Plastid in human parasites

McFadden, Geoffrey I.; Reith, Michael; Munholland, Janet; Lang‐Unnasch, Naomi

doi:10.1038/381482a0

Cited by 496 publications

(326 citation statements)

References 12 publications

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“…S2). The identification of the malaria parasite PfCRT as a CLT homolog supports this theory, because it contains a relic plastid derived from an early endosymbiotic event with a cyanobacterium (31,32). Interestingly, both clt mutants and chloroquine-resistant plasmodia carrying PfCRT mutations have altered GSH homeostasis (33).…”

Section: Discussionmentioning

confidence: 86%

Plant homologs of the Plasmodium falciparum chloroquine-resistance transporter, Pf CRT, are required for glutathione homeostasis and stress responses

Maughan

Pasternak

Cairns

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

169

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In Arabidopsis thaliana, biosynthesis of the essential thiol antioxidant, glutathione (GSH), is plastid-regulated, but many GSH functions, including heavy metal detoxification and plant defense activation, depend on cytosolic GSH. This finding suggests that plastid and cytosol thiol pools are closely integrated and we show that in Arabidopsis this integration requires a family of three plastid thiol transporters homologous to the Plasmodium falciparum chloroquine-resistance transporter, PfCRT. Arabidopsis mutants lacking these transporters are heavy metal-sensitive, GSH-deficient, and hypersensitive to Phytophthora infection, confirming a direct requirement for correct GSH homeostasis in defense responses. Compartment-specific measurements of the glutathione redox potential using redox-sensitive GFP showed that knockout of the entire transporter family resulted in a more oxidized glutathione redox potential in the cytosol, but not in the plastids, indicating the GSH-deficient phenotype is restricted to the cytosolic compartment. Expression of the transporters in Xenopus oocytes confirmed that each can mediate GSH uptake. We conclude that these transporters play a significant role in regulating GSH levels and the redox potential of the cytosol.T he potentially damaging end-products of aerobic energy metabolism, reactive oxygen species (ROS), are powerful signaling components linking growth, metabolism, and defense responses in cells (1-4). In plant cells, a complex antioxidant network with glutathione (GSH) at its center has evolved to buffer ROS. Because both the levels and oxidation state of GSH are directly influenced by ROS, GSH is a key redox-signaling component (5-10).GSH is synthesized in two steps (11) catalyzed by the ratelimiting glutamate-cysteine ligase (GSH1; EC 6.3.2.2) and glutathione synthase (GSH2; EC 6.3.2.3). In Arabidopsis, GSH1 is exclusively targeted to the plastid, while GSH2 is targeted to both plastid and cytosol (12). Consequently, the pathway intermediate, γ-glutamylcysteine (γ-EC), must be exported from the plastid to allow for cytosolic GSH biosynthesis. This finding was recently confirmed by the observation that inviable gsh2 mutants can be fully complemented by expression of functional GSH2 only in the cytosol (13), suggesting that thiol transport between compartments is essential for maintaining both GSH levels and redox-based signaling pathways, although no plastid thiol transporters have yet been identified (13-17).

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Section: Discussionmentioning

confidence: 86%

Plant homologs of the Plasmodium falciparum chloroquine-resistance transporter, Pf CRT, are required for glutathione homeostasis and stress responses

Maughan

Pasternak

Cairns

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

169

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“…Distinctive features of Apicomplexa include a specialized apical invasion machinery, termed the apical complex, and a relict plastid derived from a red algal secondary endosymbiont known as the apicoplast [1,2]. The human parasites Plasmodium spp.…”

Section: Apicomplexan Mitochondria -A Missing Link and An Absent Cyclementioning

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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“…Toxoplasma gondii causes severe toxoplasmosis in immunocompromised individuals while other species are important pathogens in wild and domestic animals (Wong and Remington, 1993). The discovery that Apicomplexa harbor a single secondary plastid, called apicoplast, more than a decade ago represented a major breakthrough in this field (McFadden et al, 1996). It is now widely believed that the apicoplast was derived from the uptake of a red algal cell and that the Apicomplexa are part of the eukaryotic supergroup Chromalveolata (Gould et al, 2008).…”

Section: Transport Processes In Secondary Plastids: a New And Promisimentioning

confidence: 99%

The Import and Export Business in Plastids: Transport Processes across the Inner Envelope Membrane

Fischer

2011

Plant Physiology

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Plastid in human parasites

Cited by 496 publications

References 12 publications

Plant homologs of the Plasmodium falciparum chloroquine-resistance transporter, Pf CRT, are required for glutathione homeostasis and stress responses

Plant homologs of the Plasmodium falciparum chloroquine-resistance transporter, Pf CRT, are required for glutathione homeostasis and stress responses

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

The Import and Export Business in Plastids: Transport Processes across the Inner Envelope Membrane

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