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  • Oral presentation
  • T72

To inhibit or not to inhibit: characterization of the Toxoplasma gondii homolog of ATPase inhibitory factor 1 (IF1)

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Goethe-Saal & Galerie

Session

Session XI: Mitochondrion & Apicoplast

Topic

  • Cell Biology

Authors

Madelaine Usey (Athens, GA / US), Dr. Diego Huet (Athens, GA / US)

Abstract

In many eukaryotes, mitochondria play a key role in the generation of cellular energy as the so-called powerhouses of the cell. Within the powerhouse, the ATP synthase is the true power generator; it harvests the proton gradient created by the complexes of the electron transport chain to produce ATP through oxidative phosphorylation. In mammals and yeast, the activity of the ATP synthase is tightly controlled via many mechanisms, including by the binding of interactor proteins. One such interactor is ATPase inhibitory factor 1 (IF1), which can inhibit the ATP synthase and mediate the induction of cytoprotective gene expression pathways through a process known as mitohormesis. As we know little about how Toxoplasma gondii ATP synthase activity is regulated, we wanted to investigate whether the T. gondii homolog of IF1 (TgIF1) played similar roles to the IF1 found in other organisms. Using CRISPR/Cas9, we tagged TgIF1 and generated TgIF1 knockout and overexpression parasite strains. With these strains, we found that TgIF1 knockout and overexpression had no observable impact on metabolism, mitochondrial membrane potential, or ATP synthase dimerization. We did, however, find that TgIF1 overexpression appeared to increase higher order oligomerization of the ATP synthase and that knockout significantly reduced cristae density. Although TgIF1 levels had no impact on parasite growth under normal culture conditions, we found that TgIF1 knockout and overexpression both negatively impacted growth under hypoxia. Further, we illustrated that TgIF1 overexpression improved growth when parasites were exposed to oxidative stress, suggesting a mitohormetic role of TgIF1. This phenotypic observation was corroborated by bulk RNAseq data which showed that the main group of genes impacted by TgIF1 overexpression is involved in gene expression regulation and RT-qPCR data indicating that TgIF1 levels correlate with expression levels of several antioxidants. In summary, it appears that while TgIF1 does not have significant effects on parasite metabolism and growth under normal conditions, it plays a key role in mitochondrial cristae biogenesis and is important for mediating the response to various stressors.

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