Surprising variety in energy metabolism within Trypanosomatidae Aloysius G.M. Tielens and Jaap J. van Hellemond Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, ’S Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands The metabolism of Trypanosomatidae differs signifi- cantly between distinct species and can even be comple- tely different between various life-cycle stages of the same species. It has been proposed that differences in energy metabolism are related to differences in nutrient supply in the environments of the various trypanosoma- tids. However, the literature shows that availability of substrates does not dictate the type of energy metab- olism of trypanosomatids, as Trypanosoma theileri, Try- panosoma lewisi and African trypanosomes all live in the bloodstream of their mammalian host, but have surpris- ingly large differences in metabolism. Furthermore, in trypanosomatids no obvious relationship exists between energy metabolism and phylogeny or mode of trans- mission. We provide an overview of the metabolic capacities in the energy metabolism of distinct trypano- somatids, and suggest that these can be divided into four different metabolic categories of increasing complexity. Introduction to the energy metabolism of Trypanosomatidae The family of Trypanosomatidae, of which all members studied so far are parasites, is part of the protozoan order Kinetoplastida. Many trypanosomatids are of clinical in- terest because they cause important diseases, such as Chagas disease, leishmaniasis and sleeping sickness in humans, and nagana in livestock. Trypanosomatids pos- sess several striking biological characteristics, such as a kinetoplast containing the catenated circular network of mitochondrial DNA, and RNA editing, a process where mitochondrial transcripts are modified by insertions or deletions of uridines [1,2]. The energy metabolism of try- panosomatids is also special because: (i) a large part of glycolysis is performed in an organelle, the glycosome [3]; and (ii) the electron transport chains of many trypanoso- matids use an alternative oxidase that is otherwise found only in some fungi and plants (Figure 1). This review deals with variations in energy metabolism within the trypanosomatid family. Comparisons of the main aspects of energy metabolism in the trypanosomatid family are feasible, although the literature on this subject is biased as most studies have been performed on some selected species, such as Trypanosoma brucei, T. cruzi and Leishmania spp. Even within this restricted number of selected species, studies have mainly been focused on two life cycle stages of T. brucei: the bloodstream form from the mammalian host, and the procyclic form, which lives in the tsetse midgut. In-silico-derived metabolic maps drawn from genome-sequencing projects show all theoretically possible pathways of the species in question. Such maps are of course valuable by themselves, as they provide information on the metabolic potential of various life cycle stages, but they give no clues on the relative importance of the fluxes through the various pathways. Discussion of the energy metabolism of trypanosomatids will be restricted in this review to the main catabolic pathways. For more details on all possible metabolic pathways the reader is referred to more extensive reviews on those subjects [4–11]. In this review, an overview of the metabolic capacities in trypanosomatid energy metabolism will be discussed and, to stimulate further discussion, an attempt is made to categorize these variations. Habitats Trypanosomatids are classified into several genera, and include monogenetic parasites of insects, as well as para- sites that alternate in their life cycle between insects and vertebrates (or between insects and plants in case of Phytomonas). Accordingly, there are many different habitats in which trypanosomatids live. The monogenetic Herpetomonas, Leptomonas and Crithidia species spend their entire lifetime in the intestinal tract of insect hosts. The intestine is also the habitat of all trypanosomatids with two hosts when the parasite enters the insect vector: the T. brucei clade in tsetse flies, T. cruzi in triatome bugs, Leishmania spp. in sand flies, and Phytomonas in phyto- phagous insects. Trypanosomatids often have a complex development within the insect host, and migrate to environments other than the midgut, ending up for instance in the salivary glands. Metabolic aspects of insect stages other than those in the intestinal midgut are, however, hardly studied. Apart from Phytomonas, which infects plants, all known trypanosomatids with two hosts parasitize vertebrates as their second host. Trypanosoma- tids live in two completely different habitats within these vertebrate hosts: either in the bloodstream or intracellu- larly, depending on the species. For example, African salivarian trypanosomes, such as T. brucei, generally live in the bloodstream of mammals, ranging from cattle to humans. By contrast, amastigotes of T. cruzi live intra- cellularly in the cytoplasm of different cell types of their vertebrate host; whereas amastigotes of Leishmania live in a parasitophorous vacuole within macrophages of their mammalian host. Review Corresponding author: Tielens, A.G.M. (a.tielens@erasmusmc.nl). 482 1471-4922/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2009.07.007