Skip to main content
SpringerLink
Log in

Thioredoxin-1 Rescues MPP+/MPTP-Induced Ferroptosis by Increasing Glutathione Peroxidase 4

  • Original Article
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD), a common neurodegenerative disease, is typically associated with the loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc). Ferroptosis is a newly identified cell death, which associated with iron accumulation, glutathione (GSH) depletion, lipid peroxidation formation, reactive oxygen species (ROS) accumulation, and glutathione peroxidase 4 (GPX4) reduction. It has been reported that ferroptosis is linked with PD.Thioredoxin-1 (Trx-1) is a redox regulating protein and plays various roles in regulating the activity of transcription factors and inhibiting apoptosis. However, whether Trx-1 plays the role in regulating ferroptosis involved in PD is still unknown. Our present study showed that 1-methyl-4-phenylpyridinium (MPP+) decreased cell viability, GPX4, and Trx-1, which were reversed by Ferrostatin-1 (Fer-1) in PC 12 cells and SH-SY5Y cells. Moreover, the decreased GPX4 and GSH, and increased ROS were inhibited by Fer-1 and Trx-1 overexpression. We further repeated that behavior deficits resulted from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were improved in Trx-1 overexpression transgenic mice. Trx-1 reversed the decreases of GPX4 and tyrosine hydroxylase (TH) induced by MPTP in the substantia nigra pars compacta (SNpc). Our results suggest that Trx-1 inhibits ferroptosis in PD through regulating GPX4 and GSH.

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

Data Availability

All data is real and guarantees the validity of experimental results.

References

  1. Jiang X, Jin T, Zhang H, Miao J, Zhao X, Su Y, Zhang Y (2019) Current progress of mitochondrial quality control pathways underlying the pathogenesis of Parkinson’s disease. Oxidative Med Cell Longev 2019:4578462–4578411. https://doi.org/10.1155/2019/4578462

    Article  CAS  Google Scholar 

  2. Mizuno Y, Suzuki K, Sone N (1990) Inhibition of ATP synthesis by 1-methyl-4-phenylpyridinium ion (MPP+) in mouse brain in vitro and in vivo. Adv Neurol 53:197–200

    CAS  PubMed  Google Scholar 

  3. Przedborski S, Tieu K, Perier C, Vila M (2004) MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr 36(4):375–379. https://doi.org/10.1023/B:JOBB.0000041771.66775.d5

    Article  CAS  PubMed  Google Scholar 

  4. Rostamian Delavar M, Baghi M, Safaeinejad Z, Kiani-Esfahani A, Ghaedi K, Nasr-Esfahani MH (2018) Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model of Parkinson’s disease. Gene 662:54–65. https://doi.org/10.1016/j.gene.2018.04.010

    Article  CAS  PubMed  Google Scholar 

  5. Masaldan S, Bush AI, Devos D, Rolland AS, Moreau C (2019) Striking while the iron is hot: iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med 133:221–233. https://doi.org/10.1016/j.freeradbiomed.2018.09.033

    Article  CAS  PubMed  Google Scholar 

  6. Angelova PR, Choi ML, Berezhnov AV, Horrocks MH, Hughes CD, De S, Rodrigues M, Yapom R et al (2020) Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation. Cell Death Differ 27:2781–2796. https://doi.org/10.1038/s41418-020-0542-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Deas E, Cremades N, Angelova PR, Ludtmann MH, Yao Z, Chen S, Horrocks MH, Banushi B et al (2016) Alpha-Synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s disease. Antioxid Redox Signal 24(7):376–391. https://doi.org/10.1089/ars.2015.6343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jelinek A, Heyder L, Daude M, Plessner M, Krippner S, Grosse R, Diederich WE, Culmsee C (2018) Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radic Biol Med 117:45–57. https://doi.org/10.1016/j.freeradbiomed.2018.01.019

    Article  CAS  PubMed  Google Scholar 

  9. Yumnamcha T, Devi TS, Singh LP (2019) Auranofin mediates mitochondrial dysregulation and inflammatory cell death in human retinal pigment epithelial cells: implications of retinal neurodegenerative diseases. Front Neurosci 13:1065. https://doi.org/10.3389/fnins.2019.01065

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cozza G, Rossetto M, Bosello-Travain V, Maiorino M, Roveri A, Toppo S, Zaccarin M, Zennaro L et al (2017) Glutathione peroxidase 4-catalyzed reduction of lipid hydroperoxides in membranes: the polar head of membrane phospholipids binds the enzyme and addresses the fatty acid hydroperoxide group toward the redox center. Free Radic Biol Med 112:1–11. https://doi.org/10.1016/j.freeradbiomed.2017.07.010

    Article  CAS  PubMed  Google Scholar 

  11. Hauser DN, Dukes AA, Mortimer AD, Hastings TG (2013) Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. Free Radic Biol Med 65:419–427. https://doi.org/10.1016/j.freeradbiomed.2013.06.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A 93(7):2696–2701. https://doi.org/10.1073/pnas.93.7.2696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mahoney-Sanchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC (2020) Ferroptosis and its potential role in the physiopathology of Parkinson’s disease. Progress in neurobiology:101890. doi:https://doi.org/10.1016/j.pneurobio.2020.101890

