An essential role for an Fe-S cluster protein in the cytochrome c oxidase complex of Toxoplasma parasites

The mitochondrial electron transport chain (ETC) of apicomplexan parasites differs considerably from the ETC of the animals that these parasites infect, and is the target of numerous anti-parasitic drugs. The cytochrome c oxidase complex (Complex IV) of the apicomplexan Toxoplasma gondii ETC is more than twice the mass and contains subunits not found in human Complex IV, including a 13 kDa protein termed TgApiCox13. TgApiCox13 is homologous to a human iron-sulfur (Fe-S) cluster-containing protein called the mitochondrial inner NEET protein (HsMiNT) which is not a component of Complex IV in humans. Here, we establish that TgApiCox13 is a critical component of Complex IV in T. gondii, required for complex activity and stability. Furthermore, we demonstrate that TgApiCox13, like its human homolog, binds two Fe-S clusters. We show that the Fe-S clusters of TgApiCox13 are critical for ETC function, having an essential role in mediating Complex IV integrity. Our study provides the first functional characterisation of an Fe-S protein in Complex IV. Author summaryComplex IV is a canonical component of the electron transport chain (ETC) of eukaryotic mitochondria. Recent evidence indicates that considerable diversity exists in the protein composition of Complex IV in eukaryotes, although the functions of most novel Complex IV proteins remain a mystery. In this study, we characterize TgApiCox13, a novel Complex IV protein from the apicomplexan parasite Toxoplasma gondii. We demonstrate that TgApiCox13 is an iron-sulfur protein that is essential for parasite survival, functioning as a critical mediator of the activity and stability of Complex IV. We show that the Fe-S clusters of TgApiCox13 are critical for Complex IV function, playing a key role in mediating integrity of the complex. Our findings provide the first functional characterization of an Fe-S cluster protein in Complex IV, highlighting the diversity that exists in a core complex of the mitochondrial ETC in eukaryotes.

Automated summary

TgApiCox13 is a critical component of the electron transport chain in the parasite Toxoplasma gondii, and is homologous to human protein HsMiNT. Both proteins bind two Fe-S clusters, which play a crucial role in the function of the electron transport chain.