-
BioRxiv : the Preprint Server For... Jun 2023Toxoplasma gondii contains an essential plastid organelle called the apicoplast that is necessary for fatty acid, isoprenoid, and heme synthesis. Perturbations affecting...
Toxoplasma gondii contains an essential plastid organelle called the apicoplast that is necessary for fatty acid, isoprenoid, and heme synthesis. Perturbations affecting apicoplast function or inheritance lead to parasite death. The apicoplast is a single copy organelle and therefore must be divided so that each daughter parasite inherits an apicoplast during cell division. In this study we identify new roles for F-actin and an unconventional myosin motor, TgMyoF, in this process. First, loss of TgMyoF and actin lead to an accumulation of apicoplast vesicles in the cytosol indicating a role for this actomyosin system in apicoplast protein trafficking or morphological integrity of the organelle. Second, live cell imaging reveals that during division the apicoplast is highly dynamic, exhibiting branched, U-shaped and linear morphologies that are dependent on TgMyoF and actin. In parasites where movement was inhibited by the depletion of TgMyoF, the apicoplast fails to associate with the parasite centrosomes. Thus, this study provides crucial new insight into mechanisms controlling apicoplast-centrosome association, a vital step in the apicoplast division cycle, which ensures that each daughter inherits a single apicoplast.
PubMed: 36711828
DOI: 10.1101/2023.01.01.521342 -
ELife Mar 2022Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in malaria parasites and is required for prenylation-dependent vesicular...
Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in malaria parasites and is required for prenylation-dependent vesicular trafficking and other cellular processes. We have elucidated a critical and previously uncharacterized role for IPP in apicoplast biogenesis. Inhibiting IPP synthesis blocks apicoplast elongation and inheritance by daughter merozoites, and apicoplast biogenesis is rescued by exogenous IPP and polyprenols. Knockout of the only known isoprenoid-dependent apicoplast pathway, tRNA prenylation by MiaA, has no effect on blood-stage parasites and thus cannot explain apicoplast reliance on IPP. However, we have localized an annotated polyprenyl synthase (PPS) to the apicoplast. PPS knockdown is lethal to parasites, rescued by IPP and long- (C) but not short-chain (≤C) prenyl alcohols, and blocks apicoplast biogenesis, thus explaining apicoplast dependence on isoprenoid synthesis. We hypothesize that PPS synthesizes long-chain polyprenols critical for apicoplast membrane fluidity and biogenesis. This work critically expands the paradigm for isoprenoid utilization in malaria parasites and identifies a novel essential branch of apicoplast metabolism suitable for therapeutic targeting.
Topics: Animals; Apicoplasts; Malaria, Falciparum; Parasites; Plasmodium falciparum; Polyprenols; Protozoan Proteins; Terpenes
PubMed: 35257658
DOI: 10.7554/eLife.73208 -
PLoS Pathogens Mar 2022Apicomplexa are obligate intracellular parasites responsible for major human infectious diseases such as toxoplasmosis and malaria, which pose social and economic... (Review)
Review
Apicomplexa are obligate intracellular parasites responsible for major human infectious diseases such as toxoplasmosis and malaria, which pose social and economic burdens around the world. To survive and propagate, these parasites need to acquire a significant number of essential biomolecules from their hosts. Among these biomolecules, lipids are a key metabolite required for parasite membrane biogenesis, signaling events, and energy storage. Parasites can either scavenge lipids from their host or synthesize them de novo in a relict plastid, the apicoplast. During their complex life cycle (sexual/asexual/dormant), Apicomplexa infect a large variety of cells and their metabolic flexibility allows them to adapt to different host environments such as low/high fat content or low/high sugar levels. In this review, we discuss the role of lipids in Apicomplexa parasites and summarize recent findings on the metabolic mechanisms in host nutrient adaptation.
