Elucidating the structure and function of the divergent and essential cytochrome bc1 complex in apicomplexan parasites

Apicomplexan parasites, which include Toxoplasma and Plasmodium, cause deadly human diseases, such as toxoplasmosis and malaria. Understanding their divergent cell biology could inform strategies to combat them.

The apicomplexan mitochondrial electron transport chain (mETC) is essential for their survival and transmission, and highly divergent from the human mETC. Cytochrome bc1 is an mETC protein-complex that is essential, and a key target for drugs, like atovaquone. Yet its composition is unknown, and the mechanism of function and inhibition poorly understood.

I propose to investigate how the cytochrome bc1 complex functions and interacts with inhibitors.

Using Toxoplasma as a model, I will uncover the role of my newly discovered apicomplexan cytochrome bc1 subunits, and decipher the role of respiratory super-complex formation, in parasite energy metabolism and survival.

Using cryo-EM technology I will solve this complex’s structure to elucidate its mechanism of action, highlighting key differences with the human complex, and understand the way inhibitors disrupt the electron flow essential for energy conversion.

These studies will provide a mechanistic understanding of the essential apicomplexan cytochrome bc1 complex and how inhibitors stop its function.

This work will fill a critical gap in our knowledge of fundamental parasite cell biology, and likely inform drug discovery.