Skip to main content
SpringerLink
Log in

The Autophagy Signaling Pathway in Necroptosis-Dependent Cerebral Ischemia/Reperfusion Injury

  • REVIEW ARTICLES
  • Published:
Neurochemical Journal Aims and scope Submit manuscript

Abstract

Cerebral ischemia/reperfusion (I/R) is a complicated brain disease involving severe inflammation, autophagy, apoptosis and necroptosis. Hippocampal CA1 neuron death in cerebral I/R injury has been proven to be a form of necroptosis that is regulated by the connection of receptor interacting protein kinase (RIP) 1 and RIP3. The RIP3 substrate molecule is mixed lineage kinase domain-like protein (MLKL). The downstream of this signal pathway triggers mitochondrial permeability transition pore (mPTP) channel opening. The occurrence of mitochondrial membrane potential disappearance and the reduction of ATP facilitate reactive oxygen species (ROS) generation. The high level of ROS is essential for engulfing damaged organelles and proteins. In many conditions, autophagy has a decisive function in determining cell outcome through intricate signaling pathway interactions with other cell death signaling mechanisms. Necroptosis also been demonstrated to be responsible for the induction of autophagy. Studies have confirmed that cyclophilin D (CypD), as a regulator of mPTP, has effects on the course of necroptosis, autophagy and apoptosis. Preliminary treatment with cyclosporine-A (CsA), an effective inhibiting agent of CypD, has partial but valid negatively regulated function in necroptosis-associated molecule markers. Administration of CsA is also attributed to inhibiting autophagy-related molecular marker expression. Cerebral I/R injury widely increased the expression levels of autophagy-associated proteins, such as light chain 3-II (LC3-II) and extracellular signal-regulated kinase (ERK), while a small molecule inhibitor of RIP1, necrostatin-1 (Nec-1) functions as a negative regulator to them. The molecular mechanisms and the interaction between necroptosis and autophagy might represent a promising therapeutic target for cerebral I/R 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.

Similar content being viewed by others

REFERENCES

  1. Randolph, S.A., Workplace Health Saf., 2016, vol. 64, p. 444.

    Article  PubMed  Google Scholar 

  2. Datta, A., Sarmah, D., Mounica, L., Kaur, H., Kesharwani, R., Verma, G., Veeresh, P., Kotian, V., Kalia, K., Borah, A., Wang, X., Dave, KR., Yavagal, D.R., and Bhattacharya, P., Transl. Stroke Res., 2020, vol. 11, no. 6, pp. 1185–1202.

    Article  PubMed  Google Scholar 

  3. Liu, L., Wang, D., Wong, K.S., and Wang, Y., Stroke, 2011, vol. 42, no. 12, pp. 3651–3654.

    Article  Google Scholar 

  4. Deng, Y.L., Ma, Y.L., Zhang, Z.L., Zhang, L.X., Guo, H., Qin, P., Hou, Y.S., Gao, Z.J., and Hou, W.G., Anesthesiology, 2018, vol. 128, no. 3, pp. 574–586.

    Article  CAS  PubMed  Google Scholar 

  5. Wang, Y., Jiang, S.W., Liu, X., Niu, L., Ge, X.L., Zhang, J.C., Wang, H.R., Fei, A.H., Gao, C.J., and Pan, S.M., Oxid. Med. Cell. Longev., 2018, vol. 2018, p. 4612727.

    PubMed  PubMed Central  Google Scholar 

  6. Kaczmarek, A., Vandenabeele, P., Krysko, D.V., Immunity, 2013, vol. 38, no. 2, pp. 209–223.

    Article  CAS  PubMed  Google Scholar 

  7. Wang, P., Shao, B.Z., Deng, Z., Chen, S., Yue, Z., and Miao, C.Y., Prog Neurobiol., 2018, vols. 163–164, pp. 98–117.

    Article  PubMed  CAS  Google Scholar 

  8. Xin, Q., Ji, B., Cheng, B., Wang, C., Liu, H., Chen, X., Chen, J., and Bai, B., Neurochem Int., 2014, vol. 68, pp. 18–27.

    Article  CAS  PubMed  Google Scholar 

  9. El Khashab, I.H., Abdelsalam, R.M., Elbrairy, A.I., Attia, A.S., Biomed. Pharmacother., 2019, vol. 112, p. 108619.

    Article  CAS  PubMed  Google Scholar 

  10. Jun-Long, H., Yi, L., Bao-Lian, Z., Jia-Si L., Ning, Z., Zhou-Heng, Y., Xue-Jun, S., and Wen-Wu, L., Curr. Neuropharmacol., 2018, vol. 16, no. 9, pp. 1327–1339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., and Kroemer, G., Nat. Rev. Mol. Cell. Biol., 2010, vol. 11, no. 10, pp. 700–714.

    Article  CAS  PubMed  Google Scholar 

  12. Yonekawa, T., Gamez, G., Kim, J., Tan, A. C., Thorburn, J., Gump, J., Thorburn, A., and Morgan, M.J., EMBO Rep., 2015, vol. 16, no. 6, pp. 700–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fakharnia, F., Khodagholi, F., Dargahi, L., and Ahmadiani, A., J. Mol. Neurosci., 2017, vol. 61, no. 1, pp. 52–60.

    Article  CAS  PubMed  Google Scholar 

  14. Ryan, F., Khodagholi, F., Dargahi, L., Minai-Tehrani, D., and Ahmadiani A., Neurotox. Res., 2018, vol. 34, no. 1, pp. 79–92.

    Article  CAS  PubMed  Google Scholar 

  15. Grishchuk, Y., Ginet, V., Truttmann, A.C., Clarke, P.G., and Puyal, J., Autophagy, 2011, vol. 7, no. 10, pp. 1115–1131.

    Article  CAS  PubMed  Google Scholar 

  16. Parzych, K.R. and Klionsky, D.J., Antioxid. Redox Signal., 2014, vol. 20, no. 3, pp. 460–473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang, J.Y., Xia, Q., Chu, K.T., Pan, J., Sun, L.N., Zeng, B., Zhu, Y.J., Wang, Q., Wang, K., and Luo, B.Y., J. Neuropathol. Exp. Neurol., 2011, vol. 70, no. 4, pp. 314–322.

    Article  CAS  PubMed  Google Scholar 

  18. Vanlangenakker, N., Vanden Berghe, T., Krysko, D.V., Festjens, N., and Vandenabeele, P., Curr. Mol. Med., 2008, vol. 8, no. 3, pp. 207–220.

    Article  CAS  PubMed  Google Scholar 

  19. Linkermann, A. and Green, D.R., N. Engl. J. Med., 2014, vol. 370, no. 5, pp. 455–465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vieira, M., Fernandes, J., Carreto, L., Anuncibay-Soto, B., Santos, M., Han, J., Fernández-López, A., Duarte, C.B., Carvalho, A.L., and Santos A.E., Neurobiol. Dis., 2014, vol. 68, pp. 26–36.

    Article  CAS  PubMed  Google Scholar 

  21. Houtkooper, R.H., Cantó, C., Wanders, R.J., and Auwerx, J., Endocr, Rev., 2010, vol. 31, no. 2, pp. 194–223.

    Article  CAS  Google Scholar 

  22. Narayan, N., Lee, I.H., Borenstein, R., Sun, J., Wong, R., Tong, G., Fergusson, M.M., Liu, J., Rovira, I.I., Cheng, H.L., Wang, G., Gucek, M., Lombard, D., Alt, F.W., Sack, M.N., Murphy, E., Cao, L., and Finkel, T., Nature, 2012, vol. 492, no. 7428, pp. 199–204.

