Our lab has a long-standing interest in the biology of the mitochondrion of apicomplexan parasites. The mitochondrion of these parasites has a range of canonical functions, including in the production of cellular energy (ATP), and the biosynthesis of important iron-containing protein co-factors such as haem and iron-sulfur clusters. There are, however, notable differences that set apicomplexan mitochondria apart from those in other eukaryotes, including components of the electron transport chain and some of the enzymes used to generate energy. Using proteomic approaches, we recently identified ~200 mitochondrially-localised proteins that have no predicted function but which are important for parasite proliferation. We aim to identify the functions of these and other essential mitochondrial proteins in Toxoplasma gondii. Through collaborations with Alex Maier and Kevin Saliba, we are also examining these processes in Plasmodium falciparum. Our current projects examine:
- the identity and roles of novel electron transport chain proteins in T. gondii and P. falciparum;
- the molecular targets of novel electron transport chain inhibitors in T. gondii and P. falciparum;
- the integration of mitochondrial metabolism with the cellular metabolism of the parasite.
Our approaches in addressing these questions include:
- identifying candidate proteins that may have a role in mitochondrial processes;
- generating knockout or regulatable mutants in genes encoding these candidate proteins;
- examining the importance of candidate proteins for parasite proliferation;
- utilising cutting-edge physiological, microscopic, biochemical and other assays to measure the effect of losing a particular protein on mitochondrial functions, and the functional role of the protein in the mitochondrion;
- establishing the contribution of the candidate protein to broader biological processes and metabolism in the parasite metabolism.
Recent papers from this project that summarise the sorts of questions we are interested in:
- Tjhin ET, Hayward JA, McFadden GI and van Dooren GG (2020) Characterization of the apicoplast-localized enzyme TgUroD in Toxoplasma gondii reveals a key role of the apicoplast in heme biosynthesis. J Biol Chem: in press.
- Hayward JA and van Dooren GG (2019) Same same, but different: uncovering unique features of the mitochondrial respiratory chain of apicomplexans. Mol Biochem Parasitol 232: 111204.
- Seidi A, Muellner-Wong LS, Rajendran E, Tjhin ET, Dagley LF, Aw VY, Faou P, Well AI, Tonkin CJ and van Dooren GG (2018) Elucidating the mitochondrial proteome of Toxoplasma gondii reveals the presence of a divergent cytochrome c oxidase. eLife e38131.
- Huet D, Rajendran E, van Dooren GG and Lourido S (2018) Identification of cryptic subunits from an apicomplexan ATP synthase. eLife e38097.
- van Dooren GG, Yeoh LM, Striepen B and McFadden GI (2016) The import of proteins into the mitochondrion of Toxoplasma gondii. J Biol Chem 291(37): 19335-50.