  14. Bai J, Nakamura H, Kwon YW, Hattori I, Yamaguchi Y, Kim YC, Kondo N, Oka S et al (2003) Critical roles of thioredoxin in nerve growth factor-mediated signal transduction and neurite outgrowth in PC12 cells. J Neurosci 23(2):503–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bai L, Zhang S, Zhou X, Li Y, Bai J (2019) Brain-derived neurotrophic factor induces thioredoxin-1 expression through TrkB/Akt/CREB pathway in SH-SY5Y cells. Biochimie 160:55–60. https://doi.org/10.1016/j.biochi.2019.02.011

    Article  CAS  PubMed  Google Scholar 

  16. Cai Y, Zhang X, Zhou X, Wu X, Li Y, Yao J, Bai J (2017) Nicotine suppresses the neurotoxicity by MPP(+)/MPTP through activating alpha7nAChR/PI3K/Trx-1 and suppressing ER stress. Neurotoxicology 59:49–55. https://doi.org/10.1016/j.neuro.2017.01.002

    Article  CAS  PubMed  Google Scholar 

  17. Zhang X, Bai L, Zhang S, Zhou X, Li Y, Bai J (2018) Trx-1 ameliorates learning and memory deficits in MPTP-induced Parkinson’s disease model in mice. Free Radic Biol Med 124:380–387. https://doi.org/10.1016/j.freeradbiomed.2018.06.029

    Article  CAS  PubMed  Google Scholar 

  18. Luo FC, Zhou J, Lv T, Qi L, Wang SD, Nakamura H, Yodoi J, Bai J (2012) Induction of endoplasmic reticulum stress and the modulation of thioredoxin-1 in formaldehyde-induced neurotoxicity. Neurotoxicology 33(3):290–298. https://doi.org/10.1016/j.neuro.2012.02.004

    Article  CAS  PubMed  Google Scholar 

  19. Zeng XS, Jia JJ, Kwon Y, Wang SD, Bai J (2014) The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease. Free Radic Biol Med 67:10–18. https://doi.org/10.1016/j.freeradbiomed.2013.10.013

    Article  CAS  PubMed  Google Scholar 

  20. Talepoor Ardakani M, Rostamian Delavar M, Baghi M, Nasr-Esfahani MH, Kiani-Esfahani A, Ghaedi K (2019) Upregulation of miR-200a and miR-204 in MPP(+) -treated differentiated PC12 cells as a model of Parkinson’s disease. Mol Genet Genomic Med 7(3):e548. https://doi.org/10.1002/mgg3.548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hayano M, Yang WS, Corn CK, Pagano NC, Stockwell BR (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23(2):270–278. https://doi.org/10.1038/cdd.2015.93

    Article  CAS  PubMed  Google Scholar 

  22. Zaobornyj T, Mazo T, Perez V, Gomez A, Contin M, Tripodi V, D’Annunzio V, Gelpi RJ (2019) Thioredoxin-1 is required for the cardioprotecive effect of sildenafil against ischaemia/reperfusion injury and mitochondrial dysfunction in mice. Free Radic Res 53(9-10):993–1004. https://doi.org/10.1080/10715762.2019.1661404

    Article  CAS  PubMed  Google Scholar 

  23. Nagatsu T, Nagatsu I (2016) Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson’s disease (PD): historical overview and future prospects. J Neural Transm 123(11):1255–1278. https://doi.org/10.1007/s00702-016-1596-4

    Article  CAS  PubMed  Google Scholar 

  24. Cassarino DS, Parks JK, Parker WD Jr, Bennett JP Jr (1999) The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta 1453(1):49–62. https://doi.org/10.1016/s0925-4439(98)00083-0

    Article  CAS  PubMed  Google Scholar 

  25. Shishido T, Nagano Y, Araki M, Kurashige T, Obayashi H, Nakamura T, Takahashi T, Matsumoto M et al (2019) Synphilin-1 has neuroprotective effects on MPP(+)-induced Parkinson’s disease model cells by inhibiting ROS production and apoptosis. Neurosci Lett 690:145–150. https://doi.org/10.1016/j.neulet.2018.10.020

    Article  CAS  PubMed  Google Scholar 

  26. Kumar H, Lim HW, More SV, Kim BW, Koppula S, Kim IS, Choi DK (2012) The role of free radicals in the aging brain and Parkinson’s disease: convergence and parallelism. Int J Mol Sci 13(8):10478–10504. https://doi.org/10.3390/ijms130810478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, Dar HH, Liu B et al (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81–90. https://doi.org/10.1038/nchembio.2238

