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Microglial SLC25A28 Deficiency Ameliorates the Brain Injury After Intracerebral Hemorrhage in Mice by Restricting Aerobic Glycolysis

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Abstract

The microglia overactivation-induced neuroinflammation is a significant cause of the brain injury after intracerebral hemorrhage (ICH). Iron homeostasis is crucial for microglia activation, but the mechanism and causality still need further study. This study aimed to explore the roles and mechanism of the mitochondrial iron transporter SLC25A28 in microglia activation after ICH. Intrastriatal injection of autologous blood was used to establish ICH model, and the neuroinflammation, iron metabolism and brain injuries were assessed in wildtype or microglia-specific SLC25A28 knockout mice after ICH. Mitochondria iron levels and microglial function were determined in SLC25A28 overexpressed or deleted microglia. The extracellular acidification rate (ECAR), lactate production, and glycolytic enzyme levels were used to determine aerobic glycolysis. The results showed that ICH stimulated mitochondrial iron overload, and synchronously upregulated the SLC25A28 expression. In vitro, SLC25A28 overexpression increased mitochondrial iron levels in microglia. Interestingly, microglial SLC25A28 deficiency ameliorated neuroinflammation, brain edema, blood–brain barrier injury and ethological alterations in mice after ICH. Mechanically, SLC25A28 deficiency inhibited microglial activation by restricting the aerobic glycolysis. Moreover, zinc protoporphyrin could reduce SLC25A28 expression and mitigated brain injury. SLC25A28 plays crucial roles in mitochondrial iron homeostasis and microglia activation after ICH, and it might be a potential therapeutic target for ICH.

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The data used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the colleagues in the Pathology Department (Xijing Hospital, Fourth Military Medical University) for their technical assistance.

Funding

This study was supported by the National Nature Science Foundation of China (No. 81972342, No. 82170589), Science Basic Research Plan in Shaanxi Province (No. 2020JZ-29, No. 2022JM-536.), and National Key R&D Project of China (2022YFA0806501).

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Author notes

  1. Ruili Han, Lei Liu and Yuying Wang These authors contributed equally to this study.

Authors and Affiliations

  1. State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi’an, Shaanxi, China

    Ruili Han, Lei Liu, Yuying Wang, Ruolin Wu, Ying Yang, Yuanlin Zhao, Lele Jian, Yuan Yuan, Yu Gu & Jing Ye

  2. Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, 710038, Xi’an, Shaanxi, China

    Ruili Han & Changjun Gao

  3. Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, 710038, Xi’an, Shaanxi, China

    Lijun Zhang

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  1. Ruili Han
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Contributions

Jing Ye, Changjun Gao, and Yu Gu designed the research and revised the manuscript. Ruili Han, Lei Liu, and Yuying Wang performed the experiments and drafted the manuscript. Ruolin Wu, Lele Jian and Ying Yang analysed the data. Yuanlin Zhao, Yuan Yuan and Lijun Zhang worked on the manuscript revision and technical assistance. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yu Gu, Changjun Gao or Jing Ye.

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The animal study protocol was approved and supervised by the Animal Ethics Committee and the Animal Care and Use Committee of the Fourth Military Medical University (IACUC-20230048).

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Han, R., Liu, L., Wang, Y. et al. Microglial SLC25A28 Deficiency Ameliorates the Brain Injury After Intracerebral Hemorrhage in Mice by Restricting Aerobic Glycolysis. Inflammation 47, 591–608 (2024). https://doi.org/10.1007/s10753-023-01931-1

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