COMM domain containing 4 inhibits hephaestin and ferroportin to enhance neuronal ferroptosis by disturbing the Cu-Fe balance in amyotrophic lateral sclerosis

IF 2.7 4区医学 Q3 NEUROSCIENCES

Brain Research Pub Date : 2025-05-17 DOI:10.1016/j.brainres.2025.149707

Xingli Tan , Xiaoli Su , Ying Wang , Weiwei Liang , Di Wang , Di Huo , Hongyong Wang , Yan Qi , Wenmo Zhang , Ling Han , Dongmei Zhang , Ming Wang , Jing Xu , Shuyu Wang , Jing Wang , Honglin Feng

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引用次数: 0

Abstract

Dysregulation of copper and iron homeostasis contributes to the progression of amyotrophic lateral sclerosis (ALS), but the role and mechanism of COMM domain containing 4 (COMMD4) in ALS remains unclear. In this research, we showed that the expression of COMMD4 was upregulated in ALS cells and animal models. The increased COMMD4 induced neuronal ferroptosis by disrupting the Cu-Fe balance. Mechanistic studies indicated that COMMD4 inhibited ferroportin (FPN)-mediated neuronal iron efflux by inhibiting intracellular copper and hephaestin (HEPH). Our findings demonstrated that COMMD4 depletion exerts neuroprotective effects on ALS by increasing intracellular copper and activating HEPH/FPN pathway, rather than affecting the interaction between HEPH and FPN. Targeting COMMD4 and its downstream signaling pathways may offer potential therapeutic avenues for ALS.

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含有4的COMM结构域通过扰乱肌萎缩性侧索硬化症的Cu-Fe平衡，抑制hephaestin和ferroportin，从而增强神经元铁下垂。

铜和铁稳态失调有助于肌萎缩性侧索硬化症（ALS）的进展，但COMM结构域4 （COMMD4）在ALS中的作用和机制尚不清楚。在本研究中，我们发现COMMD4在ALS细胞和动物模型中表达上调。COMMD4升高通过破坏Cu-Fe平衡诱导神经元铁下垂。机制研究表明COMMD4通过抑制细胞内铜和hephaestin （HEPH）抑制铁转运蛋白（FPN）介导的神经元铁外排。我们的研究结果表明，COMMD4缺失通过增加细胞内铜和激活HEPH/FPN通路来发挥神经保护作用，而不是影响HEPH和FPN之间的相互作用。靶向COMMD4及其下游信号通路可能为ALS提供潜在的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research 医学-神经科学

CiteScore

5.90

自引率

3.40%

发文量

268

审稿时长

47 days

期刊介绍： An international multidisciplinary journal devoted to fundamental research in the brain sciences. Brain Research publishes papers reporting interdisciplinary investigations of nervous system structure and function that are of general interest to the international community of neuroscientists. As is evident from the journals name, its scope is broad, ranging from cellular and molecular studies through systems neuroscience, cognition and disease. Invited reviews are also published; suggestions for and inquiries about potential reviews are welcomed. With the appearance of the final issue of the 2011 subscription, Vol. 67/1-2 (24 June 2011), Brain Research Reviews has ceased publication as a distinct journal separate from Brain Research. Review articles accepted for Brain Research are now published in that journal.