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Regulation of mitochondrial morphodynamics in Toxoplasma gondii


A unique feature of parasites of the phylum Apicomplexa, such as Toxoplasma gondii, is the presence of asingle tubular mitochondrion, which is essential for parasite survival and a validated drug target. Most studiesof the apicomplexan mitochondrion have focused on its biochemistry and physiology. By contrast little is knownabout the machinery that controls mitochondrial division and that regulate its structure, information that wouldbe critical for a thorough exploration of the mitochondrion as a drug target. Toxoplasma's singularmitochondrion is very dynamic and undergoes morphological changes throughout the parasite's life cycleincluding during the transition from the intracellular to the extracellular environment. While inside a host cell themitochondrion is maintained in a lasso shape that stretches around the parasite periphery where it has regionsof coupling with the parasite pellicle, suggesting the presence of membrane contact sites. Promptly after exitfrom the host cell, these contact sites disappear, and the mitochondrion collapses indicating that dynamicmembrane contact sites regulate the positioning of the mitochondrion. Neither the functional significance northe proteins needed for the contact between Toxoplasma's mitochondrion and pellicle are known. We havediscovered a novel protein, Fip1, that associates with the mitochondrion and that when knocked out the normalmorphology of the mitochondrion is severely affected. In intracellular fip1 knockout parasites the mitochondrionis not in a lasso shape as seen in wildtype parasites, but instead it is collapsed. Additionally, propermitochondrial segregation is disrupted in the knockout parasites, resulting in parasites with no mitochondrionand mitochondrial material outside of the parasites. These gross morphological changes are associated with asignificant reduction of parasite propagation and can be rescued by reintroduction of a wildtype copy of Fip1.Accordingly, we hypothesize that Fip1 mediates contact between the mitochondrion and the parasite pellicle ina regulatable fashion, and that the Fip1 dependent mitochondrial morphology and dynamics are critical forparasite propagation. Through a combination of molecular genetics, microscopy and proteomics we willaddress the functional relevance and the mechanics of the mitochondrial morphology. In aim one we willconduct a thorough in vivo and in vitro phenotypic characterization of Fip1 mutant strains to determine the roleof Fip1 and mitochondrial shape in parasite viability. Aim two focuses on identifying and characterizingcomponents of the Fip1 complex that mediates the association of the mitochondrion with the periphery of theparasites. Finally, in aim three we will determine the regulatory mechanisms that drive the mitochondrialmorphological changes as the parasite exits its host cell. In conjunction, these experiments will shed light ontothe molecular mechanisms driving and regulating the morphodynamics of the Toxoplasma mitochondrion. Asthe mitochondrion of this important human pathogen is essential for its survival and a validated drug target, ourstudies will uncover novel targets for the development on new therapeutics.

Arrizabalaga, Gustavo A
Purdue University
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