TgDrpC, an atypical dynamin‐related protein in <i>Toxoplasma gondii, </i>is associated with vesicular transport factors and parasite division

Heredero‐Bermejo, Irene; Varberg, Joseph M.; Charvat, Robert A.; Jacobs, Kylie; Garbuz, Tamila; Sullivan, William J.; Arrizabalaga, Gustavo

doi:10.1111/mmi.14138

Cited by 37 publications

(60 citation statements)

References 61 publications

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“…In contrast, Dnm1 depletion is not lethal in yeast: in absence of fission, the mitochondrial network is only shaped by fusion, and as a result it becomes a long, tubular structure, which can still be transferred to buds during mitosis [17]. Although our analysis suggests that Tg DrpC is essential for mitochondrial fission, which subsequently leads to non-specific secondary defects while the parasite dies, we cannot exclude that TgDrpC has additional functions during parasite replication, as suggested in a recent study [63].…”

Section: Discussionmentioning

confidence: 80%

A unique dynamin-related protein is essential for mitochondrial fission in Toxoplasma gondii

et al. 2019

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The single mitochondrion of apicomplexan protozoa is thought to be critical for all stages of the life cycle, and is a validated drug target against these important human and veterinary parasites. In contrast to other eukaryotes, replication of the mitochondrion is tightly linked to the cell cycle. A key step in mitochondrial segregation is the fission event, which in many eukaryotes occurs by the action of dynamins constricting the outer membrane of the mitochondria from the cytosolic face. To date, none of the components of the apicomplexan fission machinery have been identified and validated. We identify here a highly divergent, dynamin-related protein ( Tg DrpC), conserved in apicomplexans as essential for mitochondrial biogenesis and potentially for fission in Toxoplasma gondii . We show that Tg DrpC is found adjacent to the mitochondrion, and is localised both at its periphery and at its basal part, where fission is expected to occur. We demonstrate that depletion or dominant negative expression of Tg DrpC results in interconnected mitochondria and ultimately in drastic changes in mitochondrial morphology, as well as in parasite death. Intriguingly, we find that the canonical adaptor Tg Fis1 is not required for mitochondrial fission. The identification of an Apicomplexa-specific enzyme required for mitochondrial biogenesis and essential for parasite growth highlights parasite adaptation. This work paves the way for future drug development targeting Tg DrpC, and for the analysis of additional partners involved in this crucial step of apicomplexan multiplication.

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Section: Discussionmentioning

confidence: 80%

A unique dynamin-related protein is essential for mitochondrial fission in Toxoplasma gondii

et al. 2019

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“…No homologs for Mdv1 have been found in Toxoplasma gondii, but there are one Fis1 homolog (TGGT1_263323) and three dynamin-related proteins: DrpA, DrpB, and DrpC. Of these Drp proteins, DrpC, which lacks many of the features required for Drp function, has been associated with mitochondrial division (9). Nonetheless, we and other groups have shown that instead DrpC appears to be involved in vesicle trafficking and endocytosis (9,10).…”

Section: Discussionmentioning

confidence: 81%

“…Of these Drp proteins, DrpC, which lacks many of the features required for Drp function, has been associated with mitochondrial division (9). Nonetheless, we and other groups have shown that instead DrpC appears to be involved in vesicle trafficking and endocytosis (9,10). As Fis1 is the strongest homolog of any putative fission protein in Toxoplasma, we investigated the role of Fis1 in monensin-driven mitochondrial rearrangement.…”

Section: Discussionmentioning

confidence: 99%

“…TgDrpC is divergent from the typical Drp due to the absence of a conserved GTPase effector domain, which is generally required for function. We recently showed that TgDrpC localizes to cytoplasmic puncta that redistribute to the growing edge of the daughter parasites during endodyogeny and that it interacts with proteins that exhibit homology to those involved in vesicle transport (9,10).…”

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confidence: 99%

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Identification of Fis1 Interactors in Toxoplasma gondii Reveals a Novel Protein Required for Peripheral Distribution of the Mitochondrion

