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

PLoS Pathogens

Darren J. Creek¹  Paco Pino¹  Michael P. Barrett²  Frank Seeber²  Rebecca D. Oppenheim²  Oliver Billker²  Katarzyna K. Modrzynska³  Malcolm J. McConville⁴  Julien Limenitakis⁵  James I. Macrae⁶  Dominique Soldati-Favre⁶  Valerie Polonais⁷ 

[1] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia;Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland;Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;FG16 - Mycotic and parasitic agents and mycobacteria, Robert Koch Institute, Berlin, Germany;The National Institute for Medical Research, Mill Hill, London, United Kingdom;Wellcome Trust Centre for Molecular Parasitology and Glasgow Polyomics, University of Glasgow, Glasgow, United Kingdom;Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom

关键词: Parasitic diseases;    Plasmodium;    Toxoplasma gondii;    Citric acid cycle;    Pyruvate;    Mitochondria;    Metabolic labeling;    Tachyzoites;   

DOI  :  10.1371/journal.ppat.1004263

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY