The Expression of Lactate Dehydrogenase Is Important for the Cell Cycle of Toxoplasma gondii

Anouti, Fatme Al; Tomavo, Stanislas; Parmley, Stephen; Ananvoranich, Sirinart

doi:10.1074/jbc.m409175200

Cited by 64 publications

(47 citation statements)

References 33 publications

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“…Glycolysis 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].…”

Section: Plasmodium Falciparum and The Glycolytic Deceitmentioning

confidence: 99%

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: Plasmodium Falciparum and The Glycolytic Deceitmentioning

confidence: 99%

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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“…Toxoplasma glycolytic genes function both in glycolysis and in other parasite processes such as parasite motility (7)(8)(9). These data led several groups to conclude that glucose was the primary carbon source that was scavenged by Toxoplasma from its host cell.…”

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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“…In T. brucei, a combination of efficient RNAi and a tight tet-regulated transcription is routinely applied for large scale analysis of genome function. In contrast, the efficiency of RNAi in apicomplexans is still a matter of debate [85,86], even if previous and more recent studies have reported the successful use of antisense/ribozyme in T. gondii [87][88][89] and some studies have suggested that the mechanism of RNAi can operate in the malaria parasites [90][91][92].…”

Section: Experimental Approaches and Tools Developed To Regulate Genementioning

confidence: 99%

The transcription machinery and the molecular toolbox to control gene expression in Toxoplasma gondii and other protozoan parasites

Meissner¹,

Soldati

2005

Microbes and Infection

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The phylum of Apicomplexa groups a large variety of obligate intracellular protozoan parasites that exhibit complicated life cycles, involving transmission and differentiation within and between different hosts. Little is known about the level of regulation and the nature of the factors controlling gene expression throughout their life stages. Unravelling the mechanisms that govern gene regulation is critical for the development of adequate tools to manipulate these parasites and modulate gene expression, in order to study their function in molecular terms in vivo. A comparative analysis of the transcriptional machinery of several apicomplexan genomes and other protozoan parasites has revealed the existence of a primitive eukaryotic transcription apparatus consisting only of a subset of the general transcription factors found in higher eukaryotes. These findings have some direct implications on development of tools.

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The Expression of Lactate Dehydrogenase Is Important for the Cell Cycle of Toxoplasma gondii

Cited by 64 publications

References 33 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

The transcription machinery and the molecular toolbox to control gene expression in Toxoplasma gondii and other protozoan parasites

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