MCU knockdown mitigates post-stroke neuroinflammation through SLC33A1-mediated reduction of NR4A1 acetylation

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2026-01-01 Epub Date: 2025-12-05 DOI:10.1016/j.brainresbull.2025.111676

Zhou Zhou , Lijuan Liu , Yicong Zhou , Yan Yan , Binbin Wang , Xin Lv , Jin Qin , Zongyu Liu , Yongyang Liu , Zihou Meng , Long You , Minghan Zhao , Xuelin Wang , Guanhui Pei , Ge Bai , Chaoyue Meng , Xiaoyun Liu

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引用次数: 0

Abstract

Post-stroke neuroinflammation remains a critical contributor to disease progression and recovery. Building on our prior finding that knockdown of the mitochondrial calcium uniporter (MCU) confers protection against ischemic injury, and guided by transcriptomic evidence implicating NR4A1. We investigated the underlying mechanism using a mouse middle cerebral artery occlusion model and a microglial oxygen–glucose deprivation/reoxygenation model, coupled with protein interaction and acetylation assays. MCU knockdown significantly reduced infarct volume, improved neurological scores, and suppressed microglial cytokine expression. Mechanistically, MCU did not directly interact with NR4A1 under our conditions; immunoprecipitation–mass spectrometry identified SLC33A1 as a novel MCU interactor. Reduced MCU levels led to decreased SLC33A1 expression, diminished NR4A1 acetylation, and attenuated inflammatory outputs, whereas elevating global acetylation blunted these effects. Collectively, our findings demonstrate that MCU knockdown mitigates cerebral infarction and suppresses microglial inflammation via SLC33A1-dependent control of NR4A1 acetylation, supporting MCU knockdown as a promising strategy for post-stroke anti-inflammatory intervention.

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MCU敲低可通过slc33a1介导的NR4A1乙酰化降低减轻脑卒中后神经炎症

中风后神经炎症仍然是疾病进展和恢复的关键因素。基于我们之前的发现，线粒体钙单转运蛋白（MCU）的敲低可以保护缺血性损伤，并在NR4A1转录组学证据的指导下。我们通过小鼠大脑中动脉闭塞模型和小胶质氧-葡萄糖剥夺/再氧化模型，结合蛋白质相互作用和乙酰化实验研究了其潜在机制。MCU敲除显著减少梗死体积，改善神经学评分，抑制小胶质细胞因子表达。机制上，在我们的条件下，MCU不直接与NR4A1相互作用；免疫沉淀-质谱法鉴定SLC33A1为一种新型MCU相互作用物。MCU水平降低导致SLC33A1表达减少，NR4A1乙酰化减少，炎症输出减弱，而整体乙酰化升高则减弱了这些作用。总之，我们的研究结果表明，MCU敲低可减轻脑梗死，并通过slc33a1依赖的NR4A1乙酰化控制抑制小胶质细胞炎症，支持MCU敲低作为卒中后抗炎干预的一种有希望的策略。

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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.