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Melatti, Carmen; Pieperhoff, Manuela; Lemgruber, Leandro; Pohl, Ehmke; Sheiner, Lilach; Meissner, Markus (2019): A unique dynamin-related protein is essential for mitochondrial fission in Toxoplasma gondii.
In: PLOS Pathogens 15(4), e1007512
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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. Author summary Mitochondria fission is mediated by an elaborate fission complex of dynamin and receptor proteins, best studied in organisms such as yeast and mammalian cells. Little is known about this process in apicomplexan parasites, unicellular eukaryotes characterised by a single, lasso-shaped mitochondrion. Here, we analyse the conservation of the fission complex in Toxoplasma gondii;we find that the protein TgFis1 is the only mitochondrial adaptor that is highly conserved, but our characterisation shows that it is not essential for parasite growth or for mitochondrial dynamics. In contrast, we find that the dynamin-related protein C (TgDrpC) is a key factor of mitochondrial biogenesis in T. gondii, showing that its recruitment to the basal part of the mitochondrion is essential for the formation of mature, separate organelles. Furthermore, our analysis shows that TgDrpC GTPase domain is conserved and essential for its function, highlighting its potential as novel drug target.