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

Melatti, C., Pieperhoff, M., Lemgruber, L. , Pohl, E., Sheiner, L. and Meissner, M. (2019) A unique dynamin-related protein is essential for mitochondrial fission in Toxoplasma gondii. PLoS Pathogens, 15(4), e1007512. (doi: 10.1371/journal.ppat.1007512) (PMID:30947298) (PMCID:PMC6448817)

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Abstract

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 (TgDrpC), conserved in apicomplexans as essential for mitochondrial biogenesis and potentially for fission in Toxoplasma gondii. We show that TgDrpC 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 TgDrpC 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 TgFis1 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 TgDrpC, and for the analysis of additional partners involved in this crucial step of apicomplexan multiplication.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pieperhoff, Dr Manuela and Melatti, Miss Carmen and Meissner, Professor Markus and Sheiner, Dr Lilach and Lemgruber Soares, Dr Leandro
Creator Roles:
Melatti, C.Conceptualization, Data curation, Investigation, Writing – original draft
Pieperhoff, M.Data curation, Investigation
Lemgruber, L.Data curation
Sheiner, L.Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review and editing
Meissner, M.Conceptualization, Funding acquisition, Resources, Supervision, Writing – original draft, Writing – review and editing
Authors: Melatti, C., Pieperhoff, M., Lemgruber, L., Pohl, E., Sheiner, L., and Meissner, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:04 April 2019
Copyright Holders:Copyright © 2019 Melatti et al.
First Published:First published in PLoS Pathogens 15(4): e1007512
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
592941EndoTox: Endosomal dependent transport to the unique secretory organelles of apicomplexan parasitesMarkus MeissnerEuropean Research Council (ERC)309255III - PARASITOLOGY
501602Systematic analysis of essential parasite genes linked to invasion of the host cell in Toxoplasma gondiiMarkus MeissnerWellcome Trust (WELLCOTR)087582/Z/08/ZIII - PARASITOLOGY
692421Dissection of the unusual mitochondrial tRNA import translocon of Toxoplasma gondiiLilach SheinerBiotechnology and Biological Sciences Research Council (BBSRC)BB/N003675/1III - PARASITOLOGY