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

  • Cell Metab. 2024 Jun 14:S1550-4131(24)00192-X. doi: 10.1016/j.cmet.2024.05.016.
Jian Zhou  1 ,  Lifang Zhang  1 ,  Jianhua Peng  2 ,  Xianhui Zhang  3 ,  Fan Zhang  1 ,  Yuanyuan Wu  3 ,  An Huang  3 ,  Fengling Du  4 ,  Yuyan Liao  5 ,  Yijing He  3 ,  Yuke Xie  3 ,  Long Gu  3 ,  Chenghao Kuang  3 ,  Wei Ou  6 ,  Maodi Xie  6 ,  Tianqi Tu  5 ,  Jinwei Pang  5 ,  Dingkun Zhang  7 ,  Kecheng Guo  3 ,  Yue Feng  8 ,  Shigang Yin  9 ,  Yang Cao  10 ,  Tao Li  11 ,  Yong Jiang  12
Affiliations
  • 1. Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Sichuan Clinical Research Center for Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 2. Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou 646000, China; Academician (Expert) Workstation of Sichuan Province, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 3. Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 4. Department of Neonatology, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 5. Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 6. Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 7. Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 8. Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Department of Nuclear Medicine, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 9. Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou 646000, China; Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 10. Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China; School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: [email protected].
  • 11. Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 12. Department of Neurosurgery, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou 646000, China; Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: [email protected].
PMID: 38906140 DOI: 10.1016/j.cmet.2024.05.016
Abstract

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.

Keywords
LRP1; astrocytes; ischemic stroke; lactate; mitochondria transfer; neurons.
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