    Article  CAS  PubMed  Google Scholar 

  23. Font-Belmonte, E., Ugidos, I.F., Santos-Galdiano, M., González-Rodríguez, P., Anuncibay-Soto, B., Pérez-Rodríguez, D., Gonzalo-Orden, J.M., and Fernández-López, A., J. Neurochem., 2019, vol. 151, no. 6, pp. 777–794.

    Article  CAS  PubMed  Google Scholar 

  24. Li, J., McQuade, T., Siemer, A.B., Napetschnig, J., Moriwaki, K., Hsiao, Y.S., Damko, E., Moquin, D., Walz, T., McDermott, A., Chan, F.K., and Wu, H., Cell, 2012, vol. 150, no. 2, pp. 339–350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yin, B., Xu, Y., Wei, R.L., He, F., Luo, B.Y., and Wang, J.Y., Brain Res., 2015, vol. 1609, pp. 63–71.

    Article  CAS  PubMed  Google Scholar 

  26. Xu, Y., Wang, J., Song, X., Qu, L., Wei, R., He, F., Wang, K., and Luo, B., Sci. Rep., 2016, vol. 6, p. 29362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., and Wang, X., Cell, 2012, vol. 148, nos. 1–2, pp. 213–227.

    Article  CAS  PubMed  Google Scholar 

  28. Dondelinger, Y., Declercq, W., Montessuit, S., Roelandt, R., Goncalves, A., Bruggeman, I., Hulpiau, P., Weber, K., Sehon, C.A., Marquis, R.W., Bertin, J., Gough, P.J., Savvides, S., Martinou, J.C., Bertrand, M.J., and Vandenabeele, P., Cell Rep., 2014, vol. 7, no. 4, pp. 971–981.

    Article  CAS  PubMed  Google Scholar 

  29. Wang, Z., Jiang, H., Chen, S., Du, F., Wang, X., Cell, 2012, vol. 148, nos. 1–2, pp. 228–243.

    Article  CAS  PubMed  Google Scholar 

  30. Lu, W., Sun, J., Yoon, J.S., Zhang, Y., Zheng, L., Murphy, E., Mattson, M.P., and Lenardo, M.J., PLoS One, 2016, vol. 11, no. 1, p. e0147792.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Zhang, D.W., Shao, J., Lin, J., Zhang, N., Lu, B.J., Lin, S.C., Dong, M.Q., and Han, J., Science, 2009, vol. 325, no. 5938, pp. 332–336.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang, Y., Su, S.S., Zhao, S., Yang, Z., Zhong, C.Q., Chen, X., Cai, Q., Yang, Z.H., Huang, D., Wu, R., and Han, J., Nat. Commun., 2017, vol. 8, p. 14329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Manzanero, S., Santro, T., Arumugam, T.V., Neurochem. Int., 2013, vol. 62, no. 5, pp. 712–718.

    Article  CAS  PubMed  Google Scholar 

  34. Yorimitsu, T., Klionsky, D.J., Cell Death Differ., 2005, vol. 12, Suppl. 2, pp. 1542–1552.

  35. Jung, C.H., Jun, C.B., Ro, S.H., Kim, Y.M., Otto, N.M., Cao, J., Kundu, M., and Kim, D.H., Mol. Biol. Cell, 2009, vol. 20, no. 7, pp. 1992–2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lippai, M. and Szatmári, Z., Cell Biol. Toxicol., 2017, vol. 33, no. 2, pp. 145–168.

    Article  CAS  PubMed  Google Scholar 

  37. Tanida, I., Minematsu-Ikeguchi, N., Ueno, T., and Kominami, E., Autophagy, 2005, vol. 1, no. 2, pp. 84–91.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang, D.M., Zhang, T., Wang, M.M., Wang, X.X., Qin, Y.Y., Wu, J., Han, R., Sheng, R., Wang, Y., Chen, Z., Han, F., Ding, Y., Li, M., and Qin, Z.H., Free Radic. Biol. Med., 2019, vol. 137, pp. 13–23.

