Skip to main content
SpringerLink
Log in

CDGSH iron sulfur domain 2 mitigates apoptosis, oxidative stress and inflammatory response caused by oxygen–glucose deprivation/reoxygenation in HT22 hippocampal neurons by Akt-Nrf2-activated pathway

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

CDGSH iron sulfur domain 2 (Cisd2) is known as a key determinant factor in maintaining cellular homeostasis. However, whether Cisd2 contributes to the mediation of neuronal injury during ischemic stroke has not been well stressed. This work focuses on investigating the role of Cisd2 in regulating neuronal injury caused by oxygen–glucose deprivation/reoxygenation (OGD/R). The dramatic down-regulation of Cisd2 was observed in hippocampal neurons suffering from OGD/R injury. In Cisd2-overexpressed neurons, OGD/R-induced neuronal apoptosis, oxidative stress and inflammation were prominently mitigated. Further investigation uncovered that the forced expression of Cisd2 reinforced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in OGD/R-exposed neurons. Moreover, the overexpression of Cisd2 enhanced Akt activation, and the restraint of Akt abolished Cisd2-induced Nrf2 activation. Importantly, restraint of Nrf2 reversed Cisd2-conferred neuroprotective effects in OGD/R-exposed neurons. Taken together, our findings indicate that Cisd2 is able to protect neurons from OGD/R-induced injuries by strengthening Nrf2 activation via Akt. Our work identifies Cisd2 as a potential determinant factor for neuronal injury during cerebral ischemia/reperfusion 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
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

References

  • Amr S, Heisey C, Zhang M, Xia XJ, Shows KH, Ajlouni K, Pandya A, Satin LS, El-Shanti H, Shiang R (2007) A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet 81:673–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YF, Chou TY, Lin IH, Chen CG, Kao CH, Huang GJ, Chen LK, Wang PN, Lin CP, Tsai TF (2020) Upregulation of Cisd2 attenuates Alzheimer’s-related neuronal loss in mice. J Pathol 250:299–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YF, Kao CH, Chen YT, Wang CH, Wu CY, Tsai CY, Liu FC, Yang CW, Wei YH, Hsu MT, Tsai SF, Tsai TF (2009a) Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev 23:1183–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YF, Kao CH, Kirby R, Tsai TF (2009b) Cisd2 mediates mitochondrial integrity and life span in mammals. Autophagy 5:1043–1045

    Article  PubMed  Google Scholar 

  • Chen YF, Wu CY, Kirby R, Kao CH, Tsai TF (2010) A role for the CISD2 gene in lifespan control and human disease. Ann N Y Acad Sci 1201:58–64

    Article  CAS  PubMed  Google Scholar 

  • Cheng YH, Chavez E, Tsai KL, Yang KC, Kuo WT, Yang YP, Chiou SH, Lin FH (2017) Effects of thermosensitive chitosan-gelatin based hydrogel containing glutathione on Cisd2-deficient chondrocytes under oxidative stress. Carbohydr Polym 173:17–27

    Article  CAS  PubMed  Google Scholar 

  • Cheng YH, Lin FH, Wang CY, Hsiao CY, Chen HC, Kuo HY, Tsai TF, Chiou SH (2016) Recovery of oxidative stress-induced damage in Cisd2-deficient cardiomyocytes by sustained release of ferulic acid from injectable hydrogel. Biomaterials 103:207–218

    Article  CAS  PubMed  Google Scholar 

  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    Article  CAS  PubMed  Google Scholar 

  • Eltzschig HK, Eckle T (2011) Ischemia and reperfusion–from mechanism to translation. Nat Med 17:1391–1401

    Article  CAS  PubMed  Google Scholar 

  • Huang YL, Shen ZQ, Huang CH, Teng YC, Lin CH, Tsai TF (2021) Cisd2 Protects the Liver from Oxidative Stress and Ameliorates Western Diet-Induced Nonalcoholic Fatty Liver Disease. Antioxidants (basel) 10:559