Topics: Animals; Apicomplexa; Apicoplasts; Humans; Lipid Metabolism; Lipids; Parasites
PubMed: 35298557
DOI: 10.1371/journal.ppat.1010313 -
Current Opinion in Microbiology Feb 2023The apicoplast of Plasmodium falciparum is the only source of essential isoprenoid precursors and Coenzyme A (CoA) in the parasite. Isoprenoid precursor synthesis relies... (Review)
Review
The apicoplast of Plasmodium falciparum is the only source of essential isoprenoid precursors and Coenzyme A (CoA) in the parasite. Isoprenoid precursor synthesis relies on the iron-sulfur cluster (FeS) cofactors produced within the apicoplast, rendering FeS synthesis an essential function of this organelle. Recent reports provide important insights into the roles of FeS cofactors and the use of isoprenoid precursors and CoA both inside and outside the apicoplast. Here, we review the recent insights into the roles of these metabolites in blood-stage malaria parasites and discuss new questions that have been raised in light of these discoveries.
Topics: Animals; Humans; Apicoplasts; Parasites; Malaria; Plasmodium falciparum; Terpenes; Protozoan Proteins
PubMed: 36563485
DOI: 10.1016/j.mib.2022.102255 -
Methods in Molecular Biology (Clifton,... 2020Genetic manipulation is a powerful tool to study gene function but identifying the direct and primary functional outcomes of any gene depletion is crucial for this...
Genetic manipulation is a powerful tool to study gene function but identifying the direct and primary functional outcomes of any gene depletion is crucial for this strategy to be productive. This is a major challenge for the study of apicoplast biology, because, in the absence of an efficient isolation method, apicoplast functions must be assayed in the parasite. These assays should be performed dynamically from the time of gene depletion, and include standards and controls that separate direct from indirect phenotypes. Here, we describe a pipeline for apicoplast functional analysis and highlight relevant mutant T. gondii cell lines and apicoplast markers that are available in the field and that enhance the specificity of phenotype description.
Topics: Apicoplasts; Humans; Organelles; Oxidation-Reduction; Plastids; Protein Transport; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 31758456
DOI: 10.1007/978-1-4939-9857-9_13 -
Methods in Molecular Biology (Clifton,... 2023The ribosome is among the most complex and ancient cellular macromolecular assemblies that plays a central role in protein biosynthesis in all living cells. Its function...
The ribosome is among the most complex and ancient cellular macromolecular assemblies that plays a central role in protein biosynthesis in all living cells. Its function of translation of genetic information encoded in messenger RNA into protein molecules also extends to subcellular compartments in eukaryotic cells such as apicoplasts, chloroplasts, and mitochondria. The origin of mitochondria is primarily attributed to an early endosymbiotic event between an alpha-proteobacterium and a primitive (archaeal) eukaryotic cell. The timeline of mitochondrial acquisition, the nature of the host, and their diversification have been studied in great detail and are continually being revised as more genomic and structural data emerge. Recent advancements in high-resolution cryo-EM structure determination have provided architectural details of mitochondrial ribosomes (mitoribosomes) from various species, revealing unprecedented diversifications among them. These structures provide novel insights into the evolution of mitoribosomal structure and function. Here, we present a brief overview of the existing mitoribosomal structures in the context of the eukaryotic evolution tree showing their diversification from their last common ancestor.
Topics: Mitochondrial Ribosomes; Mitochondria; Ribosomes; Eukaryota; Eukaryotic Cells; Mitochondrial Proteins; Cryoelectron Microscopy; Ribosomal Proteins
PubMed: 37166629
DOI: 10.1007/978-1-0716-3171-3_2 -
Biomolecules Aug 2019The phylum Apicomplexa (Alveolates) comprises a group of host-associated protists, predominately intracellular parasites, including devastating parasites like , the... (Review)
Review
The phylum Apicomplexa (Alveolates) comprises a group of host-associated protists, predominately intracellular parasites, including devastating parasites like , the causative agent of malaria. One of the more fascinating characteristics of Apicomplexa is their highly reduced (and occasionally lost) remnant plastid, termed the apicoplast. Four core metabolic pathways are retained in the apicoplast: heme synthesis, iron-sulfur cluster synthesis, isoprenoid synthesis, and fatty acid synthesis. It has been suggested that one or more of these pathways are essential for plastid and plastid genome retention. The past decade has witnessed the discovery of several apicomplexan relatives, and next-generation sequencing efforts are revealing that they retain variable plastid metabolic capacities. These data are providing clues about the core genes and pathways of reduced plastids, while at the same time further confounding our view on the evolutionary history of the apicoplast. Here, we examine the evolutionary history of the apicoplast, explore plastid metabolism in Apicomplexa and their close relatives, and propose that the differences among reduced plastids result from a game of endosymbiotic roulette. Continued exploration of the Apicomplexa and their relatives is sure to provide new insights into the evolution of the apicoplast and apicomplexans as a whole.
