Localisation of gluconeogenesis and tricarboxylic acid (TCA)-cycle enzymes and first functional analysis of the TCA cycle in Toxoplasma gondii

Fleige, Tobias; Pfaff, Nils; Groß, Uwe; Bohne, Wolfgang

doi:10.1016/j.ijpara.2008.01.007

Cited by 54 publications

(58 citation statements)

References 36 publications

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“…Instead of mMDH, Plasmodium spp. appear to use an FAD-dependent mitochondrial membrane-bound MQO enzyme for malate oxidation [9,16,63,64]. The electrons produced by this reaction are sequestered into the intermembrane space, fuelling ubiquinone reduction and the ETC (Figure 2).…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

“…The electrons produced by this reaction are sequestered into the intermembrane space, fuelling ubiquinone reduction and the ETC (Figure 2). Intriguingly, while also containing a mitochondrial MQO, T. gondii locates its MDH in the mitochondrion [63], perhaps suggesting some redundancy in mitochondrial malate oxidation in these cells. It is possible that these enzymes have different isolated functions, with mMDH perhaps being responsible for TCA cycle progression, and the primary roles of MQO being structural and/or FADH production for the ETC.…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

“…Tentatively, glutaminolysis can provide carbon skeletons to the TCA in two ways in T. gondii, by conversion to /-ketoglutarate, or through the GABA shunt (Figure 3). There may be partial redundancy in these entry routes, as evident from the modest phenotypes of succinyl-CoA synthetase or GAD disruption [54,63]. However, this redundancy is not complete because GAD mutants lose extracellular motility in zoites use both host-derived glucose and glutamine to fuel a canonical TCA cycle.…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

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Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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Pages 15apicomplexan mitochondrion in energy generation has remained unclear, given the glucosereplete intracellular nature of the environmental niches of these parasites and the apparent reduction of mitochondrial metabolic pathways [4][5][6][7]. For example, apicomplexan mitochondria lack 'type I' NADH dehydrogenase (NDH, complex I of the ETC) and many apparently lack the enzymes and transporters required for fatty acid b-oxidation [8,9]. Furthermore, the pyruvate dehydrogenase complex (PDH) responsible for conversion of pyruvate into acetyl-CoA -an obligate fuel for the TCA cycle -is only present in the apicoplast [10]. Consequently, there was no obvious entry point to allow catalysis of glycolytic pyruvate by the TCA cycle [10][11][12][13][14]. Despite this, there is overwhelming evidence that apicomplexans rely on a functional and canonical TCA cycle (as reviewed [4,5,15]), and apicomplexan genome annotations indicate the presence of all enzymes of the TCA cycle. Only one clade of apicomplexans, Cryptosporidium spp., show evidence of outright loss of the TCA cycle, but these taxa retain only a highly reduced mitochondrion, the mitosome, and have also lost their apicoplast [5,8,16].This review highlights how metabolomics technologies coupled to genetic manipulation have helped in unraveling apicomplexan parasite plasticity in carbon source utilization through different life stages, revealing a complex and sometimes counter-intuitive pattern of metabolic gains, losses, and reassignments. These changes have presumably been tailored to allow these parasites to thrive within their various host niches, but may constitute some much-needed Achilles' heels in the fight against these devastating diseases. Plasmodium falciparum and the Glycolytic DeceitGlycolysis has long appeared to be the main source of ATP and NAD(P)H in the erythrocytic stages of the malaria parasites, [5,[17][18][19][20][21]. Indeed, glucose uptake in P. falciparum-infected red blood cells (RBCs) has been observed to increase 75-100-fold compared to uninfected RBC [22][23][24][25]. Up to 93% of glucose is converted directly to lactate in asexual stages [26][ 4 _ T D $ D I F F ] and is ultimately excreted into the surrounding host cell. Perturbation of glucose uptake is detrimental to parasite growth [27,28], suggesting that glycolysis is an important part of the parasite's strategy for rapid proliferation. In a manner analogous to the Warburg effect observed in highly-proliferative cancer lines and other rapidly-growing cells (e.g., yeast and bloodstream Trypanosoma spp.), Plasmodium (in erythrocytic stages) has opted for fast generation of ATP through substrate-level phosphorylation and secretion of lactate as an end-product (aerobic fermentative glycolysis), as opposed to the 'slow but efficient' mitochondrial oxidative phosphorylation and complete oxidation [29]. Reasons for this dependence on glycolytic fermentation remain unclear -after all, blood stages of Plasmodium certainly have access to oxygen -but it may be a way of avoiding excessiv...

