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Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke

Cell Death & Differentiation (2024)Cite this article

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Abstract

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4’s enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

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Fig. 1: Irg1/itaconate level is elevated in ICH mouse brains.
Fig. 2: Irg1/itaconate protects against neuronal death and improves acute outcomes after ICH.
Fig. 3: Irg1/itaconate in MMΦ didn’t protect acute hemorrhagic mouse brains in vivo.
Fig. 4: Neuronal Irg1/itaconate protects hemorrhagic mouse brains in vivo.
Fig. 5: Irg1/itaconate protects against hemin-induced ferroptosis in vitro.
Fig. 6: Itaconate increases GPx4 activity by covalently alkylating cysteine residue 66 on GPx4 in vitro.
Fig. 7: Irg1/Itaconate increases GPx4 activity and rescues neuronal ferroptosis in vivo.

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Data availability

All the data used in this manuscript are available from the corresponding author upon reasonable request.

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Acknowledgements

The purified GPx4U46C mutant protein is generously gifted from Dr. Luhua Lai (Peking University). We thank for suggestions from Dr. Zufeng Guo (Chongqing Medical University) and Dr. Li Su (Peking University Health Science Center). We thank the Computing Platform of the Center for Life Science at Peking University for supporting the LC−MS/MS data analysis. We are grateful to Prof. Renxiao Wang’s group at the School of Pharmacy, Fudan University, for their technical aid in the virtual screening job described in this work. Graphical abstract has been created with BioRender (https://BioRender.com).

Funding

National Natural Science Foundation of China (32070735 and 82371321 to Q. Li, 81971037 and 82271240 to F.Yang, 21925701, 92153301 and 91953109 to C. Wang, 22207126 to Yanling Zhang). Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li). The Special Research Fund for Central Universities, Peking Union Medical College (3332022042 to Yanling Zhang).

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  1. These authors contributed equally: Chao Wei, Zhongnan Xiao, Yanling Zhang, Zhaoli Luo.

Authors and Affiliations

  1. Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Chao Wei, Meng Liu, Xiaotong Wang, Jing Liu, Wen Chen, Yurui Zhang, Qingyu Sun, Peipei Wang & Fei Yang

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Zhongnan Xiao, Zhaoli Luo, Liye Hu, Danmin Shen, Lei Shi, Ting Lan, Weihua Wu, Chenguang Zhang & Qian Li

  3. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China

    Yanling Zhang & Chu Wang

  4. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Yanling Zhang

  5. Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China

    Dongyang Liu & Chu Wang

  6. Department of Geriatrics, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China

    Qingqing Dai

  7. Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400010, China

    Junchi Hu

  8. Laboratory for Clinical Medicine, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China

    Fei Yang

  9. Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing Key Laboratory of Neural Regeneration and Repair, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China

    Qian Li

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  1. Chao Wei
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Contributions

Conceptualization: Wei C., Xiao Z., Zhang Yanling, Luo Z., Wang C., Yang F., and Li Q. In vitro experiments: Wei C., Lan T., Liu M., and Hu L. Established ICH animal models and performed behavior tests: Xiao Z., Wei C., Luo Z., Shen D., Liu J., and Wang X. Identified GPx4 itaconation: Zhang Yanling, Wei C., Liu D., Hu J., and Wang C. Collected data: Wei C., Xiao Z., Luo Z., Shen D., Liu J., Dai Q., Zhang Yurui, Sun Q., Shi L., and Wu W. Analyzed data: Wei C., Xiao Z., Luo Z., Shen D., Zhang C., Wang P., Wang C., Yang F., and Li Q. Writing–original draft: Wei C., Xiao Z., Zhang Yanling, Luo Z., Wang C., Yang F., and Li Q. Writing—review & editing: Wei C., Xiao Z., Zhang Yanling, Luo Z., Wang C., Yang F., and Li Q. All authors have agreed on the final version to be published.

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Correspondence to Chu Wang, Fei Yang or Qian Li.

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Wei, C., Xiao, Z., Zhang, Y. et al. Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01303-8

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