The metabolic roles of the endosymbiotic organelles of Toxoplasma and Plasmodium spp.

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Highlights

  • Toxoplasma and Plasmodium possess two organelles of endosymbiotic origin: the apicoplast, and the mitochondrion.

  • The mitochondrion hosts a complete TCA cycle and an electron transport chain lacking complex I. Glutamine catabolism contributes to the TCA cycle.

  • Haem biosynthesis is an extremely unusual chimerical pathway shared between the two organelles and the cytoplasm.

  • Isoprenoid precursor synthesis and fatty acid synthesis are essential roles of the apicoplast. Different life stages show differential dependencies on these pathways.

The apicoplast and the mitochondrion of Apicomplexa cooperate in providing essential metabolites. Their co-evolution during the ancestral acquisition of a plastid and subsequent loss of photosynthesis resulted in divergent metabolic pathways compared with mammals and plants. This is most evident in their chimerical haem synthesis pathway.

Toxoplasma and Plasmodium mitochondria operate canonical tricarboxylic acid (TCA) cycles and electron transport chains, although the roles differ between Toxoplasma tachyzoites and Plasmodium erythrocytic stages. Glutamine catabolism provides TCA intermediates in both parasites.

Isoprenoid precursor synthesis is the only essential role of the apicoplast in Plasmodium erythrocytic stages. An apicoplast-located fatty acid synthesis is dispensable in these stages, which instead predominantly salvage fatty acids, while in Plasmodium liver stages and in Toxoplasma tachyzoites fatty acid synthesis is an essential role of the plastid.

Introduction

Apicomplexan parasites possess two organelles of endosymbiotic origin: a relict non-photosynthetic plastid (the apicoplast), and a mitochondrion (Figure 1), which together contribute substantially to the parasites’ metabolic needs. The apicoplast and mitochondrion show tight physical [1, 2] and functional collaboration. A chimerical haem pathway spans both organelles [3]. Apicoplast generated isopentenyl pyrophosphate (IPP) is likely used in mitochondrion co-enzyme Q synthesis, and finally the Toxoplasma mitochondrion and apicoplast shared a citrate shunt [4••].

In accordance with the adaptation of each parasite to its specific host niche, the repertoire of apicoplast and mitochondrion metabolic pathways has diverged between the different phylum members [5]. Here we focus on the unique features of these pathways in Plasmodium and Toxoplasma and review our current understanding of their roles in different host environments.

Section snippets

The apicomplexan mitochondrion

Mammalian cells have varying numbers of mitochondria that divide or fuse based on changing cellular needs, whereas Apicomplexa possess a single mitochondrion whose biogenesis coordinates with the cell-cycle [2]. Transfer of mitochondrial genes to the nucleus has occurred in all eukaryotes, allowing nuclear control over mitochondrial functions (Figure 2). The resulting loss of mitochondrial DNA-encoded genes is extreme in Apicomplexa and dinoflagellates, whose mitochondrial genomes encode only

Oxidative phosphorylation and TCA cycle

Oxidative phosphorylation is a canonical function of eukaryotic mitochondria. Tricarboxylic acid (TCA) cycle reactions are the chief source of electrons that feed the mitochondrial electron transport chain (mtETC), generating a proton gradient used for ATP synthesis by the ATP synthase complex (Figure 3).

Genomic sequencing of Toxoplasma gondii and Plasmodium spp. revealed genes encoding all TCA cycle enzymes, most mtETC components and most ATP synthase complex subunits. Selective inhibition of

Mitochondrial involvement in cell-death and differentiation

Recent studies link mitochondrial dynamics and autophagy in Toxoplasma [24•, 25, 26]. Mitochondrial fragmentation was observed in response to both autophagy inhibition [24] and activation [25, 26], creating contradictory models where autophagy either controls mitochondrial homeostasis or induces cell death. Interestingly, autophagy-mediating components associate with the apicoplast [27], and overexpression of one of them, TgATG4, results in mitochondrion and apicoplast morphological defects [27

Haem biosynthesis, a mitochondrion/apicoplast collaboration

The genomes of Plasmodium and Toxoplasma encode the complete set of haem synthesis genes [29]. Like most non-photosynthetic organisms, the pathway starts with mitochondrial conversion of glycine into δ-aminolaevulinic acid [30]. However, the cellular localization and phylogenetic origin of the downstream enzymes tell a tale of evolutionary shuffling and rejigging. The next four steps, executed by HemB/C/D/E respectively, take place in the plastid. While HemB/C/D are of plastid origin, HemE

The apicoplast

A common ancestor of Apicomplexa and dinoflagellates engulfed a red alga, which underwent reduction to become a secondary plastid (Figure 2). Most dinoflagellates maintained a photosynthetic plastid, unlike the apicomplexan plastid  the apicoplast  which lost photosynthesis. The apicoplast now supports three essential metabolic functions: the synthesis of haem (above), type II fatty acids, and isoprenoid precursors.

Type II fatty acid synthesis (FASII)

Fatty acids are a core component of cellular membranes and of essential prosthetic groups [33]. De novo fatty acid synthesis occurs either via fatty acid synthesis pathway I (FASI), typically found in animals and fungi and executed by a cytosolic multi-domain polypeptide, or via FASII, which depends on several individual enzymes and is more common in prokaryotes and plastids.

Both the Toxoplasma and Plasmodium genomes encode complete sets of FASII enzymes [34], and several kinetic, structural

Isoprenoid precursor biosynthesis

Isoprenoids are derivates of IPP or of its isomer dimethylallyl pyrophosphate (DMAPP). Apicomplexans possess the 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for IPP synthesis [29, 43], which is found mainly in eubacteria and plastids, and lack the alternative mevalonate pathway found in the cytosols of plant, animal and fungal cells.

Plasmodium spp. are sensitive to fosmidomycin [43], an inhibitor with two potential targets in the DOXP pathway [44]. Yeh and DeRisi showed that IPP can negate

Concluding remarks

The endosymbiotic organelles of Apicomplexa are crucial for parasite survival in different host settings during their complex life cycle. Studies combining metabolomics and genetic approaches have exposed interesting differences between Plasmodium and Toxoplasma in the roles of certain pathways. While genetic studies suggest that the TCA cycle is dispensable for Plasmodium erythrocytic stages, pharmacological evidence supports an essential role in Toxoplasma tachyzoite growth [4••].

Similarly,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

We thank Boris Striepen and Muthugapatti Kandasamy for access and assistance in utilizing a Zeiss ELYRA S1 (SR-SIM) for super resolution microscopy. LS is supported by an NIH pathway to independence award (K99-AI103032). ABV is supported by NIH grants (R01-AI028398, R01-AI098413 and R56-AI100569). GMcF is supported by the Australian Research Council and a Program Grant from the National Health and Medical Research Council.

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