Jacobs

Charvat

Arrizabalaga

2020

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Toxoplasma gondii's single mitochondrion is very dynamic and undergoes morphological changes throughout the parasite's life cycle. During parasite division, the mitochondrion elongates, enters the daughter cells just prior to cytokinesis, and undergoes fission. Extensive morphological changes also occur as the parasite transitions from the intracellular environment to the extracellular environment. We show that treatment with the ionophore monensin causes reversible constriction of the mitochondrial outer membrane and that this effect depends on the function of the fission-related protein Fis1. We also observed that mislocalization of the endogenous Fis1 causes a dominant-negative effect that affects the morphology of the mitochondrion. As this suggests that Fis1 interacts with proteins critical for maintenance of mitochondrial structure, we performed various protein interaction trap screens. In this manner, we identified a novel outer mitochondrial membrane protein, LMF1, which is essential for positioning of the mitochondrion in intracellular parasites. Normally, while inside a host cell, the parasite mitochondrion is maintained in a lasso shape that stretches around the parasite periphery where it has regions of coupling with the parasite pellicle, suggesting the presence of membrane contact sites. In intracellular parasites lacking LMF1, the mitochondrion is retracted away from the pellicle and instead is collapsed, as normally seen only in extracellular parasites. We show that this phenotype is associated with defects in parasite fitness and mitochondrial segregation. Thus, LMF1 is necessary for mitochondrial association with the parasite pellicle during intracellular growth, and proper mitochondrial morphology is a prerequisite for mitochondrial division. IMPORTANCE Toxoplasma gondii is an opportunistic pathogen that can cause devastating tissue damage in the immunocompromised and congenitally infected. Current therapies are not effective against all life stages of the parasite, and many cause toxic effects. The single mitochondrion of this parasite is a validated drug target, and it changes its shape throughout its life cycle. When the parasite is inside a cell, the mitochondrion adopts a lasso shape that lies in close proximity to the pellicle. The functional significance of this morphology is not understood and the proteins involved are currently not known. We have identified a protein that is required for proper mitochondrial positioning at the periphery and that likely plays a role in tethering this organelle. Loss of this protein results in dramatic changes to the mitochondrial morphology and significant parasite division and propagation defects. Our results give important insight into the molecular mechanisms regulating mitochondrial morphology.

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“…Furthermore, unlike many higher eukaryotes that possess abundant mitochondria to maintain an overall healthy organelle pool [ 54 ], the fact that these parasites contain a single mitochondrion suggests that they might lack the critical homeostatic mechanisms for mitochondrial maintenance. Such a vulnerability has prompted several groups to undertake research endeavors to identify the proteins and pathways involved in the biogenesis of the mitochondrion [ 55 , 56 , 57 , 58 ]. Likewise, our own upcoming research endeavors are focusing on the identification of the cellular target(s) of the BPZ compounds to illuminate their mechanism of action in the hope of spurring on the development of new treatment regimens against such critical processes.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Antiparasitic Activity of Novel BPZ Derivatives Against Toxoplasma gondii

et al. 2020

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Prevalence studies revealed that one-third of the human population is chronically infected with Toxoplasma gondii. Presently, such infections are without medical treatment that effectively eradicates the parasite once it is in its latent form. Moreover, the therapeutics used to treat acute infections are poorly tolerated by patients and also cause the parasite to convert into long-lasting tissue cysts. Hence, there is a dire need for compounds with antiparasitic activity against all forms of T. gondii. This study examines the antiparasitic capacity of nine novel bisphenol Z (BPZ) derivatives to determine whether they possessed any activity that prevented T. gondii replication. To begin assessing the efficacy of the novel derivatives, parasites were treated with increasing concentrations of the compounds, then doubling assays and MitoTracker staining were performed. Three of the nine compounds demonstrated strong inhibitory activity, i.e., parasite replication significantly decreased with higher concentrations. Additionally, many of the treated parasites exhibited decreases in fluorescent signaling and disruption of mitochondrial morphology. These findings suggest that bisphenol Z compounds disrupt mitochondrial function to inhibit parasite replication and may provide a foundation for the development of new and effective treatment modalities against T. gondii.

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TgDrpC, an atypical dynamin‐related protein in Toxoplasma gondii, is associated with vesicular transport factors and parasite division

Cited by 37 publications

References 61 publications

A unique dynamin-related protein is essential for mitochondrial fission in Toxoplasma gondii

A unique dynamin-related protein is essential for mitochondrial fission in Toxoplasma gondii

Identification of Fis1 Interactors in Toxoplasma gondii Reveals a Novel Protein Required for Peripheral Distribution of the Mitochondrion

Evaluating the Antiparasitic Activity of Novel BPZ Derivatives Against Toxoplasma gondii

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