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Deciphering a Novel Mechanism for Iron-sensing at Mitochondria and Its Role in Erythropoiesis

破译线粒体铁感应的新机制及其在红细胞生成中的作用

基本信息

批准号：
10560352
负责人：
Shiori Sekine
金额：
$ 53万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560352
关键词：
Address Anemia Binding Binding Proteins Biological Cell Death Cell Line Cell model Cell physiology Cells Cessation of life Characteristics Communication Cytosol Data Death Domain Defect Disease Enhancers Equilibrium Erythrocytes Erythroid Erythroid Cells Erythropoiesis Exhibits Globin Goals Heme Hemoglobin Hemoglobinopathies Homeostasis Human In Vitro Inherited Iron Iron Regulatory Protein 1 Iron deficiency anemia Knockout Mice Life Lung Mammals Mass Spectrum Analysis Mediating Messenger RNA Mitochondria Mitochondrial Matrix Mitochondrial Proteins Modeling Molecular Molecular Biology Techniques Monitor Mus Organelles Organism Outer Mitochondrial Membrane Oxygen Pathway interactions Peptide Hydrolases Phenocopy Phenotype Phosphotransferases Play Porphyrins Protein Import Proteins Proteomics Regulation Reporting Research Proposals Role Signal Transduction Signaling Molecule Stress Sulfur System Testing Transcriptional Activation Transition Elements Translations Work attenuation biological adaptation to stress cofactor erythroid differentiation erythroleukemic cell heme 1 heme a in vivo inhibitor insight iron deficiency iron metabolism novel novel therapeutic intervention progenitor proteostasis response success therapeutic target transcription factor

项目摘要

Abstract Iron is essential for eukaryotic life acting as a biological catalytic center of various proteins involved in diverse cellular processes. In human, the greatest portion of total body iron can be found as heme (an iron-containing porphyrin), the majority of which is in red blood cells in the form of hemoglobin that carries oxygen from the lung to the whole body. An imbalanced supply of iron, heme, or globin proteins leads to the shortage of functional hemoglobin, resulting in various types of anemia. Insufficient iron supply is particularly critical, as it causes so-called iron deficiency anemia, the most common form of anemia worldwide. Understanding the regulation of hemoglobin synthesis in erythroid cells is important for developing novel therapeutic strategies to treat red blood cell disorders. However, the molecular mechanisms underlying this regulation have not been fully understood. This research proposal aims to uncover these mechanisms by delineating iron-dependent regulation of the mitochondrial protein DELE1. It has been recently shown that in response mitochondrial stress, DELE1 acts as an activator of the stress responsive kinase HRI, a well-established regulator of globin translation in the erythroid lineage. Preliminary results in this proposal indicate that DELE1 activates HRI in iron-depleted cells by a novel mechanism distinct from previously reported mechanisms. These results also suggest the mitochondrial import of DELE1 and its subsequent protein stability is strictly regulated by intracellular iron availability. Thus, this proposal will test the hypothesis that iron-dependent mitochondrial proteostasis and import regulation of DELE1 are the core components of a novel mitochondrial iron-sensing pathway regulating the HRI-mediated stress response. The mechanisms how mitochondrial DELE1 activates cytosolic HRI in iron deficient conditions will be investigated using multiple advanced molecular biology techniques, in combination with mass spectrometry-based proteomics. The involvement of the DELE1-HRI pathway in terminal erythroid differentiation will be addressed using a murine erythroleukemia (MEL) cell line, an established erythroid cellular model, as well as a recently generated DELE1 deficient mouse. The success of the proposed work will provide novel molecular insights into mitochondrial iron-sensing and reveal the critical molecular players that are responsible for the communication between mitochondria and the cytosol in order to maintain cellular homeostasis under iron-deficient conditions.

摘要