Journal article

BCKDH: The Missing Link in Apicomplexan Mitochondrial Metabolism Is Required for Full Virulence of Toxoplasma gondii and Plasmodium berghei

Rebecca D Oppenheim, Darren J Creek, James I Macrae, Katarzyna K Modrzynska, Paco Pino, Julien Limenitakis, Valerie Polonais, Frank Seeber, Michael P Barrett, Oliver Billker, Malcolm J McConville, Dominique Soldati-Favre

PLoS Pathogens | PUBLIC LIBRARY SCIENCE | Published : 2014

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 ..

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Grants

Awarded by Swiss National Foundation


Awarded by BioMalPar and EVIMalaR European Networks of Excellence


Awarded by Wellcome Trust


Awarded by Medical Research Council



Funding Acknowledgements

The project was supported by the Swiss National Foundation (FN3100A0-116722), the Swiss SystemsX.ch initiative, grant LipidX-2008/011 and is part of the activities of the BioMalPar and EVIMalaR European Networks of Excellence (LSHP-CT-2004-503578 and No. 242095). Work at the Sanger Institute was funded by a Wellcome Trust grant (098051) and by the Medical Research Council (G0501670). DSF is an International Scholar of the Howard Hughes Medical Institute. MJM is a NH&MRC Principal Research Fellow. DJC is a NHMRC Biomedical Training Fellow. RDO is supported by the iGE3 program from the University of Geneva and by the Ozmalnet Travel Award from Evimalar. The authors declare that they have no conflict of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.