Biology subjects

Renaud, E. A.

Publications and source records attributed to Renaud, E. A..

4 recordsLinked to original sources

bioRxiv2024

HCF101 is a novel component of the CIA cytosolic iron-sulfur synthesis pathway in the human pathogen Toxoplasma gondii

Several key cellular functions depend on proteins harboring an iron-sulfur (Fe-S) cofactor. As these Fe-S proteins localize to several subcellular compartments, they require a dedicated machinery for cofactor assembly. For instance, in plants and algae there are Fe-S cluster synthesis pathways localizing to the cytosol, but also present in the mitochondrion and in the chloroplast, two organelles of endosymbiotic origin. Toxoplasma gondii is a plastid-bearing parasitic protist responsible for a pathology affecting humans and other warm-blooded vertebrates. We have characterized the Toxoplasma homologue of HCF101, originally identified in plants as a protein transferring Fe-S clusters to photosystem I subunits in the chloroplast. Contrarily to plants, we have shown that HCF101 does not localize to the plastid in parasites, but instead is an important component of the cytosolic Fe-S assembly (CIA) pathway which is vital for Toxoplasma. While the CIA pathway is widely conserved in eukaryotes, it is the first time the involvement of HCF101 in this pan-eukaryotic machinery is established. Moreover, as this protein is essential for parasite viability and absent from its mammalian hosts, it constitutes a novel and promising potential drug target.

microbiology↗

bioRxiv2024

The Toxoplasma gondii mitochondrial transporter ABCB7 is essential for cytosolic iron-sulfur cluster biogenesis and protein translation

Iron-sulfur (Fe-S) clusters are ubiquitous inorganic cofactors required for numerous essential cellular pathways. Since they cannot be scavenged from the environment, Fe-S clusters are synthesised de novo in cellular compartments such as the apicoplast, mitochondrion and cytosol. The cytosolic Fe-S cluster biosynthesis pathway relies on transport of an intermediate from the mitochondrial pathway. An ATP binding cassette (ABC) transporter called ABCB7 is responsible for this role in numerous commonly studied organisms, but its role in the medically important apicomplexan parasites has not yet been studied. Here we identify and characterise the Toxoplasma gondii ABCB7 homolog. Genetic depletion shows that it is essential for parasite growth, and that disruption triggers partial stage conversion. Characterisation of the knock-down line highlights a defect in cytosolic Fe-S cluster biogenesis leading to defects in protein translation and other pathways including DNA and RNA replication and metabolism. Our work provides support for a broad conservation of the connection between mitochondrial and cytosolic in Fe-S cluster biosynthesis and reveal its importance for parasite survival.

microbiology↗

bioRxiv2023

Iron depletion has different consequences on the growth and survival of Toxoplasma gondii strains

Toxoplasma gondii is an obligate intracellular parasite that is responsible for a pathology called toxoplasmosis which is primarily affecting immunocompromised individuals and developing fetuses. The parasite is able to scavenge essential nutrients from its host to support its own growth and survival. Among them, iron is one of the most important elements needed to sustain basic cellular functions, as it is involved in a number of key metabolic processes, including oxygen transport, redox balance and electron transport. We have evaluated the effects of an iron chelator on the development of several parasite strains and found that they differed in their ability to tolerate iron depletion. The growth of parasites usually associated with a model of acute toxoplasmosis was strongly impacted by iron depletion, while cystogenic strains were less sensitive as they were able to convert into persisting developmental forms which are associated with the chronic form of the disease. Ultrastructural and biochemical characterization of the impact of iron depletion on the parasites also highlighted striking changes in both in their metabolism and the one of the host, with a marked accumulation of lipid droplets and perturbation of lipid homeostasis. Overall, our study demonstrates that although acute iron depletion has an important effect on the growth of T. gondii, it has a more profound impact on actively dividing parasites, while less metabolically-active parasite forms may be able to avoid some of the most detrimental consequences.

microbiology↗

bioRxiv2022

Disruption of the plastid-hosted iron-sulfur cluster biogenesis pathway in Toxoplasma gondii has pleiotropic effects irreversibly impacting parasite viability

Like many other apicomplexan parasites, Toxoplasma gondii contains a plastid harbouring key metabolic pathways, including the SUF pathway that is involved in the biosynthesis of iron-sulfur clusters. These cofactors are key for a variety of proteins involved in important metabolic reactions, potentially including plastidic pathways for the synthesis of isoprenoid and fatty acids. It was shown previously that impairing the NFS2 cysteine desulfurase, involved in the first step of the SUF pathway, leads to an irreversible killing of intracellular parasites. However, the metabolic impact of disrupting the pathway remained unexplored. We have generated another mutant of the pathway, deficient for the SUFC ATPase, and we have investigated in details the phenotypic consequences of TgNFS2 and TgSUFC depletion on parasite homeostasis. Our analysis confirms that Toxoplasma SUF mutants are severely and irreversibly impacted in growth: cell division and membrane homeostasis are particularly affected. Lipidomic analysis suggests a defect in apicoplast-generated fatty acids, along with a simultaneous increase in scavenging of host-derived lipids. However, addition of exogenous lipids did not allow full restauration of growth, suggesting other more important cellular functions were impacted in addition to fatty acid synthesis. For instance, we have shown that the SUF pathway is also key for generating isoprenoid-derived precursors necessary for the proper targeting of GPI-anchored proteins as well as for the parasite gliding motility. Thus, plastid-generated iron-sulfur clusters support the functions of proteins involved in several vital downstream cellular pathways, which implies the SUF machinery may be explored for discovering new potential anti-Toxoplasma targets.

microbiology↗