Elucidating and Exploiting the Mitochondrial Electron Transport Chain of Apicomplexan Parasites

Abstract

Mitochondrial respiration is a critical process for the survival of many eukaryotes, including parasites in the phylum Apicomplexa. These intracellular parasites include the causative agents of numerous serious diseases in humans and animals, including toxoplasmosis (Toxoplasma gondii) and malaria (Plasmodium species). Emerging evidence indicates that the mitochondrial electron transport chain (ETC) of apicomplexans has notable differences to that of the host cells they infect. These differences make the ETC a prominent drug target in apicomplexans, with numerous inhibitors of this pathway in current use or development. In this thesis, I developed a suite of methods to assess ETC function in real time. I characterised apicomplexan ETC inhibitors that emerged from a compound library screen. I found that most of these inhibitors targeted the cytochrome bc1 complex (Complex III). I elucidated the protein composition of Complex III, characterising the apicomplexan specific protein TgQCR11, which I showed was critical for complex assembly and function. I characterised the first ever identified iron-sulfur cluster-containing protein in the cytochrome c oxidase complex (Complex IV) in T. gondii. I showed that the iron-sulfur clusters of this protein were critical for maintaining Complex IV integrity. In sum, my thesis has explored the novelty and exploitability of the ETC of apicomplexan parasites. Show more