Iron-tracking strategies: Chaperones capture iron in the cytosolic labile iron pool

Philpott, Caroline C.; Protchenko, Olga; Wang, Yübo; Novoa‐Aponte, Lorena; Leon-Torres, Andres; Grounds, Samantha; Tietgens, Amber Jean

doi:10.3389/fmolb.2023.1127690

Cited by 9 publications

(4 citation statements)

References 118 publications

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“…Parasites lack homologs of ferric reductases used in other organisms (e.g., STEAP3, Fre6) (24, 82), which represents a future challenge to fully understand Plasmodium iron mobilization from the FV. Additionally, iron exported from the FV by PfDMT1 is expected to be handed off to downstream trafficking proteins that are currently unknown (83). The proximity of PfDMT1 and the FV surface to the mitochondrion (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

Loveridge,

Sigala

2024

Preprint

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Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. falciparum requires nutritional iron to support essential metabolic pathways, but the critical mechanisms of iron acquisition and trafficking during RBC infection have remained obscure. Parasites internalize and liberate massive amounts of heme during large-scale digestion of RBC hemoglobin within an acidic food vacuole (FV) but lack a heme oxygenase to release porphyrin-bound iron. Although most FV heme is sequestered into inert hemozoin crystals, prior studies indicate that trace heme escapes biomineralization and is susceptible to non-enzymatic degradation within the oxidizing FV environment to release labile iron. Parasites retain a homolog of divalent metal transporter 1 (DMT1), a known mammalian iron transporter. This protein localizes to the FV membrane, but its role in P. falciparum iron acquisition has not been tested. Our phylogenetic and microscopy studies indicate that P. falciparum DMT1 (PfDMT1) retains conserved molecular features critical for metal transport and is oriented on the FV membrane in an export-competent topology. Conditional knockdown of PfDMT1 expression is lethal to parasites, which display broad cellular defects in iron-dependent functions, including impaired apicoplast biogenesis and mitochondrial polarization. Parasites are selectively rescued from partial PfDMT1 knockdown by supplementation with exogenous iron, but not other metals. These results support a cellular paradigm whereby PfDMT1 is the molecular gatekeeper to essential iron acquisition by blood-stage malaria parasites and suggest that therapeutic targeting of PfDMT1 may be a potent antimalarial strategy.

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Section: Discussionmentioning

confidence: 99%

“…Additionally, iron exported from the FV by PfDMT1 is expected to be handed off to downstream trafficking proteins that are currently unknown (83). The proximity of PfDMT1 and the FV surface to the mitochondrion (Fig.…”

Section: Phylogenetic Conservation and Divergence Of Dmt1 In Apicompl...mentioning

confidence: 99%

Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

Loveridge,

Sigala

2024

Preprint

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“…Sulfur combines with 2 Fe 2+ atoms and 2 reducing equivalents to form a [2Fe-2S] cluster on ISCU [56,57]. The iron necessary for cluster formation originates from an incompletely characterized pool of available iron sometimes referred to as the "chelatable or labile iron pool" [58,59]. Ligands for available iron may include glutathione [60] cytosolic iron chaperones PCPB1 and BOLA2 [61][62][63], and perhaps ATP, citrate, GAPDH, and other proteins that are not yet characterized.…”

Section: Fes Cluster Structure Geometries and Biogenesismentioning

confidence: 99%

Regulatory and Sensing Iron-Sulfur Clusters: New Insights and Unanswered Questions

SantaMaria,

Rouault

2024

Preprint

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Iron is an essential nutrient and necessary for biological functions from DNA replication and repair to transcriptional regulation, mitochondrial respiration, electron transfer, oxygen transport, photosynthesis, enzymatic catalysis, and nitrogen fixation. However, due to iron’s propensity to generate toxic radicals which can cause damage to DNA, proteins, and lipids, multiple processes regulate uptake and distribution of iron in living systems. Understanding how intracellular iron metabolism is optimized and how iron is utilized to regulate other intracellular processes is important to our overall understanding of a multitude of biological processes. One of the tools that the cell utilizes to regulate a multitude of functions is ligation of the iron-sulfur (Fe-S) cluster cofactor. Fe-S clusters comprised of iron and inorganic sulfur are ancient components of living matter on earth that are integral for physiological function in all domains of life. Here we will explore the ways in which the cell utilizes Fe-S clusters to sense the intracellular environment and respond to maintain equilibrium.

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“…Sulfur combines with two Fe 2+ atoms and two reducing equivalents to form a [2Fe-2S] cluster on ISCU [61,62]. The iron necessary for cluster formation originates from an incompletely characterized pool of available iron, sometimes referred to as the "chelatable or labile iron pool" [63,64]. Ligands for available iron may include glutathione [65], cytosolic iron chaperones PCPB1 and BOLA2 [66][67][68], and perhaps ATP, citrate, GAPDH, and other proteins that are not yet characterized.…”

Section: Fes Cluster Structure Geometries and Biogenesismentioning

confidence: 99%

Regulatory and Sensing Iron–Sulfur Clusters: New Insights and Unanswered Questions

SantaMaria,

Rouault

2024

Inorganics

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Iron is an essential nutrient and necessary for biological functions from DNA replication and repair to transcriptional regulation, mitochondrial respiration, electron transfer, oxygen transport, photosynthesis, enzymatic catalysis, and nitrogen fixation. However, due to iron’s propensity to generate toxic radicals which can cause damage to DNA, proteins, and lipids, multiple processes regulate the uptake and distribution of iron in living systems. Understanding how intracellular iron metabolism is optimized and how iron is utilized to regulate other intracellular processes is important to our overall understanding of a multitude of biological processes. One of the tools that the cell utilizes to regulate a multitude of functions is the ligation of the iron–sulfur (Fe-S) cluster cofactor. Fe-S clusters comprised of iron and inorganic sulfur are ancient components of living matter on earth that are integral for physiological function in all domains of life. FeS clusters that function as biological sensors have been implicated in a diverse group of life from mammals to bacteria, fungi, plants, and archaea. Here, we will explore the ways in which cells and organisms utilize Fe-S clusters to sense changes in their intracellular environment and restore equilibrium.

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Iron-tracking strategies: Chaperones capture iron in the cytosolic labile iron pool

Cited by 9 publications

References 118 publications

Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

Regulatory and Sensing Iron-Sulfur Clusters: New Insights and Unanswered Questions

Regulatory and Sensing Iron–Sulfur Clusters: New Insights and Unanswered Questions

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