전한울
2024년 9월 3일
- -Astrocyte의 LRP1은 healthy 미토콘드리아를 astrocyte에서 neuron으로 transfer 할수 있음
-LRP1은 astrocyte에서 ARF1의 lactylation을 감소시켜 미토콘드리아의 transfer를 매개함
-LRP1의 매개에 의한 미토콘드리아 trasnfer는 ischemic reperfusion injury 의 손상을 완화시킴
DOI: 10.1016/j.cmet.2024.05.016
Summary
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.
