Heme trafficking and recycling in iron metabolism

铁代谢中的血红素运输和回收

基本信息

批准号：
10653923
负责人：
Iqbal Hamza
金额：
$ 48万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653923
关键词：
Adult Anemia Animal Genetics Animal Model Antiparasitic Agents Biological Biological Assay Biological Availability Blood Bone Marrow Caenorhabditis elegans Candidate Disease Gene Cells Chloroquine Clinical Co-Immunoprecipitations Cytoplasm Cytosol Degradation Pathway Development Dichloromethylene Diphosphonate Dimensions Drug Metabolic Detoxication Elements Embryo Erythrocytes Erythrophagocytosis Erythropoiesis FTH1 gene Ferritin Funding Genes Genetic Genetic Transcription Goals Hematology Heme Heme Iron Hemoglobin Homeostasis Homologous Gene Human Human body Hydrophobicity Impairment In Situ Ingestion Investigation Iron Ligation Liver Lysosomal Storage Diseases Lysosomes Macrophage Mammals Mediating Membrane Metabolism Molecular Monitor Mus Mutation Nutrient Nutrition Disorders Organ Organism Oxygenases Pathway interactions Perinatal mortality demographics Phagocytosis Phagolysosome Physiological Production Proteins RNA Interference Recycling Regulation Reticuloendothelial System Role Sickle Cell Anemia Spleen Technology Testing Toxic effect Transgenic Mice Variant auxotrophy cofactor cytotoxic design feeding genetic approach hemozoin in vivo inhibitor iron deficiency iron metabolism metal transporting protein 1 pharmacologic prevent protein complex response senescence synthetic lethal interaction trafficking transcriptome sequencing

项目摘要

The long-term goals of this proposal are to define heme transport and recycling in iron metabolism. Iron deficiency is the most common nutritional disorder in the world. The most common clinical manifestation of iron deficiency is anemia due to impaired hemoglobinization of red blood cells (RBCs). This is because over 70% of iron in the human body is used as heme in hemoglobin production. In healthy adults, about 90% of body iron is derived from recycled heme-iron. Each day, reticuloendothelial system (RES) macrophages recycle heme-iron by ingesting almost 5 million senescent or damaged RBCs per second; the bone marrow utilizes this recycled iron to produce new RBCs. As a consequence genetic defects in macrophage iron recycling result in anemia. Despite the importance of heme in iron recycling, the pathways responsible for heme transport and trafficking in RES macrophages remain poorly understood. After erythrophagocytosis, the iron is enzymatically released from heme by heme oxygenases (HMOX1) in the cytosol. This iron can either be stored in ferritin (FTH1) or exported out of the cell by ferroportin (FPN1) to be reutilized for new RBC production in the bone marrow. Consequently, genetic disruption in HMOX1, FPN1, and FTH1 – steps in the heme-iron recycling pathway – causes embryonic lethality in mice. We identified the first eukaryotic heme importer/transporter, HRG1 and showed that it is essential for transporting heme from the macrophage phagolysosome into the cytoplasm in macrophages. Our recent studies show that HRG1-deficient mice are viable even though they are incapable of recycling heme-iron and accumulate 10-fold excess heme within macrophages. The mice are tolerant to heme toxicity because they sequester heme inside lysosomes, which become 10-100 times larger than normal, by forming hemozoin - large multimeric heme crystals heretofore only identified in blood-feeding organisms to detoxify heme. Heme tolerance requires a fully-operational heme degradation pathway as haploinsufficiency of HMOX1 combined with HRG1 deficiency causes perinatal lethality, demonstrating a synthetic lethal interaction. Our exciting results suggest the existence of a previously unanticipated pathway for heme detoxification and tolerance in mammals. The studies in this proposal are designed to uncover the molecular basis of HRG1-mediated heme tolerance. We will test the hypotheses that heme tolerance is conferred by the coordinated regulation of heme transport by HRG1 and its genetic and physical interactions with heme degradation and additional components of the heme trafficking machinery. We will utilize (a) a genetic approach to elucidate the regulatory mechanisms of hemozoin formation and heme tolerance; and (b) a cell biological approach to identify the mechanisms for the synthetic lethal interactions between HRG1 and HMOX1. Our goals are to acquire a deep understanding for the molecular basis for heme trafficking and recycling and its role in heme tolerance in mammals.

