Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

To investigate the role of thioredoxin 2 (Trx2) inhibition induced by intracellular methylglyoxal (MGO) in pancreatic beta-cell mitochondrial dysfunction and apoptosis.

Methods

Rat pancreatic beta-cell line INS-1 cells were treated with Glo1 siRNAs or exogenous MGO to increase intracellular MGO. AGEs formation was detected by ELISA and mitochondrial ROS was detected by probe MitoSOX. Transmission electron microscopy (TEM) analysis and ATP content were measured to evaluate mitochondrial function. Trx2 expression was manipulated by overexpression with recombinant Trx2 lentivirus or knockdown with Trx2 siRNAs, and effects on apoptosis and insulin secretion were measured by flow cytometry and ELISA, respectively.

Results

The increase of intracellular MGO by Glo1 blockage or MGO treatment led to advanced glycation end products (AGEs) overproduction, mitochondrial ROS increase, and insulin secretion paralysis. These were probably due to MGO-induced inhibition of mitochondrial Trx2. Trx2 inhibition by blockage of either Glo1 or Trx2 impaired mitochondrial integrity, inhibited cytochrome C oxidases subunit 1 and 4 (Cox1 and Cox4) expression and further reduced ATP generation, and all of these might lead to insulin paralysis; whereas Trx2 overexpression partially reversed MGO-induced oxidative stress, attenuated insulin secretion by preventing mitochondrial damage. Trx2 overexpression also retarded MGO-induced apoptosis of INS-1 cell through inhibiting ASK1 activation and downregulation of the ASK1-p38 MAPK pathway.

Conclusions

Our results reveal a possible mechanism for beta-cell oxidative damage upon intracellular MGO-induced Trx2 inactivation and mitochondrial dysfunction and apoptosis.

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

Similar content being viewed by others

References

  1. M. Bensellam, D.R. Laybutt, J.C. Jonas, The molecular mechanisms of pancreatic β-cell glucotoxicity: recent findings and future research directions. Mol. Cell Endocrinol. (2012). https://doi.org/10.1016/j.mce.2012.08.003

  2. J.C. Jonas, M. Bensellam, J. Duprez, H. Elouil, Y. Guiot, S.M.A. Pascal, Glucose regulation of islet stress responses and β-cell failure in type 2 diabetes. Diabetes Obes Metab. (2009). https://doi.org/10.1111/j.1463-1326.2009.01112.x

  3. C.J. Rhodes, Type 2 diabetes—A matter of beta—cell life and death? Science 80 (2005). https://doi.org/10.1126/science.1104345

  4. I. Allaman, M. Bélanger, P.J. Magistretti, Methylglyoxal, the dark side of glycolysis. Front. Neurosci. (2015). https://doi.org/10.3389/fnins.2015.00023

  5. M.P. Kalapos, Where does plasma methylglyoxal originate from? Diabetes Res. Clin. Pract. (2013). https://doi.org/10.1016/j.diabres.2012.11.003

  6. N. Lin, H. Zhang, Q. Su, Advanced glycation end-products induce injury to pancreatic beta cells through oxidative stress. Diabetes Metab. (2012). https://doi.org/10.1016/j.diabet.2012.01.003

  7. C. Liu, X. Wan, T. Ye, F. Fang, X. Chen, Y. Chen, et al., Matrix metalloproteinase 2 contributes to pancreatic beta cell injury induced by oxidative stress. PLoS ONE 9 (2014). https://doi.org/10.1371/journal.pone.0110227

  8. C. Liu, Y. Huang, Y. Zhang, X. Chen, X. Kong, Y. Dong, Intracellular methylglyoxal induces oxidative damage to pancreatic beta cell line INS-1 cell through Ire1α-JNK and mitochondrial apoptotic pathway. Free Radic. Res. 51 (2017). https://doi.org/10.1080/10715762.2017.1289376

  9. P. Matafome, C. Sena, R. Seiça, Methylglyoxal, obesity, and diabetes. Endocrine (2013). https://doi.org/10.1007/s12020-012-9795-8

  10. F. Giacco, X. Du, V.D. D’Agati, R. Milne, G. Sui, M. Geoffrion, et al., Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. Diabetes (2014). https://doi.org/10.2337/db13-0316

  11. J. Lu, A. Holmgren, The thioredoxin antioxidant system. Free Radic. Biol. Med. (2014). https://doi.org/10.1016/j.freeradbiomed.2013.07.036

  12. T.F. Whayne, N. Parinandi, N. Maulik, Thioredoxins in cardiovascular disease. Can. J. Physiol. Pharmacol. (2015). https://doi.org/10.1139/cjpp-2015-0105

  13. J.C. Lee, J.H. Park, I.H. Kim, G.S. Cho, J.H. Ahn, H.J. Tae, et al., Neuroprotection of ischemic preconditioning is mediated by thioredoxin 2 in the hippocampal CA1 region following a subsequent transient cerebral ischemia. Brain Pathol. (2017). https://doi.org/10.1111/bpa.12389

  14. A.L. Dafre, J. Goldberg, T. Wang, D.A. Spiegel, P. Maher, Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells. Free Radic. Biol. Med. (2015). https://doi.org/10.1016/j.freeradbiomed.2015.07.005

