NCOA4-Mediated Ferritinophagy in Iron-Dependent Brain Development

铁依赖性大脑发育中 NCOA4 介导的铁蛋白自噬

• 批准号: 10456911
• 负责人: Thomas W. Bastian
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-27 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456911
• 关键词: Acute; Adult; Affect; Anabolism; Autophagocytosis; Behavior; Brain; Brain Diseases; Buffers; Cellular Neurobiology; Child; Chronic; Clinical; Cognitive; Cognitive deficits; Data; Dendrites; Development; Education; Embryo; Energy Metabolism; Erythrocytes; Ferritin; Functional disorder; Growth; Health; Heme; Hemoglobin; Hippocampus (Brain); Homeostasis; Human; Impairment; In Vitro; Iron; Iron Overload; Knockout Mice; Learning; Life; Longevity; Lysosomes; Mediating; Memory; Memory impairment; Mental Health; Mental disorders; Metabolic; Metabolism; Mitochondria; Modeling; Morphology; Motor Skills; Mus; Neonatal; Nervous System Trauma; Neurologic; Neurons; Newborn Infant; Nuclear Receptor Coactivator 4; Occupations; Oxidative Stress; Play; Pregnant Women; Probability; Process; Proteins; Receptor Cell; Recording of previous events; Regulation; Research; Respiration; Risk; Rodent; Role; SLC11A2 gene; Site; Societies; Source; Structure; Synaptic plasticity; System; Testing; Time; Transgenic Mice; Translating; Up-Regulation; age related; cost; critical period; cytotoxic; cytotoxicity; extracellular; fetal; hippocampal pyramidal neuron; in vitro Model; in vivo; iron deficiency; neonate; neurobehavioral; neuron development; novel; novel therapeutic intervention; postnatal; prevent; protein complex; psychosocial; public health relevance; receptor; stem; synaptogenesis; uptake

ABSTRACT: Developing neurons have high iron requirements to support their metabolism, growth, and differentiation. Yet, free iron can produce oxidative stress and be cytotoxic. To avoid neurological damage from iron deficiency (ID) and overload, neuronal iron levels must be tightly regulated. Ferritin protein complexes play a critical role in regulating intracellular iron availability by storing iron that is not immediately used. During times of high iron demand (e.g., development), ferritin iron release must be controlled to prevent ID. Ferritinophagy, the process by which iron is released from ferritin and delivered to sites of high iron demand (e.g., mitochondria), was recently characterized in developing red blood cells (RBCs). Nuclear receptor coactivator 4 (NCOA4) is the specific cargo receptor that initiates mobilization of ferritin iron by directing ferritin to lysosomes via selective autophagy. Ferritinophagy is critical for maintaining the supply of iron required for mitochondrial heme synthesis in developing RBCs. There are currently no data on the role of NCOA4 or ferritinophagy during neuron development, causing a significant gap in our understanding of how the release of iron stored in ferritin is regulated during this highly iron-sensitive process. Dysregulation of neuronal ferritinophagy could result in severe iron underload or overload with significant clinical ramifications. This proposal focuses on early-life ID because it is prevalent throughout the world and permanently impairs neurobehavioral function (e.g., learning and memory) in children. ID specifically within the developing hippocampal neuron accounts for a significant portion of the learning/memory deficits. Basic principles of ferritin iron regulation discovered in this neuronal subtype will likely apply to all rapidly developing neurons. We hypothesize that, similar to iron handling during RBC development, iron released through NCOA4-mediated ferritinophagy forms an iron pool that is that is essential for normal neuron development and function. Aim 1 uses our unique in vitro model of chronic early-life hippocampal neuronal ID to test whether NCOA4 and ferritinophagy are required for optimal neuronal development by regulating iron availability. We hypothesize that loss of NCOA4 will disrupt neuronal iron homeostasis and impair critical neurodevelopmental processes (i.e., mitochondrial respiration, neuronal dendrite and synapse formation). Aim 2 translates Aim 1’s in vitro findings to the in vivo brain to reveal the developmental age-dependent role of NCOA4 and ferritinophagy in regulating hippocampal neuron iron utilization. We hypothesize that NCOA4-mediated ferritinophagy provides a source of iron that is required during the postnatal switch from iron storage to utilization and when neuronal iron supply is restricted (i.e., ID). We will test this using two unique hippocampal-specific transgenic mouse lines that model disruptions to neuronal iron uptake (Slc11a2 KO) or storage (Ncoa4 KO). Findings from the proposed studies will shift the current paradigm of how neuronal iron homeostasis is controlled during development, opening up a wealth of new research avenues with the potential to inform new therapeutic strategies for common iron-related brain disorders.

摘要：发育中的神经元需要大量的铁，以支持其代谢、生长和生理功能

项目成果

Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells.

• DOI: 10.3389/fnut.2023.1054852
• 发表时间: 2023
• 期刊: FRONTIERS IN NUTRITION
• 影响因子: 5
• 作者: Bengson, Emily F.;Guggisberg, Cole A.;Bastian, Thomas W.;Georgieff, Michael K.;Ryu, Moon-Suhn
• 通讯作者: Ryu, Moon-Suhn