New insights into apicoplast metabolism in blood-stage malaria parasites

Elahi, Rubayet; Prigge, Sean T.

doi:10.1016/j.mib.2022.102255

Cited by 10 publications

(6 citation statements)

References 98 publications

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“…The apicoplast is a non-photosynthetic organelle with important roles in the production of isoprenoids, fatty acids, iron-sulfur clusters, heme, and coenzyme A (36)(37)(38). It has also been tied to dormancy in blood stages of P. falciparum.…”

Section: Discussionmentioning

confidence: 99%

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts inP. falciparumpersister blood stages after drug treatment

Micchelli,

Percopo,

Traver

et al. 2024

Preprint

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Morphological modifications and shifts in organelle relationships are hallmarks of dormancy in eukaryotic cells. Communications between altered mitochondria and nuclei are associated with metabolic quiescence of cancer cells that can survive chemotherapy. In plants, changes in the pathways between nuclei, mitochondria, and chloroplasts are associated with cold stress and bud dormancy. Plasmodium falciparum parasites, the deadliest agent of malaria in humans, contain a chloroplast-like organelle (apicoplast) derived from an ancient photosynthetic symbiont. Antimalarial treatments can fail because a small fraction of the blood stage parasites enter dormancy and recrudesce after drug exposure. Altered mitochondrial-nuclear interactions in these persisters have been described for P. falciparum, but interactions of the apicoplast remained to be characterized. In the present study, we examined the apicoplasts of dormant persisters obtained after exposure to dihydroartemisinin (a first-line antimalarial drug) followed by sorbitol treatment, or after exposure to sorbitol treatment alone. As previously observed, the mitochondrion of persisters was consistently enlarged and in close association with the nucleus. In contrast, the apicoplast varied from compact and oblate, like those of active ring stage parasites, to enlarged and irregularly shaped. Enlarged apicoplasts became more prevalent later in dormancy, but regular size apicoplasts subsequently predominated when actively replicating parasites recrudesced. All three organelles, nucleus, mitochondrion, and apicoplast, became closer during dormancy. Understanding their relationships in erythrocytic-stage persisters may lead to new strategies to prevent recrudescences and protect the future of malaria chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts inP. falciparumpersister blood stages after drug treatment

Micchelli,

Percopo,

Traver

et al. 2024

Preprint

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“…Due to its reciprocal dependence on isoprenoid precursor synthesis, apicoplast biogenesis also requires organelle functions that support MEP pathway activity, including Suf-mediated Fe-S cluster biogenesis, replication of the apicoplast genome and expression of SufB, pyruvate kinase II activity, and membrane transporters that import the requisite biosynthetic substrates ( Fig 1 ) [ 4 ]. Several of these pathways also have separate essential roles in apicoplast biogenesis in addition to and independent of their direct support of MEP pathway activity.…”

Section: Apicoplast Biogenesis Requires Isoprenoid Precursor Synthesi...mentioning

confidence: 99%

The interdependence of isoprenoid synthesis and apicoplast biogenesis in malaria parasites

Okada,

Sigala

2023

PLoS Pathog

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Isoprenoid precursor synthesis is an ancient and fundamental function of plastid organelles and a critical metabolic activity of the apicoplast in Plasmodium malaria parasites [1–3]. Over the past decade, our understanding of apicoplast properties and functions has increased enormously [4], due in large part to our ability to rescue blood-stage parasites from apicoplast-specific dysfunctions by supplementing cultures with isopentenyl pyrophosphate (IPP), a key output of this organelle [5,6]. In this Pearl, we explore the interdependence between isoprenoid metabolism and apicoplast biogenesis in P. falciparum and highlight critical future questions to answer.

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“…The apicoplast is a unique four-membrane-surrounded structure originating from a cyanobacterium through primary and secondary endosymbiosis [13][14][15][16] . It has been the target of antibiotics used to treat malaria since the 1950s 17 and continues to be an important target for developing novel antimalarials [18][19][20][21][22] . These two organelles house numerous essential pathways, such as synthesis of pyrimidines 23 , iron-sulfur clusters 24 , adenosine triphosphate (ATP) 25 , Heme 26 , lipids 27 , isoprenoids 28 , and coenzyme A (CoA) 29 .…”

Section: Introductionmentioning

confidence: 99%

The dynamin-related protein Dyn2 is essential for both apicoplast and mitochondrial fission inPlasmodium falciparum

Morano,

Xu,

Shadija

et al. 2024

Preprint

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Dynamins, or dynamin-related proteins (DRPs), are large mechano-sensitive GTPases mediating membrane dynamics or organellar fission/fusion events. Plasmodium falciparum encodes three dynamin-like proteins whose functions are poorly understood. Here, we demonstrate that PfDyn2 mediates both apicoplast and mitochondrial fission. Using super-resolution and ultrastructure expansion microscopy, we show that PfDyn2 is expressed in the schizont stage and localizes to both the apicoplast and mitochondria. Super-resolution long-term live cell microscopy shows that PfDyn2-deficient parasites cannot complete cytokinesis because the apicoplast and mitochondria do not undergo fission. Further, the basal complex or cytokinetic ring in Plasmodium cannot fully contract upon PfDyn2 depletion, a phenotype secondary to physical blockage of undivided organelles in the middle of the ring. Our data suggest that organellar fission defects result in aberrant schizogony, generating unsuccessful merozoites. The unique biology of PfDyn2, mediating both apicoplast and mitochondrial fission, has not been observed in other organisms possessing two endosymbiotic organelles.

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New insights into apicoplast metabolism in blood-stage malaria parasites

Cited by 10 publications

References 98 publications

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts inP. falciparumpersister blood stages after drug treatment

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts inP. falciparumpersister blood stages after drug treatment

The interdependence of isoprenoid synthesis and apicoplast biogenesis in malaria parasites

The dynamin-related protein Dyn2 is essential for both apicoplast and mitochondrial fission inPlasmodium falciparum

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