The Importance of Thioredoxin (Trx) and Glutathione-Glutaredoxin (GSH/Grx) Systems in Terms of Aging

Öz

Oxidative stress results from an imbalance between the production of free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the body's ability to counteract their harmful effects. This imbalance can lead to cellular damage, contributing to the development of aging and various aging-related diseases, such as cardiovascular disease, neurodegenerative disorders, and cancer. ROS are produced by cellular sources such as the endogenous mitochondrial respiratory chain, the cytochrome P450 system's detoxification of xenobiotics, and the phagocytes' nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and myeloperoxidase (MPO) killing of bacteria. These ROS are generated by both endogenous and exogenous sources and are protected against by enzymatic antioxidant systems, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), thioredoxin (Trx), and glutathione-glutaredoxin (GSH/Grx) systems, as well as non-enzymatic antioxidant systems like GSH, urate, and coenzyme Q10. Apart from providing antioxidant defense, the Trx and GSH/Grx systems also play roles in thiol-based redox signaling and redox homeostasis. Thiol-based cysteine modifications mediated by redox signals, including S-glutathionylation, S-nitrosylation, and S-sulfhydration, can be reversed by Trx and GSH/Grx systems. Trx, TrxR, and Grx may also alter cellular senescence and lifetime through their interactions with different signaling pathways and transcription factors. These systems' important properties may increase interest in them in the near future. Understanding the complex interactions between the Trx and GSH/Grx systems might help develop novel anti-aging novel treatment strategies that increase cellular resilience and longevity.

Anahtar Kelimeler

• Thioredoxin (Trx)
• glutathione (GSH)
• glutaredoxin (Grx)
• antioxidant system
• aging.

Destekleyen Kurum

No

Proje Numarası

No

Etik Beyan

No

Teşekkür

No

Tiyoredoksin (Trx) ve Glutatyon-Glutaredoksin (GSH/Grx) Sistemlerinin Yaşlanma Açısından Önemi

Öz

Oksidatif stres, reaktif oksijen türleri (ROT) ile reaktif nitrojen türleri (RNT) gibi serbest radikallerin üretimi ile vücudun bunların zararlı etkilerine karşı koyma yeteneği arasındaki dengesizlikten kaynaklanır. Bu dengesizlik hücresel hasara yol açarak yaşlanma ve yaşlanmaya bağlı kardiyovasküler hastalıklar, nörodejeneratif bozukluklar ve kanser gibi çeşitli hastalıkların gelişimine katkıda bulunabilir. Mitokondriyal solunum zinciri, fagositlerde nikotinamit adenin dinükleotid fosfat (NADPH) oksidaz (NOX) ve miyeloperoksidaz (MPO) ile bakterilerin öldürülmesinde, sitokrom P450 sistemi ile ksenobiyotiklerin detoksifikasyonu gibi hücresel kaynaklar endojen olarak ROS üretirler. Endojen ve eksojen kaynaklı üretilen bu ROT'lara karşı vücutta süperoksit dismuaz (SOD), katalaza (CAT), glutatyon peroksidaz (GPx), tiyoredoksin (Trx) ve glutatyon-glutaredoksin (GSH/Grx) sistemleri gibi enzimatik ve redükte glutatyon (GSH), ürat, koenzim Q10 gibi nonenzimatik antioksidan sistemler savunmaya geçerler. Trx ve GSH/Grx sistemleri, antioksidan koruma haricinde redoks homeostazisinde, tiyol - bazlı redoks sinyalizasyonunda rol oynarlar. Trx ve GSH/Grx sistemleri, redoks sinyalleri tarafından aracılık edilen S-glutatyonilasyon, S-nitrozilasyon ve S-sülfhidrasyon gibi tiyol - bazlı sistein modifikasyonlarını tersine dönüştürebilir. Yine Trx, TrxR ve Grx farklı sinyal yolları ve transkripsiyon faktörleriyle etkileşimleri sonucunda hücresel yaşlanma ve yaşam süresi üzerinde değişiklikler yapabilir. Böyle önemli özelliklere sahip olmaları yakın gelecekte bu sistemlere olan ilgiyi arttırabilir. Trx ve GSH/Grx sistemleri arasındaki karmaşık ilişkilerin anlaşılması, hücresel dayanıklılığı ve ömrü artıran yeni yaşlanma karşıtı tedavi stratejilerinin geliştirilmesine yardımcı olabilir.

Anahtar Kelimeler

• Tiyoredoksin (Trx)
• glutatyon (GSH)
• glutaredoksin (Grx)
• antioksidan sistem
• yaşlanma.

Destekleyen Kurum

Yok

Proje Numarası

No

Etik Beyan

Yok

Teşekkür

Yok

Kaynakça

1. 1. Partridge L., & Gems, D. (2002). Mechanisms of ageing: public or private? Nat. Rev. Genet., 3, 165–175.
2. 2. Kennedy, B.K., Berger, S.L., Brunet, A, Campisi, J, Cuervo, A.M., Epel, E.S., Franceschi, C, Lithgow, G.J., Morimoto, R.I., Pessin, J.E., Rando, T.A., Richardson, A., Schadt, E.E., Wyss-Coray. T., & Sierra. F. (2014). Geroscience: linking aging to chronic disease. Cell., 159(4), 709-13.
3. 3. DiLoreto, R., & Murphy, C.T. (2015). The cell biology of aging. Mol. Biol. Cell., 26(25), 4524–4531.
4. 4. Mandal, M., Sarkar, M., Khan, A., Biswas, M., Masi, A., Rakwal, R., Agrawal, G.K., Srivastava, A., & Sarkar, A. (2022). Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) in plants–maintenance of structural individuality and functional blend. Advances in Redox Research, 5, 100039.
5. 5. Zorov, D.B., Juhaszova, M., & Sollott, S.J. (2014). Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev., 94(3), 909-50.
6. 6. Phaniendra, A., Jestadi, D.B., & Periyasamy, L. (2015). Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem., 30(1), 11-26.
7. 7. Martemucci, G., Costagliola, C., Mariano, M., D’andrea, L., Napolitano, P., & D’Alessandro, A. G. (2022). Free Radical Properties, Source and Targets, Antioxidant Consumption and Health. Oxygen, 2(2), 48-78.
8. 8. Chandimali, N., Bak, S.G., Park, E.H., Lim, H.J., Won, Y.S., Kim, E.K., Park, S.I., & Lee, S.J. (2025). Free radicals and their impact on health and antioxidant defenses: a review. Cell Death Discov., 11(1), 19.

9. 9. Collin, F. (2019). Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases. Int J Mol Sci., 20(10), 2407.
10. 10. Pacher, P., Beckman, J.S., & Liaudet, L. (2007). Nitric oxide and peroxynitrite in health and disease. Physiol Rev., 87(1), 315-424.
11. 11. Radi, R. (2004). Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA., 101(12), 4003-8.
12. 12. Hajam, Y.A., