Skip to main content
SpringerLink
Log in

Ferritinophagy is Involved in Experimental Subarachnoid Hemorrhage-Induced Neuronal Ferroptosis

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Ferroptosis is a novel form of regulated cell death involved in the pathophysiological process of experimental subarachnoid hemorrhage (SAH), but how neuronal ferroptosis occurs remains unknown. In this study, we report that SAH-induced ferroptosis is macroautophagy/autophagy dependent because the inhibition of autophagy by knocking out autophagy-related gene 5 (ATG5) apparently mitigated SAH-induced ferroptosis. We created an experimental SAH model in Sprague–Dawley rats to determine the possible mechanism. We found that SAH can trigger neuronal ferroptosis, as evidenced by the disruption of iron homeostasis, elevation of intracellular lipid peroxidation (LPO) and decreased expression of ferroptosis–protective proteins. Then, we inhibited autophagy by ATG5 gene knockout, showing that autophagy inhibition can reduce the intracellular iron level and LPO, improve the expression of ferroptosis–protective proteins, and subsequently alleviate SAH-induced cell death. Additionally, autophagy inhibition also attenuated SAH prognostic indicators, such as brain edema, blood–brain barrier permeability, and neurological deficits. These findings not only present an opinion that SAH triggers neuronal ferroptosis via activation of ferritinophagy but also indicate that regulating ferritinophagy and maintaining iron homeostasis could provide clues for the prevention of early brain injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lee JY, He Y, Sagher O, Keep R, Hua Y, Xi G (2009) Activated autophagy pathway in experimental subarachnoid hemorrhage. Brain Res 1287:126–135. https://doi.org/10.1016/j.brainres.2009.06.028

    Article  CAS  PubMed  Google Scholar 

  2. Zhao H, Ji Z, Tang D, Yan C, Zhao W, Gao C (2013) Role of autophagy in early brain injury after subarachnoid hemorrhage in rats. Mol Biol Rep 40:819–827. https://doi.org/10.1007/s11033-012-2120-z

    Article  CAS  PubMed  Google Scholar 

  3. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Van Do B, Gouel F, Jonneaux A, Timmerman K, Gele P, Petrault M, Bastide M, Laloux C, Moreau C, Bordet R, Devos D, Devedjian JC (2016) Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC. Neurobiol Dis 94:169–178. https://doi.org/10.1016/j.nbd.2016.05.011

    Article  CAS  Google Scholar 

  5. Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R, Tang D (2016) Ferroptosis: process and function. Cell Death Differ 23:369–379. https://doi.org/10.1038/cdd.2015.158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 张红霞, 蒋登志, 车旭东, 赵清, 赵俊, 向祥 and 何朝晖 (2017) 依布硒林减轻DMT1诱导的铁死亡在实验性大鼠蛛网膜下腔出血中的研究. 第三军医大学学报 39:1618–1624

  7. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, Kang R, Tang D (2016) Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12:1425–1428. https://doi.org/10.1080/15548627.2016.1187366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X (2016) Ferroptosis is an autophagic cell death process. Cell Res 26:1021–1032. https://doi.org/10.1038/cr.2016.95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Suzuki H, Hasegawa Y, Kanamaru K, Zhang JH (2010) Mechanisms of osteopontin-induced stabilization of blood-brain barrier disruption after subarachnoid hemorrhage in rats. Stroke 41:1783–1790. https://doi.org/10.1161/strokeaha.110.586537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sugawara T, Ayer R, Jadhav V, Zhang JH (2008) A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods 167:327–334. https://doi.org/10.1016/j.jneumeth.2007.08.004

    Article  PubMed  Google Scholar 

  11. He Z, Ostrowski RP, Sun X, Ma Q, Huang B, Zhan Y, Zhang JH (2012) CHOP silencing reduces acute brain injury in the rat model of subarachnoid hemorrhage. Stroke 43:484–490. https://doi.org/10.1161/strokeaha.111.626432