    Article  CAS  Google Scholar 

  • Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2016) Ischemia/reperfusion Compr Physiol 7:113–170

    Article  PubMed  Google Scholar 

  • Kim EH, Shin D, Lee J, Jung AR, Roh JL (2018) CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer. Cancer Lett 432:180–190

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Mittal R (2017) Nrf2: a potential therapeutic target for diabetic neuropathy. Inflammopharmacology 25:393–402

    Article  CAS  PubMed  Google Scholar 

  • Kung WM, Chang CJ, Chen TY, Lin MS (2020a) Cryogen spray cooling mitigates inflammation and injury-induced CISD2 decline in rat spinal cord hemisection model. J Integr Neurosci 19:619–628

    Article  PubMed  Google Scholar 

  • Kung WM, Lin CC, Chen WJ, Jiang LL, Sun YY, Hsieh KH, Lin MS (2022) Anti-Inflammatory CDGSH Iron-Sulfur Domain 2: A Biomarker of Central Nervous System Insult in Cellular. Animal Models and Patients Biomedicines 10:777

    CAS  PubMed  Google Scholar 

  • Kung WM, Lin CC, Kuo CY, Juin YC, Wu PC, Lin MS (2020b) Wild Bitter Melon Exerts Anti-Inflammatory Effects by Upregulating Injury-Attenuated CISD2 Expression following Spinal Cord Injury. Behav Neurol 2020:1080521

    Article  PubMed  PubMed Central  Google Scholar 

  • Kung WM, Lin MS (2021) The NFkappaB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases. Int J Mol Sci 22:934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuo CY, Kung WM, Lin MS (2020) Neuronal CISD2 plays a minor anti-inflammatory role in LPS-stimulated neuron-like SH-SY5Y cells. J Neurol Sci 408:116549

    Article  PubMed  Google Scholar 

  • Li SM, Chen CH, Chen YW, Yen YC, Fang WT, Tsai FY, Chang JL, Shen YY, Huang SF, Chuu CP, Chang IS, Hsiung CA, Jiang SS (2017) Upregulation of CISD2 augments ROS homeostasis and contributes to tumorigenesis and poor prognosis of lung adenocarcinoma. Sci Rep 7:11893

    Article  PubMed  PubMed Central  Google Scholar 

  • Liao HY, Liao B, Zhang HH (2021) CISD2 plays a role in age-related diseases and cancer. Biomed Pharmacother 138:111472

    Article  CAS  PubMed  Google Scholar 

  • Lin CC, Chiang TH, Chen WJ, Sun YY, Lee YH, Lin MS (2015) CISD2 serves a novel role as a suppressor of nitric oxide signalling and curcumin increases CISD2 expression in spinal cord injuries. Injury 46:2341–2350

    Article  PubMed  Google Scholar 

  • Lin MS (2020) CISD2 Attenuates Inflammation and Regulates Microglia Polarization in EOC Microglial Cells-As a Potential Therapeutic Target for Neurodegenerative Dementia. Front Aging Neurosci 12:260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navis A, Garcia-Santibanez R, Skliut M (2019) Epidemiology and Outcomes of Ischemic Stroke and Transient Ischemic Attack in the Adult and Geriatric Population. J Stroke Cerebrovasc Dis 28:84–89

    Article  PubMed  Google Scholar 

  • Nobili A, Krashia P, D’Amelio M (2020) Cisd2: a promising new target in Alzheimer’s disease. J Pathol 251:113–116

    Article  CAS  PubMed  Google Scholar 

  • Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD, Cuadrado A (2011) SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol 31:1121–1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao F, Li Y, Hu W, Yu J, Wu H, Ying K, Xia J, Du J (2020) Downregulation of CISD2 Has Prognostic Value in Non-Small Cell Lung Cancer and Inhibits the Tumorigenesis by Inducing Mitochondrial Dysfunction. Front Oncol 10:595524