该提案的长期目标是定义铁代谢中的血红素运输和再循环。缺铁是世界上最常见的营养性疾病，缺铁最常见的临床表现是红细胞血红蛋白化受损导致的贫血。这是因为人体中超过 70% 的铁在血红蛋白生产中被用作血红素，每天大约 90% 的身体铁来自回收的血红素铁。网状内皮系统 (RES) 巨噬细胞每秒摄取近 500 万个衰老或受损的红细胞来回收血红素铁；骨髓利用这种回收的铁来产生新的红细胞，尽管如此，巨噬细胞铁回收的遗传缺陷仍会导致贫血。对于血红素在铁回收中的作用，RES 巨噬细胞中负责血红素运输和运输的途径仍然知之甚少。通过细胞质中的血红素加氧酶 (HMOX1) 从血红素中酶促释放，这种铁可以储存在铁蛋白 (FTH1) 中，也可以通过铁转运蛋白 (FPN1) 输出到细胞外，以便在骨髓中重新利用以产生新的红细胞。 HMOX1、FPN1 和 FTH1（血红素-铁循环途径中的步骤）的基因破坏导致小鼠胚胎死亡。我们最近的研究表明，HRG1 缺陷的小鼠即使无法回收血红素铁并积累 10，也能存活。小鼠对血红素毒性具有耐受性，因为它们将血红素隔离在溶酶体中，溶酶体变成了溶酶体。比正常大 10-100 倍，通过形成疟原虫色素 - 迄今为止仅在食血生物中发现的大型多聚血红素晶体来解毒血红素，血红素耐受性需要完全可操作的血红素降解途径，因为 HMOX1 的单倍体不足与 HRG1 缺陷相结合会导致围产期死亡。我们令人兴奋的结果表明，哺乳动物中存在以前未预料到的血红素解毒和耐受途径。本提案中的研究旨在揭示 HRG1 介导的血红素耐受性的分子基础，我们将检验这样的假设：血红素耐受性是由 HRG1 血红素运输的协调调节及其与血红素降解和其他成分的遗传和物理相互作用赋予的。我们将利用（a）遗传学方法来阐明疟原虫色素形成和血红素耐受性的调节机制；以及（b）细胞生物学方法来确定HRG1和HRG1之间合成致死相互作用的机制。我们的目标是深入了解血红素运输和回收的分子基础及其在哺乳动物血红素耐受性中的作用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular Mechanisms of Iron and Heme Metabolism.

DOI：
10.1146/annurev-nutr-062320-112625
发表时间：
2022-08-22
期刊：
Annual review of nutrition
影响因子：
8.9
作者：
通讯作者：

Normal Iron Homeostasis Requires the Transporter SLC48A1 for Efficient Heme-Iron Recycling in Mammals.

DOI：
10.3389/fgeed.2020.00008
发表时间：
2020
期刊：
Frontiers in genome editing
影响因子：
0
作者：
Simmons WR;Wain L;Toker J;Jagadeesh J;Garrett LJ;Pek RH;Hamza I;Bodine DM
通讯作者：
Bodine DM

HRG-9 homologues regulate haem trafficking from haem-enriched compartments.

HRG-9 同源物调节来自富含血红素区室的血红素运输

DOI：
10.1038/s41586-022-05347-z
发表时间：
2022-10
期刊：
NATURE
影响因子：
64.8
作者：
Sun, Fengxiu;Zhao, Zhenzhen;Willoughby, Mathilda M.;Shen, Shuaiqi;Zhou, Yu;Shao, Yiyan;Kang, Jing;Chen, Yongtian;Chen, Mengying;Yuan, Xiaojing;Hamza, Iqbal;Reddi, Amit R.;Chen, Caiyong
通讯作者：
Chen, Caiyong

One ring to bring them all and in the darkness bind them: The trafficking of heme without deliverers.

DOI：
10.1016/j.bbamcr.2020.118881
发表时间：
2021-01
期刊：
Biochimica et biophysica acta. Molecular cell research
影响因子：
0
作者：
Chambers IG;Willoughby MM;Hamza I;Reddi AR
通讯作者：
Reddi AR

Heme oxygenase-2 (HO-2) binds and buffers labile ferric heme in human embryonic kidney cells.

DOI：
10.1016/j.jbc.2021.101549
发表时间：
2022-03
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Hanna DA;Moore CM;Liu L;Yuan X;Dominic IM;Fleischhacker AS;Hamza I;Ragsdale SW;Reddi AR
通讯作者：
Reddi AR