星形胶质细胞 LRP1 通过抑制 ARF1 乳化作用使线粒体转移到神经元并缓解脑缺血中风

IF 27.7 1区 生物学 Q1 CELL BIOLOGY
Jian Zhou, Lifang Zhang, Jianhua Peng, Xianhui Zhang, Fan Zhang, Yuanyuan Wu, An Huang, Fengling Du, Yuyan Liao, Yijing He, Yuke Xie, Long Gu, Chenghao Kuang, Wei Ou, Maodi Xie, Tianqi Tu, Jinwei Pang, Dingkun Zhang, Kecheng Guo, Yue Feng, Yong Jiang
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引用次数: 0

摘要

低密度脂蛋白受体相关蛋白-1(LRP1)是一种内细胞/信号细胞表面受体,可调节细胞的多种功能,包括细胞存活、分化和增殖。LRP1 以前曾被认为与神经退行性疾病的发病机制有关,但其功能并不一致。因此,LRP1 是否以及如何维持大脑稳态仍有待明确。在这里,我们报告了星形胶质细胞 LRP1 通过减少乳酸的产生和 ADP 核糖基化因子 1(ARF1)的乳酸化来促进星形胶质细胞到神经元线粒体的转移。在星形胶质细胞中,LRP1抑制了葡萄糖摄取、糖酵解和乳酸产生,从而导致ARF1的乳化减少。在缺血性中风小鼠模型中,抑制星形胶质细胞 LRP1 会减少线粒体向受损神经元的转移,加重缺血再灌注损伤。此外,我们还检测了人类中风患者的乳酸水平。中风患者脑脊液(CSF)乳酸升高,并与星形胶质细胞线粒体成反比。这些发现揭示了 LRP1 通过线粒体介导的星形胶质细胞-神经元串联在脑缺血中风中的保护作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation

Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation

Low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytic/signaling cell-surface receptor that regulates diverse cellular functions, including cell survival, differentiation, and proliferation. LRP1 has been previously implicated in the pathogenesis of neurodegenerative disorders, but there are inconsistencies in its functions. Therefore, whether and how LRP1 maintains brain homeostasis remains to be clarified. Here, we report that astrocytic LRP1 promotes astrocyte-to-neuron mitochondria transfer by reducing lactate production and ADP-ribosylation factor 1 (ARF1) lactylation. In astrocytes, LRP1 suppressed glucose uptake, glycolysis, and lactate production, leading to reduced lactylation of ARF1. Suppression of astrocytic LRP1 reduced mitochondria transfer into damaged neurons and worsened ischemia-reperfusion injury in a mouse model of ischemic stroke. Furthermore, we examined lactate levels in human patients with stroke. Cerebrospinal fluid (CSF) lactate was elevated in stroke patients and inversely correlated with astrocytic mitochondria. These findings reveal a protective role of LRP1 in brain ischemic stroke by enabling mitochondria-mediated astrocyte-neuron crosstalk.

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来源期刊
Cell metabolism
Cell metabolism 生物-内分泌学与代谢
CiteScore
48.60
自引率
1.40%
发文量
173
审稿时长
2.5 months
期刊介绍: Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.
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