Investigating the role(s) of mammalian heme transport by HRG1

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dc.contributor.advisorHamza, Iqbalen_US
dc.contributor.authorPek, Rinien_US
dc.contributor.departmentCell Biology & Molecular Geneticsen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2019-06-22T05:37:02Z
dc.date.available2019-06-22T05:37:02Z
dc.date.issued2019en_US
dc.description.abstractThe recycling of hemoglobin from damaged or senescent red blood cells (RBCs) contributes almost 90% of daily body iron requirements in humans for bone marrow erythropoiesis. Previously, our cell biological studies have shown that HRG1, a four transmembrane protein first discovered in C. elegans, facilitates the transport of heme within reticuloendothelial system (RES) macrophages during the turnover of RBCs, a process termed erythrophagocytosis. HRG1 transports heme from the phagolysosomes into the cytosol where heme is degraded to liberate iron for erythropoiesis. Here we show that mice deficient for HRG1 are defective in heme- iron recycling by RES macrophages, resulting in over ten-fold excess heme accumulation as visible dark pigments within lysosomal compartments that are 10- 100 times larger than normal. The sequestered heme is tolerated by macrophages through polymerization into crystallized hemozoin, a phenomenon typically observed in blood-feeding parasites as a detoxification method to protect against heme toxicity. HRG1-/- mice display ineffective bone marrow erythropoiesis which results in a reduction in hematocrit and extramedullary erythropoiesis in the spleen. Under iron- deficient conditions HRG1-/- mice are unable to utilize hemozoin as an iron source to sustain erythropoiesis, causing severe anemia and lethality. Our studies establish that polymerizing cytotoxic heme into hemozoin is a previously-unanticipated heme tolerance pathway in mammals.en_US
dc.identifierhttps://doi.org/10.13016/8on9-u05y
dc.identifier.urihttp://hdl.handle.net/1903/22190
dc.language.isoenen_US
dc.subject.pqcontrolledMolecular biologyen_US
dc.subject.pqcontrolledCellular biologyen_US
dc.subject.pqcontrolledAnimal sciencesen_US
dc.subject.pquncontrollederythropoiesisen_US
dc.subject.pquncontrolledhemeen_US
dc.subject.pquncontrolledhemozoinen_US
dc.subject.pquncontrolledironen_US
dc.subject.pquncontrolledmetabolismen_US
dc.subject.pquncontrolledrecyclingen_US
dc.titleInvestigating the role(s) of mammalian heme transport by HRG1en_US
dc.typeDissertationen_US

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