Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells.
Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells.
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DOI：
10.3389/fnut.2023.1054852
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发表时间：
2023
影响因子：
5
通讯作者：
Ryu, Moon-Suhn
中科院分区：
文献类型：
--
作者：
Bengson, Emily F.;Guggisberg, Cole A.;Bastian, Thomas W.;Georgieff, Michael K.;Ryu, Moon-Suhn
神经元需要铁来支持其代谢、生长和分化，但也容易受到铁诱导的氧化应激和细胞毒性的影响。铁蛋白是一种胞浆铁储存单位，介导细胞对铁传递波动的适应。NC0A4已被表征为促进从铁蛋白动员细胞内铁的选择性自噬货物受体。这个过程称为铁蛋白吞噬导致铁蛋白的降解和随后的铁释放到胞质溶胶中。在这里，我们表明，NCOA 4是重要的HT22小鼠海马神经元细胞系的适应细胞铁限制。此外，我们通过对NCOA 4缺陷的HT 22细胞的组学特征进行功能分析，确定了铁蛋白吞噬受损的病理生理学意义。NCOA4沉默损害铁蛋白周转，并且当细胞限制铁时具有细胞毒性。定量蛋白质组学鉴定了在HT22细胞中由NC0A4消耗产生的最突出的蛋白质应答中的IRP 2积累，这指示功能性铁缺乏。此外，细胞凋亡信号通路的蛋白质被那些响应于NCOA 4缺陷的蛋白质富集。NC0A4耗尽的转录组谱揭示神经元细胞死亡、神经元分化和神经元发育为受铁蛋白吞噬受损影响的潜在疾病和生物功能，特别是当铁被限制时。这些发现确定了NCOA 4介导的铁蛋白吞噬在HT22细胞维持铁稳态中的不可或缺的作用，以及其在控制神经发育和神经退行性疾病的遗传途径中的潜在意义。
Neurons require iron to support their metabolism, growth, and differentiation, but are also susceptible to iron-induced oxidative stress and cytotoxicity. Ferritin, a cytosolic iron storage unit, mediates cellular adaptation to fluctuations in iron delivery. NCOA4 has been characterized as a selective autophagic cargo receptor facilitating the mobilization of intracellular iron from ferritin. This process named ferritinophagy results in the degradation of ferritin and the consequent release of iron into the cytosol. Here we demonstrate that NCOA4 is important for the adaptation of the HT22 mouse hippocampal neuronal cell line to cellular iron restriction. Additionally, we determined the pathophysiological implications of impaired ferritinophagy via functional analysis of the omics profile of HT22 cells deficient in NCOA4. NCOA4 silencing impaired ferritin turnover and was cytotoxic when cells were restricted of iron. Quantitative proteomics identified IRP2 accumulation among the most prominent protein responses produced by NCOA4 depletion in HT22 cells, which is indicative of functional iron deficiency. Additionally, proteins of apoptotic signaling pathway were enriched by those responsive to NCOA4 deficiency. Transcriptome profiles of NCOA4 depletion revealed neuronal cell death, differentiation of neurons, and development of neurons as potential diseases and bio functions affected by impaired ferritinophagy, particularly, when iron was restricted. These findings identify an integral role of NCOA4-mediated ferritinophagy in the maintenance of iron homeostasis by HT22 cells, and its potential implications in controlling genetic pathways of neurodevelopment and neurodegenerative diseases.
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影响因子：
10.1
作者：
Nai A;Lidonnici MR;Federico G;Pettinato M;Olivari V;Carrillo F;Geninatti Crich S;Ferrari G;Camaschella C;Silvestri L;Carlomagno F
通讯作者：
Carlomagno F
铁蛋白铁调节剂PCBP1和NCOA4对发育中的红细胞中的细胞铁状态反应。
DOI：
10.1016/j.bcmd.2017.09.009
发表时间：
2018-03
期刊：
Blood cells, molecules & diseases
影响因子：
--
作者：
Ryu MS;Duck KA;Philpott CC
通讯作者：
Philpott CC
影响因子：
20.3
作者：
Das, Nupur K.;Jain, Chesta;Shah, Yatrik M.
通讯作者：
Shah, Yatrik M.
影响因子：
64.8
作者：
Mancias, Joseph D.;Wang, Xiaoxu;Gygi, Steven P.;Harper, J. Wade;Kimmelman, Alec C.
通讯作者：
Kimmelman, Alec C.
影响因子：
8
作者：
Andersen, Hjalte Holm;Johnsen, Kasper Bendix;Moos, Torben
通讯作者：
Moos, Torben