    Article  PubMed  Google Scholar 

  • Shaw P, Chattopadhyay A (2020) Nrf2-ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. J Cell Physiol 235:3119–3130

    Article  CAS  PubMed  Google Scholar 

  • Shen ZQ, Chen YF, Chen JR, Jou YS, Wu PC, Kao CH, Wang CH, Huang YL, Chen CF, Huang TS, Shyu YC, Tsai SF, Kao LS, Tsai TF (2017) CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma. Cell Rep 21:2198–2211

    Article  CAS  PubMed  Google Scholar 

  • Shen ZQ, Huang YL, Teng YC, Wang TW, Kao CH, Yeh CH, Tsai TF (2021) CISD2 maintains cellular homeostasis. Biochim Biophys Acta Mol Cell Res 1868:118954

    Article  CAS  PubMed  Google Scholar 

  • Soares ROS, Losada DM, Jordani MC, Evora P, Castro ESO (2019) Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies. Int J Mol Sci 20:5034

    Article  CAS  PubMed Central  Google Scholar 

  • Ucar BI, Ucar G, Saha S, Buttari B, Profumo E, Saso L (2021) Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway. Antioxidants (basel) 10:823

    Article  CAS  Google Scholar 

  • Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, Elkind MSV, Evenson KR, Ferguson JF, Gupta DK, Khan SS, Kissela BM, Knutson KL, Lee CD, Lewis TT, Liu J, Loop MS, Lutsey PL, Ma J, Mackey J, Martin SS, Matchar DB, Mussolino ME, Navaneethan SD, Perak AM, Roth GA, Samad Z, Satou GM, Schroeder EB, Shah SH, Shay CM, Stokes A, VanWagner LB, Wang NY, Tsao CW, American Heart Association Council on E, Prevention Statistics C and Stroke Statistics S (2021) Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 143:e254–e743

  • Wang L, Ouyang F, Liu X, Wu S, Wu HM, Xu Y, Wang B, Zhu J, Xu X, Zhang L (2016) Overexpressed CISD2 has prognostic value in human gastric cancer and promotes gastric cancer cell proliferation and tumorigenesis via AKT signaling pathway. Oncotarget 7:3791–3805

    Article  PubMed  Google Scholar 

  • Yeh CH, Chou YJ, Kao CH, Tsai TF (2020) Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing. Int J Mol Sci 21:9238

    Article  CAS  PubMed Central  Google Scholar 

  • Zhang DD (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38:769–789

    Article  CAS  PubMed  Google Scholar 

  • Zhang R, Xu M, Wang Y, Xie F, Zhang G, Qin X (2017) Nrf2-a Promising Therapeutic Target for Defensing Against Oxidative Stress in Stroke. Mol Neurobiol 54:6006–6017

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Anesthesiology Department, The First Affiliated Hospital of China Medical University, No.155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China

    Xiaoyan Ren, Jiangang Yu, Lili Guo & Zaili Zhang

Authors
  1. Xiaoyan Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiangang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lili Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zaili Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xiaoyan Ren conceived the work, performed the experiments and drafted the manuscript. Jiangang Yu performed the experiments. Lili Guo performed the experiments. Zaili Zhang conceived the work and reviewed the manuscript. All authors have read and approved the final version of this manuscript.

Corresponding author

Correspondence to Zaili Zhang.

Ethics declarations

Conflicts of interest

The authors declare that there are no conflicts of interest.

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

Ren, X., Yu, J., Guo, L. et al. CDGSH iron sulfur domain 2 mitigates apoptosis, oxidative stress and inflammatory response caused by oxygen–glucose deprivation/reoxygenation in HT22 hippocampal neurons by Akt-Nrf2-activated pathway. Metab Brain Dis 37, 2417–2429 (2022). https://doi.org/10.1007/s11011-022-01043-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-022-01043-z

Keywords

Search

Navigation