西南医科大学姜勇、四川大学李涛和中国科学技术大学曹洋研究组合作的最新研究发现，星形胶质细胞低密度脂蛋白受体相关蛋白-1（LRP1）通过抑制ARF1乳酸化使线粒体转移到神经元并缓解脑缺血中风。该项研究成果发表在2024年6月20日出版的《细胞-代谢》上。

研究人员发现星形胶质细胞LRP1通过减少乳酸产生和ADP核糖基化因子1（ARF1）的乳酸化来促进线粒体由星形胶质细胞到神经元的转移。在星形胶质细胞中，LRP1抑制葡萄糖摄取、糖酵解和乳酸产生，从而导致ARF1乳酸化减少。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，研究还检测了人中风患者的乳酸水平。中风患者脑脊液（CSF）中乳酸升高，并与星形胶质细胞线粒体成反比。这些发现揭示了LRP1通过调控线粒体的星形胶质细胞-神经元串联在脑缺血中风中起保护作用。

据介绍，LRP1是一种内分泌/信号细胞表面受体，可调节细胞包括存活、分化和增殖等多种功能。先前认为LRP1与神经退行性疾病的发病机制有关，但其功能存在争议。因此，尚不清楚LRP1是否以及如何维持大脑稳态的。

附：英文原文

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

Author: 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, Shigang Yin, Yang Cao, Tao Li, Yong Jiang

Issue&Volume: 2024-06-20

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

DOI: 10.1016/j.cmet.2024.05.016

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00192-X