METTL14通过m6A修饰FDX1 mRNA促进脑缺血再灌注损伤海马神经元铜突起。

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-08-05 DOI:10.1016/j.brainresbull.2025.111504

Wanqiu Ding, Hongmei Gao, Ruijia Liu, Hanshu Zhao, Sihan Liu, Jinru Shen, Xinyue Zhao, Yuanqi Xu, Zhongling Zhang

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引用次数: 0

摘要

目的：铜体畸形是铜浓度过高的结果，被认为是脑缺血再灌注损伤（IRI）的潜在治疗靶点。甲基转移酶是通过n6 -甲基腺苷（m6A）修饰铁氧还蛋白1 (FDX1) mRNA介导铜还原的关键调节剂。本研究旨在确定甲基转移酶样14 （methyltransferase-like 14, METTL14）是否通过m6A对FDX1 mRNA的修饰调控脑IRI中的cupropsis。方法：分别采用大脑中动脉闭塞/再灌注（MCAO/R）处理小鼠和氧糖剥夺/再氧处理小鼠海马原代神经元在体内和体外模拟脑IRI。通过敲低实验检测神经功能、脑梗死、海马CA1组织变化、神经元活力和铜突起，确定METTL14在脑IRI中的功能作用。通过过表达FDX1，证实了FDX1参与METTL14调控通路。结果：MCAO/R小鼠海马组织中METTL14表达增加。METTL14敲除可减少MCAO/R小鼠的神经功能缺损、梗死面积和海马CA1神经元铜突起。此外，海马CA1神经元铜突起的激活通过敲低METTL14部分避免了脑IRI的减轻。这些结果在体外研究中得到了重复。此外，机制研究表明，METTL14敲低通过m6A修饰降低FDX1 mRNA的稳定性，从而限制FDX1的表达。重要的是，FDX1过表达可以部分逆转METTL14敲低诱导的cuprotosis抑制。结论：本研究创新性地论证了METTL14敲低对脑IRI海马CA1神经元的神经保护作用是通过调控FDX1实现的，这可能有助于设计改善脑IRI的新疗法。

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METTL14 promotes hippocampal neuronal cuproptosis via m6A modification on FDX1 mRNA in cerebral ischemia-reperfusion injury

Objective

Cuproptosis, a consequence of excessively high copper concentrations, is considered a potential therapeutic target for cerebral ischemia-reperfusion injury (IRI). Methyltransferases are key modulators of cuproptosis through N6-methyladenosine (m⁶A) modification on ferredoxin 1 (FDX1) mRNA. This study aims to determine whether methyltransferase-like 14 (METTL14) regulates cuproptosis in cerebral IRI via m⁶A modification on FDX1 mRNA.

Methods

The middle cerebral artery occlusion/reperfusion (MCAO/R)-treated mice, and oxygen glucose deprivation/reoxygenation-treated mouse primary hippocampal neurons were used to mimic cerebral IRI in vivo and in vitro, respectively. The functional role of METTL14 in cerebral IRI was determined by examining neurological functions, cerebral infarction, hippocampal CA1 tissue changes, neuronal viability, and cuproptosis using knockdown experiments. The involvement of FDX1 in the METTL14 regulatory pathway was verified by overexpressing FDX1.

Results

METTL14 expression was increased in the hippocampal tissue of mice subjected to MCAO/R. METTL14 knockdown reduced neurological deficits, infarct size, and hippocampal CA1 neuronal cuproptosis in MCAO/R mice. Furthermore, activation of hippocampal CA1 neuronal cuproptosis partly averted the alleviation of cerebral IRI by METTL14 knockdown. These results were reproduced in in vitro studies. Furthermore, mechanistic studies revealed that METTL14 knockdown reduced the stability of FDX1 mRNA through m⁶A modification and consequently limited FDX1 expression. Importantly, FDX1 overexpression could partly reverse the cuproptosis inhibition induced by METTL14 knockdown.

Conclusion

Taken together, this research innovatively demonstrates the neuroprotective effect of METTL14 knockdown on hippocampal CA1 neurons in cerebral IRI via its regulation of FDX1, which might help design new therapies to improve cerebral IRI.

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.