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：发展神经元具有高铁的要求，以支持其新陈代谢，生长和 分化。然而，游离铁可以产生氧化应激并具有细胞毒性。避免神经系统损害 铁缺乏症（ID）和过载，必须严格调节神经元铁水平。铁蛋白蛋白络合物发挥 通过存储未立即使用的铁来确定细胞内铁的可用性的关键作用。在时间 高铁的需求（例如开发），必须控制铁蛋白铁的释放以防止ID。铁毒素， 铁从铁蛋白释放并传递到高铁需求（例如线粒体）的过程， 核受体共激活因子4（NCOA4）是 通过选择性将铁蛋白引导到溶酶体来引发铁蛋白铁的动员的特定货物接收器 自噬。铁毒素对于维持线粒体血红素所需的铁的供应至关重要 在开发RBC中。目前尚无关于NCOA4或铁蛋白磷在神经元期间的作用的数据 开发，导致我们对铁蛋白中储存的铁的释放的理解有很大的差距 在这个高度铁敏感的过程中受到调节。神经元毒素的失调可能导致严重 铁不足或超负荷具有重大的临床影响。该提案重点介绍了早期ID，因为 它在世界各地都普遍，并永久损害神经行为功能（例如，学习和 记忆）。 ID在发展中的海马神经元内有很大一部分 学习/记忆的定义。在这种神经元亚型中发现的铁蛋白铁调节的基本原理将 可能适用于所有快速发育的神经元。我们假设这是类似于RBC期间的铁处理 开发，通过NCOA4介导的铁蛋白噬菌释放的铁形成了必不可少的铁池 用于正常的神经元发育和功能。 AIM 1使用我们独特的慢性早期体外模型 海马神经元ID测试最佳神经元是否需要NCOA4和铁毒素 通过调节铁的可用性开发。我们假设NCOA4的损失会破坏神经元铁 稳态和损害关键神经发育过程（即线粒体呼吸，神经元树突 和突触形成）。 AIM 2将AIM 1的体外发现转换为体内大脑，以揭示 NCOA4和铁毒素在调节海马神经元铁中的发育依赖性作用 利用率。我们假设NCOA4介导的铁毒素提供了铁的来源 从铁存储到利用的产后转换以及限制神经元铁供应时（即ID）。我们将 使用两种独特的海马特异性转基因小鼠系进行测试，这些小鼠线模拟神经元铁 吸收（SLC11A2 KO）或存储（NCOA4 KO）。拟议研究的发现将改变当前的范例 关于在开发过程中如何控制神经元铁稳态的方式，开辟了大量新研究 有潜力为常见的铁相关脑疾病提供新的治疗策略的途径。

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