Contribution of the TCA cycle in the central carbon metabolism of apicomplexan parasites

Abstract

The absence of mitochondrial pyruvate dehydrogenase complex had failed to establish a link between glycolysis and mitochondrial carboxylic acid metabolism and posed a dilemma regarding the possible alternative source(s) of mitochondrial acetyl-CoA to fuel a canonical oxidative TCA cycle in the apicomplexan parasites such as Toxoplasma gondii and Plasmodium species. Using a combination of reverse genetics and metabolic profiling by mass spectrometry, we have established that the branched chain amino acid (BCAA) degradation pathway and the 2-methylcitrate cycle which detoxifies propionyl-CoA concomitantly produced during BCAAs degradation are both dispensable and not the source of mitochondrial acetyl-CoA for these parasites. Rather we provide evidence that the BCKDH complex has evolved towards the use of glycolytic pyruvate and act as a substitute for the PDH complex to generate mitochondrial acetyl-CoA and sustain a complete TCA cycle. Furthermore, we investigated the routes to generate cytoplasmic acetyl-CoA and their importance in T. gondii.