    Article  CAS  PubMed  Google Scholar 

  39. He, G., Xu, W., Tong, L., Li, S., Su, S., Tan, X., and Li, C., Apoptosis, 2016, vol. 21, no. 4, pp. 390–403.

    Article  CAS  PubMed  Google Scholar 

  40. Wei, K., Wang, P., and Miao, C.Y., CNS Neurosci. Ther., 2012, vol. 18, no. 11, pp. 879–886.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhang, X., Yan, H., Yuan, Y., Gao, J., Shen, Z., Cheng, Y., Shen, Y., Wang, R.R, Wang, X, Hu, W.W, Wang, G., and Chen, Z., Autophagy, 2013, vol. 9, no. 9, pp. 1321–1333.

    Article  CAS  PubMed  Google Scholar 

  42. Cui, D., Wang, L., Qi, A., Zhou, Q., Zhang, X., and Jiang, W., PLoS One, 2012, vol. 7, no. 4, p. e35324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shi, R., Weng, J., Zhao, L., Li, X.M., Gao, T.M., and Kong, J., CNS Neurosci. Ther., 2012, vol. 18, no. 3, pp. 250–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Meng, X., Xie, W., Xu, Q., Liang, T., Xu, X., Sun, G., and Sun, X., Molecules., 2018, vol. 23, no. 9, p. 2401.

    Article  PubMed Central  CAS  Google Scholar 

  45. Cao, M., Chen, F., Xie, N., Cao, M.Y., Chen, P., Lou, Q., Zhao, Y., He, C., Zhang, S., Song, X., Sun, Y., Zhu, W., Mou, L., Luan, S., and Gao, H., Cell Death Dis., 2018, vol. 9, no. 12, p. 1140.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Wei, Y., Pattingre, S., Sinha, S., Bassik, M., and Levine, B., Mol. Cell, 2008, vol. 30, no. 6, pp. 678–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ye, Y.C., Wang, H.J., Chen, L., Liu, W.W., Tashiro, S., Onodera, S., Xia, M.Y., and Ikejima, T., Int. Immunopharmacol., 2013, vol. 17, no. 3, pp. 548–555.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang, M., Li, J., Geng, R., Ge, W., Zhou, Y., Zhang, C., Cheng, Y., and Geng, D., Neurotox. Res., 2013, vol. 24, no. 1, pp. 64–70.

    Article  CAS  PubMed  Google Scholar 

  49. Lin, S.Y., Hsieh, S.Y., Fan, Y.T., Wei, W.C., Hsiao, P.W., Tsai, D.H., Wu, T.S., and Yang, N.S., Autophagy, 2018, vol. 14, no. 5, pp. 778–795.

    Article  CAS  PubMed  Google Scholar 

  50. Ye, Y.C., Yu, L., Wang, H.J., Tashiro, S., Onodera, S., and Ikejima, T., J. Pharmacol. Sci., 2011, vol. 117, no. 3, pp. 160–169.

    Article  CAS  PubMed  Google Scholar 

  51. Frank, D., Vaux, D.L., Murphy, J.M., Vince, J.E., and Lindqvist, L.M., J. Cell Sci., 2019, vol. 132, no. 5, p. jcs220996.

    Article  CAS  PubMed  Google Scholar 

  52. Goodall, M.L., Fitzwalter, B.E., Zahedi, S., Wu, M., Rodriguez, D., Mulcahy-Levy, J.M., Green, D.R., Morgan, M., Cramer, S.D., and Thorburn, A., Dev. Cell, 2016, vol. 37, no. 4, pp. 337–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Itakura, E. and Mizushima, N., J. Cell Biol., 2011, vol. 192, no. 1, pp. 17–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Suzuki, K., Kubota, Y., Sekito, T., and Ohsumi, Y., Genes Cells, 2007, vol. 12, no. 2, pp. 209–218.