    Article  PubMed  Google Scholar 

  12. Shi L, Liang F, Zheng J, Zhou K, Chen S, Yu J, Zhang J (2018) Melatonin regulates apoptosis and autophagy via ROS-MST1 pathway in subarachnoid hemorrhage. Front Mol Neurosci 11:93. https://doi.org/10.3389/fnmol.2018.00093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu H, Niu H, Wu C, Li Y, Wang K, Zhang J, Wang Y, Yang S (2016) The autophagy-lysosomal system in subarachnoid haemorrhage. J Cell Mol Med 20:1770–1778. https://doi.org/10.1111/jcmm.12855

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC (2014) Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509:105–109. https://doi.org/10.1038/nature13148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Santana-Codina N, Mancias JD (2018) The role of NCOA4-mediated ferritinophagy in health and disease. Pharmaceuticals (Basel). https://doi.org/10.3390/ph11040114

    Article  Google Scholar 

  16. Bauckman KA, Mysorekar IU (2016) Ferritinophagy drives uropathogenic Escherichia coli persistence in bladder epithelial cells. Autophagy 12:850–863. https://doi.org/10.1080/15548627.2016.1160176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rockfield S, Flores I, Nanjundan M (2018) Expression and function of nuclear receptor coactivator 4 isoforms in transformed endometriotic and malignant ovarian cells. Oncotarget 9:5344–5367. https://doi.org/10.18632/oncotarget.23747

    Article  PubMed  Google Scholar 

  18. Masaldan S, Clatworthy SAS, Gamell C, Meggyesy PM, Rigopoulos AT, Haupt S, Haupt Y, Denoyer D, Adlard PA, Bush AI, Cater MA (2018) Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol 14:100–115. https://doi.org/10.1016/j.redox.2017.08.015

    Article  CAS  PubMed  Google Scholar 

  19. Jing CH, Wang L, Liu PP, Wu C, Ruan D, Chen G (2012) Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. Neuroscience 213:144–153. https://doi.org/10.1016/j.neuroscience.2012.03.055

    Article  CAS  PubMed  Google Scholar 

  20. Fang Y, Chen S, Reis C, Zhang J (2018) The role of autophagy in subarachnoid hemorrhage: an update. Curr Neuropharmacol 16:1255–1266. https://doi.org/10.2174/1570159x15666170406142631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ho WM, Akyol O, Reis H, Reis C, McBride D, Thome C, Zhang J (2018) Autophagy after subarachnoid hemorrhage: can cell death be good? Curr Neuropharmacol 16:1314–1319. https://doi.org/10.2174/1570159x15666171123200646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wen YD, Sheng R, Zhang LS, Han R, Zhang X, Zhang XD, Han F, Fukunaga K, Qin ZH (2008) Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 4:762–769

    Article  CAS  Google Scholar 

  23. Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, Kawahara N, Kuida K, Nagata S, Kominami E, Tanaka K, Uchiyama Y (2008) Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 172:454–469. https://doi.org/10.2353/ajpath.2008.070876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xing S, Zhang Y, Li J, Zhang J, Li Y, Dang C, Li C, Fan Y, Yu J, Pei Z, Zeng J (2012) Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction. Autophagy 8:63–76. https://doi.org/10.4161/auto.8.1.18217

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81870927), the Natural Science Foundation Project of Chongqing Science and Technology Commission (Grant cstc2019jcyj-msxmX0239 to Prof. Zhaohui He) and the Natural Science Foundation Project of Chongqing Science and Technology Commission (Grant cstc2020jcyj-msxmX0769 to Dr. Yongbing Deng).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Chongqing Emergency Medical Center, Chongqing, China

    Yidan Liang, Yongbing Deng, Liu Liu, Jia Wang, Peng Chen, Qingtao Zhang, Chao Sun, Yanglingxi Wang & Yi Xiang

  2. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Jun Zhao & Zhaohui He

Authors
  1. Yidan Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongbing Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qingtao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanglingxi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yi Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhaohui He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhaohui He.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, Y., Deng, Y., Zhao, J. et al. Ferritinophagy is Involved in Experimental Subarachnoid Hemorrhage-Induced Neuronal Ferroptosis. Neurochem Res 47, 692–700 (2022). https://doi.org/10.1007/s11064-021-03477-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-021-03477-w

Keywords

Search

Navigation