The Role of Oxyglutamate Carrier in Cerebral Ischemia-Reperfusion Injury

Academic Background

Cerebral ischemia-reperfusion injury (I/R) is a significant issue in the treatment of ischemic stroke. Although rapid blood flow restoration through thrombectomy and intravenous rt-PA (recombinant tissue plasminogen activator) administration can effectively treat ischemic stroke, these therapies may lead to reperfusion injury, further exacerbating neuronal death. The pathological process of cerebral ischemia-reperfusion injury is complex, involving neuronal death, inflammatory responses, excessive production of reactive oxygen species (ROS), disruption of the blood-brain barrier, and impairment of neuronal function. Among these, mitochondrial dysfunction is considered a key factor leading to neuronal death, including reduced energy homeostasis, excessive ROS generation, and the release of apoptotic factors.

Oxyglutamate Carrier (OGC, also known as SLC25A11) is an important carrier protein on the inner mitochondrial membrane responsible for transporting metabolites from the cytoplasm into the mitochondria. The role of OGC has been studied in various pathological conditions, but its specific role in cerebral ischemia-reperfusion injury remains unclear. This study aims to explore the role of OGC in cerebral ischemia-reperfusion injury and its mechanisms, particularly its potential to alleviate brain damage by regulating mitochondrial function.

Source of the Paper

This paper was co-authored by Wenhao Liu, Xin Liu, Min Liu, Rui Zhao, Zhiyuan Zhao, Jingrui Xiao, Dongdong Wan, Qi Wan, and Rui Xu. The authors are affiliated with the Department of Interventional Radiology at the Affiliated Hospital of Qingdao University, Qingdao University Medical College, and the People’s Hospital of Rizhao in China. The paper was published in 2025 in the European Journal of Neuroscience with the DOI 10.1111/ejn.16659.

Research Process and Results

1. Expression Changes of OGC in Cerebral Ischemia-Reperfusion Injury

The study first investigated the expression changes of OGC in cerebral ischemia-reperfusion injury using a mouse model. Researchers performed transient middle cerebral artery occlusion (tMCAO) surgery on C57BL/6 mice to simulate cerebral ischemia-reperfusion injury. Through Western blot and immunofluorescence staining, researchers found that OGC protein expression was significantly upregulated after reperfusion, peaking at 12 hours post-reperfusion. This result suggests that OGC may play a protective role in cerebral ischemia-reperfusion injury.

2. The Impact of OGC Inhibition on Neuronal Death

To further explore the function of OGC, researchers used an oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro to simulate cerebral ischemia-reperfusion injury. By using the OGC inhibitor phenylsuccinic acid (PSA), researchers found that inhibiting OGC significantly increased neuronal death after OGD/R treatment. Additionally, through CCK-8 assays and immunofluorescence staining, researchers confirmed that inhibiting OGC reduced neuronal viability and increased the proportion of neuronal death.

3. The Role of OGC in Mitochondrial Function

OGC is a metabolite transporter on the inner mitochondrial membrane responsible for transporting glutathione (GSH) from the cytoplasm into the mitochondria. Researchers found through immunofluorescence staining that OGC colocalized with mitochondrial markers, indicating that OGC is primarily located within the mitochondria. Further studies showed that inhibiting OGC increased mitochondrial ROS levels and decreased ATP production after OGD/R treatment. These results suggest that OGC protects neurons from ischemia-reperfusion injury by regulating mitochondrial GSH transport, reducing ROS accumulation, and maintaining ATP production.

4. The Reversal Effect of GSH Supplementation on OGC Inhibition

To validate the hypothesis that OGC exerts its protective role through GSH transport, researchers supplemented GSH in vitro. The results showed that GSH supplementation reversed the increased neuronal death caused by OGC inhibition and restored ATP production. Furthermore, GSH supplementation reduced mitochondrial ROS accumulation, further confirming the mechanism by which OGC maintains mitochondrial function through GSH transport.

5. In Vivo Validation of OGC’s Protective Role

In in vivo experiments, researchers validated the protective role of OGC using the tMCAO model. The results showed that inhibiting OGC significantly increased brain infarct volume and worsened neurological deficits. However, GSH supplementation alleviated the brain infarction and neurological deficits caused by OGC inhibition. These results further support the conclusion that OGC alleviates cerebral ischemia-reperfusion injury through GSH transport.

Conclusions and Significance

This study found that OGC plays a crucial protective role in cerebral ischemia-reperfusion injury. By promoting the transport of GSH from the cytoplasm to the mitochondria, OGC reduces mitochondrial ROS accumulation and maintains ATP production, thereby protecting neurons from ischemia-reperfusion injury. This discovery not only reveals a new mechanism of OGC in cerebral ischemia-reperfusion injury but also provides a new target for developing therapeutic strategies against cerebral ischemia-reperfusion injury.

Research Highlights

1. New Role of OGC in Cerebral Ischemia-Reperfusion Injury: This study is the first to reveal the protective role of OGC in cerebral ischemia-reperfusion injury, particularly its mechanism of maintaining mitochondrial function through GSH transport.
2. Reversal Effect of GSH Supplementation: The study confirmed that GSH supplementation can reverse the increased neuronal death and mitochondrial dysfunction caused by OGC inhibition, offering new insights for clinical treatment.
3. Integration of In Vitro and In Vivo Experiments: The study comprehensively validated the protective role of OGC and its mechanisms by combining in vitro OGD/R models and in vivo tMCAO models.

Other Valuable Information

The experimental design of this study is rigorous, with robust data support, particularly in the regulation of mitochondrial function, which holds significant scientific value. Additionally, the study provides evidence for OGC as a potential therapeutic target, laying the foundation for future clinical research.

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Through this study, we have not only deepened our understanding of the mechanisms of cerebral ischemia-reperfusion injury but also provided important theoretical foundations for developing new therapeutic strategies. As a key regulator of mitochondrial function, OGC holds promise as an important target for treating cerebral ischemia-reperfusion injury in the future.