Topics: Apicomplexa; Light
PubMed: 31430853
DOI: 10.3390/biom9080378 -
Proceedings of the National Academy of... Jun 2024Pyruvate lies at a pivotal node of carbon metabolism in eukaryotes. It is involved in diverse metabolic pathways in multiple organelles, and its interorganelle shuttling...
Pyruvate lies at a pivotal node of carbon metabolism in eukaryotes. It is involved in diverse metabolic pathways in multiple organelles, and its interorganelle shuttling is crucial for cell fitness. Many apicomplexan parasites harbor a unique organelle called the apicoplast that houses metabolic pathways like fatty acid and isoprenoid precursor biosyntheses, requiring pyruvate as a substrate. However, how pyruvate is supplied in the apicoplast remains enigmatic. Here, deploying the zoonotic parasite as a model apicomplexan, we identified two proteins residing in the apicoplast membranes that together constitute a functional apicoplast pyruvate carrier (APC) to mediate the import of cytosolic pyruvate. Depletion of APC results in reduced activities of metabolic pathways in the apicoplast and impaired integrity of this organelle, leading to parasite growth arrest. APC is a pyruvate transporter in diverse apicomplexan parasites, suggesting a common strategy for pyruvate acquisition by the apicoplast in these clinically relevant intracellular pathogens.
Topics: Apicoplasts; Toxoplasma; Pyruvic Acid; Protozoan Proteins; Animals; Membrane Transport Proteins; Biological Transport; Metabolic Networks and Pathways
PubMed: 38865262
DOI: 10.1073/pnas.2314314121 -
The Journal of Eukaryotic Microbiology Nov 2022Toxoplasma gondii is a member of the apicomplexan phylum, a group of single-celled eukaryotic parasites that cause significant human morbidity and mortality around the... (Review)
Review
Toxoplasma gondii is a member of the apicomplexan phylum, a group of single-celled eukaryotic parasites that cause significant human morbidity and mortality around the world. T. gondii harbors two organelles of endosymbiotic origin: a non-photosynthetic plastid, known as the apicoplast, and a single mitochondrion derived from the ancient engulfment of an α-proteobacterium. Due to excitement surrounding the novelty of the apicoplast, the T. gondii mitochondrion was, to a certain extent, overlooked for about two decades. However, recent work has illustrated that the mitochondrion is an essential hub of apicomplexan-specific biology. Development of novel techniques, such as cryo-electron microscopy, complexome profiling, and next-generation sequencing have led to a renaissance in mitochondrial studies. This review will cover what is currently known about key features of the T. gondii mitochondrion, ranging from its genome to protein import machinery and biochemical pathways. Particular focus will be given to mitochondrial features that diverge significantly from the mammalian host, along with discussion of this important organelle as a drug target.
Topics: Animals; Humans; Toxoplasma; Parasites; Cryoelectron Microscopy; Apicoplasts; Mitochondria; Mammals
PubMed: 35315174
DOI: 10.1111/jeu.12906 -
Proceedings of the National Academy of... Jul 2023The malaria parasite has a nonphotosynthetic plastid called the apicoplast, which contains its own genome. Regulatory mechanisms for apicoplast gene expression remain...
The malaria parasite has a nonphotosynthetic plastid called the apicoplast, which contains its own genome. Regulatory mechanisms for apicoplast gene expression remain poorly understood, despite this organelle being crucial for the parasite life cycle. Here, we identify a nuclear-encoded apicoplast RNA polymerase σ subunit (sigma factor) which, along with the α subunit, appears to mediate apicoplast transcript accumulation. This has a periodicity reminiscent of parasite circadian or developmental control. Expression of the apicoplast subunit gene, , together with apicoplast transcripts, increased in the presence of the blood circadian signaling hormone melatonin. Our data suggest that the host circadian rhythm is integrated with intrinsic parasite cues to coordinate apicoplast genome transcription. This evolutionarily conserved regulatory system might be a future target for malaria treatment.
Topics: Animals; Apicoplasts; Parasites; Cues; Plasmodium falciparum; Malaria; Protozoan Proteins
PubMed: 37406097
DOI: 10.1073/pnas.2214765120