    Article  CAS  PubMed  Google Scholar 

  29. Forred BJ, Daugaard DR, Titus BK, Wood RR, Floen MJ, Booze ML, Vitiello PF (2017) Detoxification of mitochondrial oxidants and apoptotic signaling are facilitated by Thioredoxin-2 and Peroxiredoxin-3 during hyperoxic injury. PLoS One 12(1):e0168777. https://doi.org/10.1371/journal.pone.0168777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62(6):649–671. https://doi.org/10.1016/s0301-0082(99)00060-x

    Article  CAS  PubMed  Google Scholar 

  31. Branco V, Coppo L, Sola S, Lu J, Rodrigues CMP, Holmgren A, Carvalho C (2017) Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury. Redox Biol 13:278–287. https://doi.org/10.1016/j.redox.2017.05.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schriever SC, Zimprich A, Pfuhlmann K, Baumann P, Giesert F, Klaus V, Kabra DG, Hafen U et al (2017) Alterations in neuronal control of body weight and anxiety behavior by glutathione peroxidase 4 deficiency. Neuroscience 357:241–254. https://doi.org/10.1016/j.neuroscience.2017.05.050

    Article  CAS  PubMed  Google Scholar 

  33. Bellinger FP, Bellinger MT, Seale LA, Takemoto AS, Raman AV, Miki T, Manning-Bog AB, Berry MJ et al (2011) Glutathione peroxidase 4 is associated with neuromelanin in substantia nigra and dystrophic axons in putamen of Parkinson’s brain. Mol Neurodegener 6(1):8. https://doi.org/10.1186/1750-1326-6-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, Pratt DA (2017) On the Mechanism of cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the role of lipid peroxidation in FERROPTOTIC CELL DEATH. ACS central science 3(3):232–243. https://doi.org/10.1021/acscentsci.7b00028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Booty LM, Gawel JM, Cvetko F, Caldwell ST, Hall AR, Mulvey JF, James AM, Hinchy EC et al (2019) Selective disruption of mitochondrial thiol redox state in cells and in vivo. Cell Chem Biol 26(3):449–461 e448. https://doi.org/10.1016/j.chembiol.2018.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Watanabe T, Sekine S, Naguro I, Sekine Y, Ichijo H (2015) Apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway-dependent cytoplasmic translocation of the orphan nuclear receptor NR4A2 Is required for oxidative stress-induced necrosis. J Biol Chem 290(17):10791–10803. https://doi.org/10.1074/jbc.M114.623280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Du Y, Zhang H, Zhang X, Lu J, Holmgren A (2013) Thioredoxin 1 is inactivated due to oxidation induced by peroxiredoxin under oxidative stress and reactivated by the glutaredoxin system. J Biol Chem 288(45):32241–32247. https://doi.org/10.1074/jbc.M113.495150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sun Y, He L, Wang T, Hua W, Qin H, Wang J, Wang L, Gu W et al (2020) Activation of p62-Keap1-Nrf2 Pathway Protects 6-Hydroxydopamine-induced ferroptosis in dopaminergic cells. Mol Neurobiol 57:4628–4641. https://doi.org/10.1007/s12035-020-02049-3

    Article  CAS  PubMed  Google Scholar 

  39. Luo M, Shang L, Brooks MD, Jiagge E, Zhu Y, Buschhaus JM, Conley S, Fath MA et al (2018) Targeting breast cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab 28(1):69–86 e66. https://doi.org/10.1016/j.cmet.2018.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Zhizhou Shi and Zewen Fang for their technical assistance with quantitative polymerase chain reaction analysis.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81660222, U1202227); the Yunling Scholar (No. 1097821401); and the Key Lab for Oxidative Stress Damage and Defense in University of Yunnan Province (2018).

Author information

Authors and Affiliations

  1. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China

    Liping Bai & Rou Gu

  2. Laboratory of Molecular Neurobiology, Medical School, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming, 650500, China

    Liping Bai, Fang Yan, Ruhua Deng, Rou Gu, Xianwen Zhang & Jie Bai

Authors
  1. Liping Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fang Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruhua Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rou Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xianwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Liping Bai performed the biochemical analyses, the western blot, and PCR analysis. Jie Bai designed and supervised the study. Liping Bai and Jie Bai analyzed the data and wrote the paper. Fang Yan and Xianwen Zhang performed the behavioral experiments and contributed to part of the acquisition of animal data. Ruhua Deng and Rou Gu assisted with getting mice tissues. All authors have read and approved final version.

Corresponding author

Correspondence to Jie Bai.

Ethics declarations

Ethics Approval

Our study followed the conventional requirements of experimental operation and was approved by the local Committee on Animal Use and Protection of Yunnan province (No. LA2008305).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare 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

Bai, L., Yan, F., Deng, R. et al. Thioredoxin-1 Rescues MPP+/MPTP-Induced Ferroptosis by Increasing Glutathione Peroxidase 4. Mol Neurobiol 58, 3187–3197 (2021). https://doi.org/10.1007/s12035-021-02320-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02320-1

Keywords

Search

Navigation