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

Ischemic stroke is a severe neurological condition that can cause neuronal damage and dysfunction when the blood supply to the brain is interrupted. With the growing prevalence of risk factors such as hypertension, obesity, and diabetes, coupled with an aging population, the societal burden of ischemic stroke continues to rise.

In this context, the transfer of mitochondria between astrocytes and neuronal cells in the central nervous system warrants attention. It is significant to maintain the aerobic respiration and energy supply of neuronal cells, and interventions targeting mitochondrial transfer have shown promise in disease prevention and treatment. Therefore, further exploration is urgently needed to understand how astrocytes regulate mitochondrial transfer to alleviate ischemic stroke.

On June 14, 2024, Professor Jiang Yong from the Department of Neurosurgery at the Affiliated Hospital of Southwest Medical University, in collaboration with Professor Li Tao from West China Hospital of Sichuan University and Professor Cao Yang from the University of Science and Technology of China, published their latest research findings in the internationally renowned academic journal Cell Metabolism (IF: 27.7, five-year average IF: 31.2). The article, titled “Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation,” systematically elucidates the important regulatory role of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) in the transfer of mitochondria in astrocytes. It reveals for the first time the mechanism by which LRP1 modulates cellular metabolism to affect ARF1 lactylation, thereby regulating the transfer of mitochondria between astrocytes and neuronal cells.

Previous literature has reported that LRP1 is involved in the homeostatic regulation of the nervous system, with some results in preclinical studies. To explore the important regulatory role of LRP1 in the transfer of mitochondria in astrocytes, Professor Jiang Yong’s team used lentivirus transfection to construct primary astrocytes and cell lines with LRP1 knockdown. By centrifuging to collect mitochondria from the cell culture medium, they confirmed a significant reduction in the number of mitochondria in the medium after LRP1 deficiency, but its function was not significantly affected. Further oxygen-glucose deprivation (OGD) experiments confirmed that LRP1-mediated mitochondrial extrusion plays an important role in the process of astrocytes protecting neurons from injury. The team further found that the absence of LRP1 does not affect the previously reported signaling pathways, indicating that there may be a new mechanism in the process of LRP1 regulating the extrusion of mitochondria in astrocytes.

Further exploration of the new mechanism by which LRP1 regulates the extrusion of mitochondria in astrocytes, combing through previous literature reports, indicates that LRP1 is involved in the regulation of metabolic homeostasis in the central nervous system. To clarify the impact of LRP1 on astrocyte metabolism, research members confirmed through metabolomics combined with 13C isotope labeling that LRP1 is involved in regulating the glucose uptake of astrocytes, thereby affecting the production of lactate. They further confirmed that lactate metabolism regulated by LRP1 affects the process of mitochondrial extrusion in astrocytes. The team used immunoprecipitation and lactylation modification site antibodies to confirm that ARF1 Kla73 changed significantly after the absence of LRP1 and further clarified through point mutation intervention that the lactylation modification of ARF1 K73 is involved in regulating the extrusion of mitochondria in astrocytes. Subsequently, the team used an animal model, injected AAV to intervene in the expression of LRP1, and overexpressed the ARF1 lactylation modification mutant, verifying a decrease in the number of mitochondria derived from astrocytes in the cerebrospinal fluid of mice.

Next, the team established an animal model of cerebral ischemia (middle cerebral artery occlusion MCAO, suture-occluded method) to verify whether LRP1-induced mitochondrial transfer can protect against brain ischemic injury. The team used 7.0T magnetic resonance, behavioral assessment, and confocal microscopy to confirm the important role of the LRP1-ARF1 Kla73 axis in regulating the transfer of mitochondria in astrocytes. Finally, the team further verified their research findings with clinical samples from stroke patients.

(The authors used RWD MCAO suture to construct the MCAO model, and laser speckle blood flow imaging system to monitor cerebral blood flow changes)

In summary, the study reveals a new mechanism by which astrocytes regulate mitochondrial transfer through the LRP1 – ARF1 axis to alleviate ischemic stroke, providing a new target for the treatment of ischemic stroke. It provides direction for further exploration of the specific molecular mechanism by which LRP1 regulates ARF1 lactylation and how to translate this finding into clinical treatment strategies.

What does RWD offer to this study

This work delves into the role of the molecule LRP1 in astrocytes, providing a new perspective on understanding the cellular mechanisms of ischemic stroke by exploring its role in facilitating the transfer of mitochondria to neurons. In this study, researchers used RWD’s laser speckle blood flow imaging system, MCAO suture, single-cell suspension preparation instrument, and other equipment and reagents, providing support for the smooth progress of the experiment.

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