SummaryOur understanding of the Plasmodium mitochondrion and apicoplast has been greatly assisted by the genome sequence project. Sequence data have seeded recent research showing that the apicoplast is the site of several anabolic pathways including fatty acid synthesis. The discovery of an active apicoplast pyruvate dehydrogenase complex implies this enzyme generates the acetyl-CoA needed for fatty acid synthesis. However, the absence of a corresponding mitochondrial complex suggests that energy generation in Plasmodium is considerably different from pathways described in other eukaryotes.Eight years ago it was shown that apicomplexans including Plasmodium , the causative agent of malaria, possessed a plastid (later known as the apicoplast). Apicomplexans are non-photosynthetic, so the much-asked question was why keep a plastid? The riddle is by no means solved, but bioinformatic analyses, enzyme biochemistry and inhibitor studies all point to dependence on the plastid for anabolic pathways whose cytosolic counterparts were lost after the plastid was acquired. The first such pathway discovered in Plasmodium falciparum and Toxoplasma gondii was fatty acid biosynthesis, a pathway that shows much potential as a chemotherapeutic target (Surolia and Surolia, 2001;Waller et al ., 2003). In this issue of Molecular Microbiology , two articles (by Foth et al . and by McMillan et al . respectively) describe the characterization of a key enzyme at the starting point of this pathway, the multiprotein complex pyruvate dehydrogenase (PDH). The authors discovered that each of the four subunits required to form PDH contained an Nterminal apicoplast-like targeting sequence, suggesting post-translational trafficking. GFP fusion constructs made for three of these four subunits confirmed that their leaders are sufficient to mediate apicoplast targeting. A second isoform of the E3 (or dihydrolipoamide dehydrogenase) subunit targets to the mitochondria, where it is probably required by branched chain a -keto acid dehydrogenase, a -ketoglutarate dehydrogenase or the glycine decarboxylase complex.The demonstration that the apicoplast contains a PDH suggests that the carbon (and some reducing power) required for apicoplast fatty acid synthesis comes from the conversion of pyruvate to acetyl-CoA by PDH. This fits nicely with the recent consensus that pyruvate is the most important carbon source for fatty acids in plant plastids. However, in clearing up one metabolic conundrum the authors pose another: if the single PDH in Plasmodium belongs to the plastid, where is the mitochondrial PDH? The authors performed a rigorous screen for PDH subunits from available data for six Plasmodium species and for T. gondii -with the same results for all speciesabundant PDH subunits with apicoplast leaders, but only E3 subunits for the mitochondria. Several mitochondrial complexes generally share E3, so the evidence for the absence of mitochondrial PDH in Plasmodium is strong.Like plastids, mitochondria result from the endosymbiosis of a eubacterial ...