  15. J. Lu, E. Randell, Y.C. Han, K. Adeli, J. Krahn, Q.H. Meng, Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin. Biochem. (2011). https://doi.org/10.1016/j.clinbiochem.2010.11.004

  16. X. Kong, M. zhe Ma, K. Huang, L. Qin, H. mei Zhang, Z. Yang, et al., Increased plasma levels of the methylglyoxal in patients with newly diagnosed type 2 diabetes. J. Diabetes (2014). https://doi.org/10.1111/1753-0407.12160

  17. P.J. Beisswenger, Methylglyoxal in diabetes: link to treatment, glycaemic control and biomarkers of complications. Biochem. Soc. Trans. (2014). https://doi.org/10.1042/BST20130275

  18. Z. Turk, Glycotoxines, carbonyl stress and relevance to diabetes and its complications. Physiol. Res. (2010)

  19. M.J. Nokin, F. Durieux, P. Peixoto, B. Chiavarina, O. Peulen, A. Blomme, et al., Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP- mediated tumor growth and metastasis. Elife (2016). https://doi.org/10.7554/eLife.19375

  20. M. Yamamoto, E. Yamato, T. Shu-Ichi, F. Tashiro, H. Ikegami, J. Yodoi, et al., Transgenic expression of antioxidant protein thioredoxin in pancreatic β cells prevents progression of type 2 diabetes mellitus. Antioxid. Redox. Signal. (2008). https://doi.org/10.1089/ars.2007.1586

  21. X.L. Wang, W.B. Lau, Y.X. Yuan, Y.J. Wang, W. Yi, T.A. Christopher, et al., Methylglyoxal increases cardiomyocyte ischemia-reperfusion injury via glycative inhibition of thioredoxin activity. Am. J. Physiol. Endocrinol. Metab. (2010). https://doi.org/10.1152/ajpendo.00215.2010

  22. D.F.D. Mahmood, A. Abderrazak, K. El Hadri, T. Simmet, M. Rouis, The thioredoxin system as a therapeutic target in human health and disease. Antioxid. Redox. Signal. (2013). https://doi.org/10.1089/ars.2012.4757

  23. H. Zhang, Y.M. Go, D.P. Jones, Mitochondrial thioredoxin-2/peroxiredoxin-3 system functions in parallel with mitochondrial GSH system in protection against oxidative stress. Arch. Biochem. Biophys. (2007). https://doi.org/10.1016/j.abb.2007.05.001

  24. Q. Huang, H.J. Zhou, H. Zhang, Y. Huang, F. Hinojosa-Kirschenbaum, P. Fan, et al., Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function. Circulation (2015). https://doi.org/10.1161/CIRCULATIONAHA.114.012725

  25. M. He, J. Cai, Y.M. Go, J.M. Johnson, W.D. Martin, J.M. Hansen, et al., Identification of thioredoxin-2 as a regulator of the mitochondrial permeability transition. Toxicol. Sci. (2008). https://doi.org/10.1093/toxsci/kfn116

  26. K. Takeda, T. Noguchi, I. Naguro, H. Ichijo, Apoptosis Signal-Regulating Kinase 1 in Stress and Immune Response. Annu. Rev. Pharmacol. Toxicol. (2008). https://doi.org/10.1146/annurev.pharmtox.48.113006.094606

  27. R. Zhang, R. Al-Lamki, L. Bai, J.W. Streb, J.M. Miano, J. Bradley, et al., Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Circ. Res. (2004). https://doi.org/10.1161/01.RES.0000130525.37646.a7

  28. L. Yang, D. Wu, X. Wang, A.I. Cederbaum, Depletion of cytosolic or mitochondrial thioredoxin increases CYP2E1-induced oxidative stress via an ASK-1-JNK1 pathway in HepG2 cells. Free Radic. Biol. Med. (2011). https://doi.org/10.1016/j.freeradbiomed.2011.04.030

  29. K.H. Huh, Y. Cho, B.S. Kim, J.H. Do, Y.J. Park, D.J. Joo, et al., The role of thioredoxin 1 in the mycophenolic acid-induced apoptosis of insulin-producing cells. Cell Death Dis. (2013). https://doi.org/10.1038/cddis.2013.247

Download references

Funding

This work was supported by the Grant of National Natural Science Foundation of China (No. 81800729) and Pudong New Area Health System Research Project (PW2018B-09).

Author information

Authors and Affiliations

  1. Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Chongxiao Liu, Baige Cao, Qianren Zhang, Yifan Zhang, Xueru Chen & Yan Dong

  2. Department of Endocrinology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China

    Chongxiao Liu

  3. Department of Endocrinology, Yijishan Hospital Affiliated Wannan Medical College, Anhui, 241000, China

    Xiang Kong

  4. Shanghai Institute for Pediatric Research, Shanghai, 200092, China

    Yan Dong

Authors
  1. Chongxiao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Baige Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qianren Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yifan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xueru Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yan Dong.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, C., Cao, B., Zhang, Q. et al. Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells. Endocrine 68, 103–115 (2020). https://doi.org/10.1007/s12020-020-02191-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-020-02191-x

Keywords

Search

Navigation