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Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

See 1 more Smart Citation

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

View full text Add to dashboard Cite

show abstract

“…Fleige and coworkers reported that reduced expression of the TCA enzyme succinyl-CoA synthase did not impact parasite growth, whereas MacRae et al reported that chemical inhibition of aconitase did (11,13). These seemingly contradictory data were reconciled by the discovery that Toxoplasma synthesizes ␥-aminobutyric acid (GABA) from glutamine and that this compound can be shunted into the TCA cycle as succinate via succinic-semialdehyde dehydrogenase and thus bypasses succinyl-CoA synthase (11).…”

Section: Glucose and Glutamine Power The Parasitementioning

confidence: 99%

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

Blader

Koshy

2014

Eukaryot Cell

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b Intracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections. Toxoplasma gondii is an obligate intracellular protozoan that infects ϳ30% of the world's population and causes severe and lifethreatening disease in developing fetuses, in immune-comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence of Toxoplasma in humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by which Toxoplasma interacts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells.T oxoplasma gondii is a protozoan, obligate intracellular parasite that is considered one of the world's most successful pathogens (1). Multiple factors contribute to this success, including a complex life cycle in which the parasite can be transmitted by both vertical and horizontal means, efficient propagation within both its primary (felines) and intermediate hosts, extensive mechanisms to evade and disarm host immunity, an ability to form chronic lifelong infections in intermediate hosts, and a wide host tropism in which the parasite can infect most nucleated cells of warm-blooded animals (2). Central to most of these factors is that Toxoplasma has developed the means to replicate efficiently within the hostile intracellular environment of its host cell. In this review, we highlight recent data that have shed light on how parasite growth is achieved by the parasite interacting with its host cell to manipulate host signaling cascades, transcription, cell survival pathways, and membrane transport. In addition, we discuss how parasites interact with neighboring host cells and propose how this may contribute to establishing a permissive microenvironment to improve its overall success. In particular, we focus on those processes that are essential for the growth of all parasite strains and we refer readers to recent reviews that highlight how polymorphic parasite molecules contribute to Toxoplasma virulence (3-5). NUTRIENT ACQUISITIONAs an obligate intracellular parasite that resides within a nonfusogenic vacuole, Toxoplasma must satisfy its nutritional needs by scavenging essential nutrients from its host cell. These nutrients include carbon sources (glucose and glutamine) to fuel its energy demands, specific amino acids, lipids, and other nutrients. Below, we discuss each of these and highlight pathways and processes that are unique to the parasite that could serve as novel drug targets (Fig. 1). GLUCOSE AND GLUTAMINE POWER THE PARASITEToxoplasma expresses a full complement of glycolytic and tr...

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“…The obvious advantage of this strategy is that hypothetical genes that might otherwise be neglected in targeted approaches will be identified with equal probability. The Tet-inducible transactivator system is currently the most robust method to generate conditional mutants for essential genes in a targeted approach and appears to be especially well suited for the characterisation of factors involved in invasion and apicoplast biology (Meissner et al 2002, Mital et al 2005, Huynh & Carruthers 2006, Mazumdar et al 2006, Kessler et al 2008, Plattner et al 2008) whereas employment of the system for other essential GOIs might result only in weak phenotypes (Fleige et al 2008) or might not be possible at all (unpublished observations). A major advantage of the Tet-inducible system is that virtually any GOI can be regulated whereas regulation at the protein level using ddFKBP might not work for proteins targeted to the secretory system (Herm-Gotz et al 2007, and unpublished observations).…”

Section: Molecular Tools For Identification and Characterisation Of Ementioning

confidence: 99%

What new cell biology findings could bring to therapeutics: is it time for a phenome-project in Toxoplasma gondii?

Meissner

Klaus

2009

Mem. Inst. Oswaldo Cruz

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Localisation of gluconeogenesis and tricarboxylic acid (TCA)-cycle enzymes and first functional analysis of the TCA cycle in Toxoplasma gondii

Cited by 54 publications

References 36 publications

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

What new cell biology findings could bring to therapeutics: is it time for a phenome-project in Toxoplasma gondii?

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