    Article  CAS  PubMed  Google Scholar 

  55. Pietrzak, M. and Puzianowska-Kuznicka, M., Biol. Chem., 2008, vol. 389, no. 4, pp. 383–393.

    Article  CAS  PubMed  Google Scholar 

  56. Yamada, K. and Yoshida, K., Biochim. Biophys. Acta Mol. Cell Res., 2019, vol. 1866, no. 5, pp. 839–848.

    CAS  Google Scholar 

  57. Wang, P., Liang, J., Li, Y., Li, J., Yang, X., Zhang, X., Han, S., Li, S., and Li, J., Neurochem. Res., 2014, vol. 39, no. 7, pp. 1279–1291.

    Article  CAS  PubMed  Google Scholar 

  58. Wang, X., Li, R., Wang, X., Fu, Q., and Ma, S., Neurosci. Lett., 2015, vol. 600, pp. 182–187.

    Article  CAS  PubMed  Google Scholar 

  59. Li, X., Cheng, S., Hu, H., Zhang, X., Xu, J., Wang, R., and Zhang, P., Biochem. Biophys. Res. Commun., 2020, vol. 521, no. 3, pp. 569–576.

    Article  CAS  PubMed  Google Scholar 

  60. Wang, M., Li, Y.J., Ding, Y., Zhang, H.N., Sun, T., Zhang, K., Yang, L., Guo, Y.Y., Liu, S.B., Zhao, M.G., and Wu, Y.M., Mol. Neurobiol., 2016, vol. 53, no. 2, pp. 932–943.

    Article  CAS  PubMed  Google Scholar 

  61. Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G.D., Mitchison, T.J., Moskowitz, M.A., and Yuan, J., Nat. Chem. Biol., 2005, vol. 1, no. 2, pp. 112–119.

    Article  CAS  PubMed  Google Scholar 

  62. Yang, R., Hu, K., Chen, J., Zhu, S., Li, L., Lu, H., Li, P., and Dong, R., Neurosci. Lett., 2017, vol. 651, pp. 207–215.

    Article  CAS  PubMed  Google Scholar 

  63. Xu, Y., Wang, J., Song, X., Wei, R., He, F., Peng, G., and Luo, B., Brain Res. Bull., 2016, vol. 120, pp. 97–105.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by the National Natural Science Foundation of China (81701161). This work was financially supported by the State Scholarship Fund of China Scholarship (201908340015); the Scientific Research Fund Project for Talent Introduction of Yijishan Hospital, Wannan Medical College, Anhui, China (Grant nos. YR201802 and KY24520346); and the “Peak” Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College (KGF2019G02).

Author information

Author notes

    Authors and Affiliations

    1. Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, 241001, Wuhu, Anhui, China

      Yang Xu

    2. Department of Ophthalmology, Wuhu Eye Hospital, 241000, Wuhu, Anhui, China

      Dijing Yu

    3. Department of Neurology, The First Affiliated Hospital of Wannan Medical College, 241001, Wuhu, Anhui, China

      Yang Xu, Yingying Zhou, Wenjie Hu, Xiaodong Wu, Jianfei Wang, Simei Huang, Shoucai Zhao, Xiaoli Fan, Zhaohu Chu & Lingsong Ma

    4. Non-coding RNA Research Center of Wannan Medical College, 241001, Wuhu, Anhui, China

      Yang Xu

    5. Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, 238000, China, Anhui, China

      Xiaodong Wu

    Authors
    1. Yang Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yingying Zhou
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Dijing Yu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Wenjie Hu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xiaodong Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jianfei Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Simei Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Shoucai Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Xiaoli Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Zhaohu Chu
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Lingsong Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Xiaoli Fan.

    Ethics declarations

    Conflict of interest. The authors declare that there is no conflict of interest.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Xu, Y., Zhou, Y., Yu, D. et al. The Autophagy Signaling Pathway in Necroptosis-Dependent Cerebral Ischemia/Reperfusion Injury. Neurochem. J. 15, 247–253 (2021). https://doi.org/10.1134/S1819712421030132

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1134/S1819712421030132

    Keywords:

    Search

    Navigation