Determination of glutathione redox potential and pH value in subcellular compartments of malaria parasites

Mohring, Franziska; Rahbari, Mahsa; Zechmann, Bernd; Rahlfs, Stefan; Przyborski, Jude M.; Meyer, Andreas; Becker, Katja

doi:10.1016/j.freeradbiomed.2017.01.001

Cited by 30 publications

(72 citation statements)

References 109 publications

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“…This scenario is not hard to imagine since the glutathione redox potential in the mitochondria of blood stage P . falciparum parasites is −328 mV (Mohring et al ., ), a value similar to that of lipoate.…”

Section: Discussionsupporting

confidence: 56%

“…In this context, the redox-dependent lipoylation of the H-protein that we observe in vitro may make sense since H-protein lipoylation would tend to increase under conditions of elevated oxidative stress. This scenario is not hard to imagine since the glutathione redox potential in the mitochondria of blood stage P. falciparum parasites is 2328 mV (Mohring et al, 2017), a value similar to that of lipoate.…”

Section: Discussionmentioning

confidence: 99%

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A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species

Afanador

Guerra

Swift

et al. 2017

Molecular Microbiology

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Summary Lipoate is an essential cofactor for enzymes that are important for central metabolism and other processes. In malaria parasites, scavenged lipoate from the human host is required for survival. The Plasmodium falciparum mitochondrion contains two enzymes (PfLipL1 and PfLipL2) that are responsible for activating mitochondrial proteins through the covalent attachment of lipoate (lipoylation). Lipoylation occurs via a novel redox-gated mechanism that remains poorly understood. We show that PfLipL1 functions as a redox switch that determines which downstream proteins will be activated. Based on the lipoate redox state, PfLipL1 either functions as a canonical lipoate ligase or as a lipoate activating enzyme which works in conjunction with PfLipL2. We demonstrate that PfLipL2 is a lipoyltransferase and is a member of a novel clade of lipoate attachment enzymes. We show that a LipL2 enzyme from Chlamydia trachomatis has similar activity, demonstrating conservation between intracellular pathogens from different phylogenetic kingdoms and supporting the hypothesis that an early ancestor of malaria parasites once contained a chlamydial endosymbiont. Redox-dependent lipoylation may regulate processes such as central metabolism and oxidative defense pathways.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species

Afanador

Guerra

Swift

et al. 2017

Molecular Microbiology

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“…For these experiments, we used the ratiometric redox-sensor hGrx1-roGFP2, consisting of human glutaredoxin 1 fused to an oxidation-reduction sensitive GFP and an N-terminal leader sequence that targets this reporter protein to parasite mitochondria. Assays used P. falciparum 3D7 parasites episomally transfected with pARL1a-Mito-hGrx1-roGFP2 (referred to herein as 3D7 WT Mito-hGrx1-roGFP2) [56] for confocal live-cell imaging. For these studies, we tested DHA, ATQ, and the β-hematin binding drug chloroquine (CQ).…”

Section: Dha Leads To An Oxidizing Effect In the Mitochondriamentioning

confidence: 99%

Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13

et al. 2020

Self Cite

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The emergence of artemisinin (ART) resistance in Plasmodium falciparum intra-erythrocytic parasites has led to increasing treatment failure rates with first-line ART-based combination therapies in Southeast Asia. Decreased parasite susceptibility is caused by K13 mutations, which are associated clinically with delayed parasite clearance in patients and in vitro with an enhanced ability of ring-stage parasites to survive brief exposure to the active ART metabolite dihydroartemisinin. Herein, we describe a panel of K13-specific monoclonal antibodies and gene-edited parasite lines co-expressing epitope-tagged versions of K13 in trans. By applying an analytical quantitative imaging pipeline, we localize K13 to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes. These latter structures form at the parasite plasma membrane and traffic hemoglobin to the digestive vacuole wherein artemisinin-activating heme moieties are released. We also provide evidence of K13 partially localizing near the parasite mitochondria upon treatment with dihydroartemisinin. Immunoprecipitation data generated with K13-specific monoclonal antibodies identify multiple putative K13-associated proteins, including endoplasmic reticulum-resident molecules, mitochondrial proteins, and Rab GTPases, in both K13 mutant and wild-type isogenic lines. We also find that mutant K13-mediated resistance is reversed upon co-expression of wild-type or mutant K13. These data help define the biological properties of K13 and its role in mediating P. falciparum resistance to ART treatment.

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“…Sustained pH homeostasis is essential for viable Plasmodium invasion/multiplication in mosquito tissues 60 . Manipulation of NDAE1 expression in the whole vector may produce a synergetic effect, resulting in an acute reduction of sporozoites in SGs due to pH alteration.…”

Section: Resultsmentioning

confidence: 99%

Solute carriers affect Anopheles stephensi survival and Plasmodium berghei infection in the salivary glands

Couto

Antunes

Pinheiro-Silva

et al. 2017

Sci Rep

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Malaria is caused by mosquito-borne Plasmodium spp. parasites that must infect and survive within mosquito salivary glands (SGs) prior to host transmission. Recent advances in transcriptomics and the complete genome sequencing of mosquito vectors have increased our knowledge of the SG genes and proteins involved in pathogen infection and transmission. Membrane solute carriers are key proteins involved in drug transport and are useful in the development of new interventions for transmission blocking. Herein, we applied transcriptomics analysis to compare SGs mRNA levels in Anopheles stephensi fed on non-infected and P. berghei-infected mice. The A. stephensi solute carriers prestinA and NDAE1 were up-regulated in response to infection. These molecules are predicted to interact with each other, and are reportedly involved in the maintenance of cell homeostasis. To further evaluate their functions in mosquito survival and parasite infection, these genes were knocked down by RNA interference. Knockdown of prestinA and NDAE1 resulted in reduction of the number of sporozoites in mosquito SGs. Moreover, NDAE1 knockdown strongly impacted mosquito survival, resulting in the death of half of the treated mosquitoes. Overall, our findings indicate the importance of prestinA and NDAE1 in interactions between mosquito SGs and Plasmodium, and suggest the need for further research.Over the last 15 years, massive prevention measures and new treatment tools have greatly decreased the global malaria burden. However, despite these advances, about 214 million new malaria cases and 438,000 associated deaths were registered in 2015 alone 1 . Malaria is caused by mosquito-borne Plasmodium parasites. In particular, adult female mosquitoes of the genus Anopheles are efficient Plasmodium vectors in many diverse ecosystems 2, 3 . Anopheles stephensi is a competent vector for both Plasmodium falciparum and P. vivax, the most virulent malaria-associated species 3 , as well as for Plasmodium species that infect rodents and, thus, this mosquito species is widely used as a laboratory model. A. stephensi is found throughout the Indian subcontinent-with its territory extending from the Arabian Peninsula, Iran, and Iraq, to Bangladesh, southern China, Myanmar, and Thailand 4 .Malaria transmission from mosquitoes to vertebrate hosts occurs through the mosquito's salivary glands (SGs), and for this reason many studies have focused on this organ to develop new malaria control measures [5][6][7][8][9] . Sporozoite invasion of mosquito SGs is receptor-mediated, and involves several parasite and SG proteins 10,11 . Characterization of the salivary components involved in parasite infection and transmission would greatly enhance our understanding of the mosquito-host-pathogen interface, and potentially reveal candidate targets for malaria prevention and control.

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Determination of glutathione redox potential and pH value in subcellular compartments of malaria parasites

Cited by 30 publications

References 109 publications

A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species

A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species

Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13

Solute carriers affect Anopheles stephensi survival and Plasmodium berghei infection in the salivary glands

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