoform of pyruvate dehydrogenase and the identity of the enzyme that catalyses the conversion of pyruvate to acetyl-CoA remains enigmatic. Here we demonstrate that the mitochondrial branched chain ketoacid dehydrogenase (BCKDH) complex is the missing link, functionally replacing mitochondrial PDH in both T. gondii and P. berghei. Deletion of the E1a subunit of T. gondii and P. berghei BCKDH significantly impacted on intracellular growth and virulence of both parasites. Interestingly, disruption of the P. berghei E1a restricted parasite development to reticulocytes only and completely prevented maturation of oocysts during mosquito transmission. Overall this study highlights the importance of the molecular adaptation of BCKDH in this important class of pathogens.
authors.affiliation: Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Oppenheim
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia; Wellcome Trust Centre for Molecular Parasitology and Glasgow Polyomics, University of Glasgow, Glasgow, United Kingdom; Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia; The National Institute for Medical Research, Mill Hill, London, United Kingdom.
authors.forename: James I
authors.initials: JI
authors.lastname: Macrae
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Katarzyna K
authors.initials: KK
authors.lastname: Modrzynska
authors.affiliation: Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Paco
authors.initials: P
authors.lastname: Pino
authors.affiliation: Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Limenitakis
authors.affiliation: Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Polonais
authors.affiliation: FG16 - Mycotic and parasitic agents and mycobacteria, Robert Koch Institute, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Seeber
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology and Glasgow Polyomics, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Billker
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.affiliation: Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Soldati-Favre
mesh_terms: D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D010962:Plasmodium berghei / Q000201:enzymology / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D014122:Toxoplasma / Q000201:enzymology / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; D015800:Protozoan Proteins; D010088:Oxidoreductases