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.
Highlights
The phylum of Apicomplexa comprises a large number of obligate intracellular parasites that infect organisms across the whole animal kingdom
They lack a key mitochondrial enzyme complex that is normally required for production of acetyl-CoA from pyruvate, allowing further oxidation of glycolytic intermediates in the tricarboxylic acid (TCA) cycle
We show that T. gondii and P. bergei utilize a second mitochondrial dehydrogenase complex, branched chain ketoacid dehydrogenase (BCKDH), that is normally involved in branched amino acid catabolism, to convert pyruvate to acetyl-CoA and further catabolize glucose in the TCA cycle
Summary
The phylum of Apicomplexa comprises a large number of obligate intracellular parasites that infect organisms across the whole animal kingdom. Malaria remains one of the most significant global public health challenges (World Malaria Report 2012, www.who.int), while toxoplasmosis causes severe disease and death in immunocompromised individuals and can lead to complications in development of the foetus if contracted during pregnancy [1]. Both Plasmodium spp and T. gondii invade a range of mammalian cells and replicate within a membrane-enclosed compartment called the parasitophorous vacuole (PV). The absence of a mitochondrial PDH complex in these parasites suggested that glycolytic pyruvate was not converted to acetyl-CoA in the mitochondrion and further catabolised through the TCA cycle [13,14,15]
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