Iron–Sulfur Cluster Metabolism Impacts Iron Homeostasis, Ferroptosis Sensitivity, and Human Disease

Sviderskiy, Vladislav O.; Terzi, Erdem M.; Possemato, Richard

doi:10.1007/978-3-030-26780-3_12

Cited by 5 publications

(3 citation statements)

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“…However, only few metabolites change in response to SLCO2B1 overexpression, suggesting that SLCO2B1 expression does not cause a strong change in the levels of cellular metabolites (Figures S3A and S3B). Cellular iron homeostasis is tightly controlled in cells by a posttranslational mechanism mediated by IRP1/2 pathway (Sviderskiy et al, 2019). An increase in iron levels negatively regulates IRP2, enhancing mRNA stability of ferritin heavy chain 1 (FTH1), the major iron storage protein in mammalian cells.…”

Section: Slco2b1 Promotes Iron Availability Independently Of Transfer...mentioning

confidence: 99%

Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

et al. 2022

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Section: Slco2b1 Promotes Iron Availability Independently Of Transfer...mentioning

confidence: 99%

Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

et al. 2022

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“…Excessive iron accumulation enhances oxidation of various macromolecules and can lead to cell death by mechanisms that include ferroptosis, a recently described irondependent form of cell death characterized by membrane lipid peroxidation (2,3). Consequently, cellular iron regulation has a central role in modulating the sensitivity to ferroptosis, either facilitating it via iron accumulation or hindering it via iron sequestration (4).…”

Section: Introductionmentioning

confidence: 99%

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

et al. 2021

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Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5–mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich’s ataxia.

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“…However, only few metabolites change in response to SLCO2B1 overexpression, suggesting that SLCO2B1 expression does not cause a strong change in the levels of cellular metabolites ( Figures S2A, S2B and S2C ). Cellular iron homeostasis is tightly controlled in cells by a post-translational mechanism mediated by IRP1/2 pathway (Sviderskiy et al, 2019). An increase in iron levels negatively regulate IRP2, enhancing mRNA stability of ferritin heavy chain 1 (FTH1), the major iron storage protein in mammalian cells.…”

Section: Resultsmentioning

confidence: 99%

Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

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et al. 2022

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Iron is the most abundant transition metal in cells and essential for a wide range of biochemical processes. While most mammalian cells take up iron through receptor-mediated endocytosis of transferrin, molecular players involved in iron utilization under iron-limiting conditions are incompletely understood. To address this, we performed several parallel metabolism-focused CRISPRa gain of function screens, which revealed metabolic limitations under stress conditions. Screens for iron restriction identified expected members of iron utilization pathways, but also SLCO2B1, a poorly characterized membrane carrier. Expression of SLCO2B1 is sufficient to increase intracellular iron stores, bypass the essentiality of transferrin receptor-mediated iron uptake and enable cell proliferation under iron restriction. Mechanistically, SLCO2B1 mediates heme-analog import in cellular assays. Heme uptake by SLCO2B1 provides sufficient iron for cell proliferation through heme oxygenases. Notably, SLCO2B1 is predominantly expressed in microglia in the brain and primary microglia from Slco2b1-/- mice exhibit a strong defect in heme analog import. Altogether, our work identifies SLCO2B1 as a microglia-enriched plasma membrane heme importer and provides a genetic platform to identify metabolic limitations under stress conditions.

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Iron–Sulfur Cluster Metabolism Impacts Iron Homeostasis, Ferroptosis Sensitivity, and Human Disease

Cited by 5 publications

References 98 publications

Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

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