Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation by Jian Zhou, Lifang Zhang,Jianhua Peng, ..., Yang Cao, Tao Li,Yong Jiang ISBN 101016/JCMET202405016 instant download

Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation by Jian Zhou, Lifang Zhang,Jianhua Peng, ..., Yang Cao, Tao Li,Yong Jiang ISBN 101016/JCMET202405016 instant download

SUMMARYLow-density lipoprotein receptor-related protein-1 (LRP1) is an endocytic/signaling cell-surface receptorthat regulates diverse cellular functions, including cell survival, differentiation, and proliferation. LRP1 hasbeen 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 reducinglactate production and ADP-ribosylation factor 1 (ARF1) lactylation. In astrocytes, LRP1 suppressed glucoseuptake, glycolysis, and lactate production, leading to reduced lactylation of ARF1. Suppression of astrocyticLRP1 reduced mitochondria transfer into damaged neurons and worsened ischemia-reperfusion injury in amouse 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 astrocyticmitochondria. These findings reveal a protective role of LRP1 in brain ischemic stroke by enabling mitochondria-mediated astrocyte-neuron crosstalk.