Metabolic Flexibility and Essentiality of the Tricarboxylic Acid Cycle in Plasmodium

The complete tricarboxylic acid (TCA) cycle, comprising a series of 8 oxidative reactions, occurs in most eukaryotes in the mitochondria and in many prokaryotes. The net outcome of these 8 chemical reactions is the release of the reduced electron carriers NADH and FADH₂, water, and carbon dioxide. The parasites of the Plasmodium spp., belonging to the phylum Apicomplexa, have all the genes for a complete TCA cycle. The parasite completes its life cycle across two hosts, the insect vector mosquito and a range of vertebrate hosts including humans. As the niches that the parasite invades and occupies in the two hosts vary dramatically in their biochemical nature and availability of nutrients, the parasite's energy metabolism has been accordingly adapted to its host environment. One such pathway that shows extensive metabolic plasticity in parasites of the Plasmodium spp. is the TCA cycle. Recent studies using isotope-tracing targeted-metabolomics have highlighted conserved and parasite-specific features in the TCA cycle. This Review provides a comprehensive summary of what is known of this central pathway in the Plasmodium spp.