In an article published in BMC Biology, Malcolm McConville and colleagues from the University of Melbourne, Australia provide a timely reassessment of carbon metabolism of the malarial parasite Plasmodium falciparum. Overturning previous misconceptions and exposing a new possibility for therapeutic intervention, their research shows that both the asexual and sexual blood stages of P.falciparum development can catabolize glucose and glutamine through a conventional mitochondrial tricarboxylic acid (TCA) cycle. This contradicts the current understanding and clears up confusion caused by a 2010 Nature article that was retracted in May 2013.
Scanning electron micrograph of a red blood cell infected with malaria parasites (in cyan). Image source: Flickr, NIH NIAID
Red blood cells infected by P. falciparum consume 75-fold more glucose than uninfected ones, and previous literature had suggested that the rapidly dividing asexual stages of the parasite rely almost completely on the glycolytic catabolism of glucose for ATP synthesis. Glycolysis results in the production not only of ATP but also of pyruvate, which feeds into the TCA cycle via the action of pyruvate dehydrogenase. P. falciparum has a single mitochondrion and possesses all the enzymes needed for a conventional TCA cycle, but because it lacks a mitochondrial isoform of pyruvate dehydrogenase, it was thought to be incapable of further catabolizing the end-products of glycolysis through oxidative phosphorylation.
This view was further supported by a metabolomics study published in Nature in 2010, which concluded that P. falciparum asexual blood stages catabolize glutamine via an atypical branched TCA cycle that precludes the catabolism of pyruvate. But other work suggested that the conventional TCA cycle can operate both in the insect stages of malaria and in other apicomplexan parasites. After finding that the TCA cycle is essential for the intracellular growth of the apicomplexan parasite Toxoplasma gondii, McConville and colleagues decided it was worth taking another look at the metabolomics of malaria
Their data shows no evidence of the branched TCA cycle proposed in the recently retracted Nature article, and instead their findings indicate a compartmentalized but conventional oxidative TCA cycle is in operation in asexual blood stages. Here glutamate serves as the major source of carbon skeletons entering the TCA cycle, via catabolism to α-ketoglutarate and subsequent conversion to malate and oxaloacetate, following the conventional pathway. Glucose-derived pyruvate and oxaloacetate meanwhile serve as a minor source of carbon skeletons. Although 93 percent of glucose internalized in asexual stages results in lactate production, the TCA cycle is a far more efficient producer of ATP. These results mark a significant correction of the perception that a conventional TCA cycle does not function at all.
In the non-dividing gametocyte stages that are essential for parasite transmission to mosquitoes, the data indicates that glucose rather than glutamine is the major fuel for the TCA cycle. This metabolic reprogramming coincides with an increase in glucose uptake. Unlike the asexual stages, the developing gametocytes are sensitive to an inhibitor of aconitase – an enzyme that acts upstream of α-ketoglutarate in the TCA cycle. This finding exposes a vulnerability that could be exploited with transmission blocking therapeutic drugs. The authors comment that field studies have suggested that such transmission-blocking inhibitors will be essential for the elimination of malaria in the long term.