The vacuolar iron transporter mediates iron detoxification inToxoplasma gondii

Abstract

Iron is essential to living cells, acting as a cofactor in a number of essential enzymes in metabolism; however, iron requires proper storage or it can be dangerous to the cell. In both yeast and plants, iron is stored in a vacuole through the action of a vacuolar iron transporter (VIT). This transporter is conserved in the apicomplexan family of obligate intracellular parasites, including in Toxoplasma gondii, a pathogen of medical and veterinary importance. Here, we assess the role of VIT in T. gondii. We show that deletion of VIT causes a slight growth defect in vitro, however leads to hypersensitivity in the presence of excess iron, confirming its essential role in iron detoxification in the parasite. In the absence of VIT, parasites contain less iron and are at a growth disadvantage when moving into an iron-depleted environment. We show parasite VIT expression is regulated by environmental iron levels at both the transcript and protein level, and by altering the distribution of VIT within the cell. In the absence of VIT, we find that the T. gondii responds by altering expression of genes with a role in iron metabolism and by increasing the activity of the antioxidant protein catalase. We also show that iron detoxification has an important role both in parasite survival within macrophages and in pathogenesis in a mouse model. Together, by demonstrating a critical role for VIT during iron detoxification in T. gondii, we reveal the importance of iron storage in the parasite and provide the first insight into the machinery involved.

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

“…gondii [ 32 ], and modulation of intracellular iron levels is critical for the survival of T . gondii parasites [ 33 ]. Directly linking iron metabolism in the parasite and ETC activity through the Fe-S clusters of Tg ApiCox13 provides these parasites with a means of regulating the ETC (and associated processes such as ATP synthesis and pyrimidine synthesis) in response to iron availability.…”

“…Given that loss of its Fe-S clusters led to decreased Complex IV stability and activity, we speculate that TgApiCox13 has a role in the iron-dependent regulation of ETC function. Iron is an important micronutrient for many intracellular parasites, including T. gondii [32], and modulation of intracellular iron levels is critical for the survival of T. gondii parasites [33]. Directly linking iron metabolism in the parasite and ETC activity through the Fe-S clusters of TgApiCox13 provides these parasites with a means of regulating the ETC (and associated processes such as ATP synthesis and pyrimidine synthesis) in response to iron availability.…”

The Toxoplasma plant‐like vacuolar compartment (PLVAC)

“…A Vacuolar Iron Transporter (VIT) was recently characterized and found to localize to a vesicular compartment that partially colocalized with TgCPL (Aghabi et al, 2021). The study found that the VIT was important for detoxification of excess iron and for parasite virulence (Aghabi et al, 2021).…”