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MBio Aug 2021Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum, are the cause of many important human and animal diseases. While T. gondii tachyzoites... (Review)
Review
Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum, are the cause of many important human and animal diseases. While T. gondii tachyzoites replicate through endodyogeny, during which two daughter cells are formed within the parental cell, P. falciparum replicates through schizogony, where up to 32 parasites are formed in a single infected red blood cell and even thousands of daughter cells during mosquito- or liver-stage development. These processes require a tightly orchestrated division and distribution over the daughter parasites of one-per-cell organelles such as the mitochondrion and apicoplast. Although proper organelle segregation is highly essential, the molecular mechanism and the key proteins involved remain largely unknown. In this review, we describe organelle dynamics during cell division in T. gondii and P. falciparum, summarize the current understanding of the molecular mechanisms underlying organelle fission in these parasites, and introduce candidate fission proteins.
Topics: Animals; Apicoplasts; Erythrocytes; Humans; Mitochondria; Parasites; Plasmodium falciparum; Protozoan Proteins; Toxoplasma
PubMed: 34425697
DOI: 10.1128/mBio.01409-21 -
Frontiers in Cellular and Infection... 2022The deadly malaria parasite, , contains a unique subcellular organelle termed the apicoplast, which is a clinically-proven antimalarial drug target. The apicoplast is a... (Review)
Review
The deadly malaria parasite, , contains a unique subcellular organelle termed the apicoplast, which is a clinically-proven antimalarial drug target. The apicoplast is a plastid with essential metabolic functions that evolved secondary endosymbiosis. As an ancient endosymbiont, the apicoplast retained its own genome and it must be inherited by daughter cells during cell division. During the asexual replication of inside human red blood cells, both the parasite, and the apicoplast inside it, undergo massive morphological changes, including DNA replication and division. The apicoplast is an integral part of the cell and thus its development is tightly synchronized with the cell cycle. At the same time, certain aspects of its dynamics are independent of nuclear division, representing a degree of autonomy in organelle biogenesis. Here, we review the different aspects of organelle dynamics during intraerythrocytic replication, summarize our current understanding of these processes, and describe the many open questions in this area of parasite basic cell biology.
Topics: Animals; Apicoplasts; Cell Cycle; Cell Division; Humans; Malaria, Falciparum; Parasites; Plasmodium; Plasmodium falciparum; Protozoan Proteins
PubMed: 35573785
DOI: 10.3389/fcimb.2022.864819 -
The Journal of Eukaryotic Microbiology Nov 2022Toxoplasma gondii belongs to the phylum Apicomplexa and is an important cause of congenital disease and infection in immunocompromised patients. T. gondii shares... (Review)
Review
Toxoplasma gondii belongs to the phylum Apicomplexa and is an important cause of congenital disease and infection in immunocompromised patients. T. gondii shares several characteristics with plants including a nonphotosynthetic plastid termed apicoplast and a multivesicular organelle that was named the plant-like vacuole (PLV) or vacuolar compartment (VAC). The name plant-like vacuole was selected based on its resemblance in composition and function to plant vacuoles. The name VAC represents its general vacuolar characteristics. We will refer to the organelle as PLVAC in this review. New findings in recent years have revealed that the PLVAC represents the lysosomal compartment of T. gondii which has adapted peculiarities to fulfill specific Toxoplasma needs. In this review, we discuss the composition and functions of the PLVAC highlighting its roles in ion storage and homeostasis, endocytosis, exocytosis, and autophagy.
Topics: Humans; Toxoplasma; Vacuoles; Protozoan Proteins; Apicoplasts; Plants
PubMed: 36218001
DOI: 10.1111/jeu.12951 -
Current Opinion in Microbiology Oct 2021The apicoplast is the relict of a plastid organelle found in several disease-causing apicomplexan parasites such as Plasmodium spp. and Toxoplasma gondii. In these... (Review)
Review
The apicoplast is the relict of a plastid organelle found in several disease-causing apicomplexan parasites such as Plasmodium spp. and Toxoplasma gondii. In these organisms, the organelle has lost its photosynthetic capability but harbours several fitness-conferring or essential metabolic pathways. Although maintaining the apicoplast and fuelling the metabolic pathways within requires the challenging constant import and export of numerous metabolites across its four membranes, only few apicoplast transporters have been identified to date, most of which are orphan transporters. Here we review the roles of metabolic pathways within the apicoplast and what is currently known about the few identified apicoplast metabolite transporters. We discuss what metabolites must get in and out of the apicoplast, the many transporters that are yet to be discovered, and what role these might play in parasite metabolism and as putative drug targets.
Topics: Animals; Apicomplexa; Apicoplasts; Metabolic Networks and Pathways; Parasites; Plasmodium; Toxoplasma
PubMed: 34455306
DOI: 10.1016/j.mib.2021.07.016 -
Biochemical Society Transactions Aug 2019Malaria continues to be one of the leading causes of human mortality in the world, and the therapies available are insufficient for eradication. Severe malaria is caused... (Review)
Review
Malaria continues to be one of the leading causes of human mortality in the world, and the therapies available are insufficient for eradication. Severe malaria is caused by the apicomplexan parasite Apicomplexan parasites, including the spp., are descendants of photosynthetic algae, and therefore they possess an essential plastid organelle, named the apicoplast. Since humans and animals have no plastids, the apicoplast is an attractive target for drug development. Indeed, after its discovery, the apicoplast was found to host the target pathways of some known antimalarial drugs, which motivated efforts for further research into its biological functions and biogenesis. Initially, many apicoplast inhibitions were found to result in 'delayed death', whereby parasite killing is seen only at the end of one invasion-egress cycle. This slow action is not in line with the current standard for antimalarials, which seeded scepticism about the potential of compounds targeting apicoplast functions as good candidates for drug development. Intriguingly, recent evidence of apicoplast inhibitors causing rapid killing could put this organelle back in the spotlight. We provide an overview of drugs known to inhibit apicoplast pathways, alongside recent findings in apicoplast biology that may provide new avenues for drug development.
