Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility

Harding, Clare R.; Sidik, Saima; Petrova, Boryana; Gnädig, Nina F.; Okombo, John; Herneisen, Alice L; Ward, Kurt E.; Markus, Benedikt M.; Boydston, Elizabeth A.; Fidock, David A.; Lourido, Sebastian

doi:10.1038/s41467-020-18624-0

Cited by 51 publications

(37 citation statements)

References 139 publications

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“…A consequence would then be altered Hz inhibition in ARTR parasites, as has also been measured (7). Interestingly, the introduction of a substitution in the Toxoplasma gondii K13 protein orthologue, analogous to the C580Y PfK13 substitution, also confers reduced ART susceptibility in T. gondii (76).…”

Section: Discussionmentioning

confidence: 89%

Artemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification Pathway

Ribbiso

Heller

Taye

et al. 2021

Antimicrob Agents Chemother

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Artemisinin – based antimalarial drugs are believed to exert lethal effects on malarial parasites by alkylating a variety of intracellular molecular targets. Recent work with live parasites has shown that one of the alkylated targets is free heme within the parasite digestive vacuole, which is liberated upon hemoglobin catabolism by the intraerythrocytic parasite, and that reduced levels of heme alkylation occur in artemisinin resistant parasites. One implication of heme alkylation is that these drugs may inhibit parasite detoxification of free heme via inhibition of heme to hemozoin crystallization; however, previous reports that have investigated this hypothesis present conflicting data. By controlling reducing conditions and hence the availability of ferrous vs ferric forms of free heme, we modify a previously reported hemozoin inhibition assay to quantify the ability of ART – based drugs to target the heme detoxification pathway under reduced vs oxidizing conditions. Contrary to some previous reports, we find that artemisinins are potent inhibitors of hemozoin crystallization, with effective half maximal concentrations approximately an order of magnitude lower than those for most quinoline – based antimalarial drugs. We also examine hemozoin and in vitro parasite growth inhibition for drug pairs found in the most commonly used ART – based combination therapies (ACTs). All ACTs examined inhibit hemozoin crystallization in an additive fashion, and all but one inhibit parasite growth in additive fashion.

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Section: Discussionmentioning

confidence: 89%

Artemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification Pathway

Ribbiso

Heller

Taye

et al. 2021

Antimicrob Agents Chemother

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“…Our data suggest a metabolic rewiring in P. falciparum parasites, with a dysfunctional mitochondrion that can be perturbed by combining ATQ with DHA. Interestingly, a genome-wide CRISPR/Cas9 screen in the Apicomplexan parasite Toxoplasma gondii recently identified components of the TCA cycle and heme biosynthesis as mitochondrial determinants of DHA susceptibility 65 . One important distinction, however, is that unlike Plasmodium , Toxoplasma parasites do not endocytose or metabolize hemoglobin, thereby removing this pathway for ART activation.…”

Section: Discussionmentioning

confidence: 99%

Artemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival

et al. 2021

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The emergence and spread of artemisinin resistance, driven by mutations in Plasmodium falciparum K13, has compromised antimalarial efficacy and threatens the global malaria elimination campaign. By applying systems-based quantitative transcriptomics, proteomics, and metabolomics to a panel of isogenic K13 mutant or wild-type P. falciparum lines, we provide evidence that K13 mutations alter multiple aspects of the parasite’s intra-erythrocytic developmental program. These changes impact cell-cycle periodicity, the unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. K13-mediated artemisinin resistance in the Cambodian Cam3.II line was reversed by atovaquone, a mitochondrial electron transport chain inhibitor. These results suggest that mitochondrial processes including damage sensing and anti-oxidant properties might augment the ability of mutant K13 to protect P. falciparum against artemisinin action by helping these parasites undergo temporary quiescence and accelerated growth recovery post drug elimination.

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“…Artemisinin-resistant T. gondii selected in vitro provided further evidence for the involvement of mitochondrial pathways, as demonstrated by amplifications of mitochondrial cytochrome b and cytochrome c oxidase I genes and mutations in the mitochondrial protease DegP2 ortholog (33). The same DegP2 ortholog was identified in a genetic screen: its disruption in T. gondii facilitated survival to lethal concentrations of DHA and its deletion in P. falciparum resulted in higher survival in the RSA (44). Interestingly, in breast cancer cells and mouse embryonic fibroblasts the responses to mitochondrial stress include formation of tethers between nuclei and mitochondria, coined Nuclear Associated Mitochondria (NAM) (45).…”

Section: Discussionmentioning

confidence: 91%

Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

Connelly

Manzella-Lapeira

Levine

et al. 2020

Preprint

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Artemisinin and its semi-synthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstream Plasmodium parasites that enter into and later reactivate from a dormant persister state. Here we show that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Persister forms exhibit restructured mitochondrial-nuclear associations and an altered metabolic state consistent with stress from reactive oxygen species. New contacts between the mitochondria and nuclei may support communication pathways of mitochondrial retrograde signaling, resulting in transcriptional changes in the nucleus as a survival response. Further characterization of the organellar interactions and metabolic dependencies of persisters may suggest strategies to combat recrudescences of malaria after treatment.

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Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility

Cited by 51 publications

References 139 publications

Artemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification Pathway

Artemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification Pathway

Artemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival

Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

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