Topics: Animals; Antimalarials; Apicoplasts; Humans; Malaria; Oxidation-Reduction; Plasmodium
PubMed: 31383817
DOI: 10.1042/BST20170563 -
Life (Basel, Switzerland) Sep 2021is a unicellular eukaryote with a very polarized secretory system composed of micronemes rhoptries and dense granules that are required for host cell invasion. , like... (Review)
Review
is a unicellular eukaryote with a very polarized secretory system composed of micronemes rhoptries and dense granules that are required for host cell invasion. , like its relative , uses the endolysosomal system to produce the secretory organelles and to ingest host cell proteins. The parasite also has an apicoplast, a secondary endosymbiotic organelle, which depends on vesicular trafficking for appropriate incorporation of nuclear-encoded proteins into the apicoplast. Recently, the central molecules responsible for sorting and trafficking in and have been characterized. From these studies, it is now evident that has repurposed the molecules of the endosomal system to the secretory pathway. Additionally, the sorting and vesicular trafficking mechanism seem to be conserved among apicomplexans. This review described the most recent findings on the molecular mechanisms of protein sorting and vesicular trafficking in and revealed that has an amazing secretory machinery that has been cleverly modified to its intracellular lifestyle.
PubMed: 34575086
DOI: 10.3390/life11090937 -
PLoS Pathogens Nov 2022Many apicomplexan parasites harbor a non-photosynthetic plastid called the apicoplast, which hosts important metabolic pathways like the methylerythritol 4-phosphate...
Many apicomplexan parasites harbor a non-photosynthetic plastid called the apicoplast, which hosts important metabolic pathways like the methylerythritol 4-phosphate (MEP) pathway that synthesizes isoprenoid precursors. Yet many details in apicoplast metabolism are not well understood. In this study, we examined the physiological roles of four glycolytic enzymes in the apicoplast of Toxoplasma gondii. Many glycolytic enzymes in T. gondii have two or more isoforms. Endogenous tagging each of these enzymes found that four of them were localized to the apicoplast, including pyruvate kinase2 (PYK2), phosphoglycerate kinase 2 (PGK2), triosephosphate isomerase 2 (TPI2) and phosphoglyceraldehyde dehydrogenase 2 (GAPDH2). The ATP generating enzymes PYK2 and PGK2 were thought to be the main energy source of the apicoplast. Surprisingly, deleting PYK2 and PGK2 individually or simultaneously did not cause major defects on parasite growth or virulence. In contrast, TPI2 and GAPDH2 are critical for tachyzoite proliferation. Conditional depletion of TPI2 caused significant reduction in the levels of MEP pathway intermediates and led to parasite growth arrest. Reconstitution of another isoprenoid precursor synthesis pathway called the mevalonate pathway in the TPI2 depletion mutant partially rescued its growth defects. Similarly, knocking down the GAPDH2 enzyme that produces NADPH also reduced isoprenoid precursor synthesis through the MEP pathway and inhibited parasite proliferation. In addition, it reduced de novo fatty acid synthesis in the apicoplast. Together, these data suggest a model that the apicoplast dwelling TPI2 provides carbon source for the synthesis of isoprenoid precursor, whereas GAPDH2 supplies reducing power for pathways like MEP, fatty acid synthesis and ferredoxin redox system in T. gondii. As such, both enzymes are critical for parasite growth and serve as potential targets for anti-toxoplasmic intervention designs. On the other hand, the dispensability of PYK2 and PGK2 suggest additional sources for energy in the apicoplast, which deserves further investigation.
Topics: Animals; Toxoplasma; Apicoplasts; Metabolic Networks and Pathways; Parasites; Pyruvic Acid; Fatty Acids; Protozoan Proteins
PubMed: 36449552
DOI: 10.1371/journal.ppat.1011009 -
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 -
MBio Oct 2023and most other parasites in the phylum Apicomplexa contain an apicoplast, a non-photosynthetic plastid organelle required for fatty acid, isoprenoid, iron-sulfur...
and most other parasites in the phylum Apicomplexa contain an apicoplast, a non-photosynthetic plastid organelle required for fatty acid, isoprenoid, iron-sulfur cluster, and heme synthesis. Perturbation of apicoplast function results in parasite death. Thus, parasite survival critically depends on two cellular processes: apicoplast division to ensure every daughter parasite inherits a single apicoplast, and trafficking of nuclear encoded proteins to the apicoplast. Despite the importance of these processes, there are significant knowledge gaps in regards to the molecular mechanisms which control these processes; this is particularly true for trafficking of nuclear-encoded apicoplast proteins. This study provides crucial new insight into the timing of apicoplast protein synthesis and trafficking to the apicoplast. In addition, this study demonstrates how apicoplast-centrosome association, a key step in the apicoplast division cycle, is controlled by the actomyosin cytoskeleton.
Topics: Apicoplasts; Toxoplasma; Actins; Centrosome; Nuclear Proteins; Myosins; Protozoan Proteins
PubMed: 37732764
DOI: 10.1128/mbio.01640-23 -
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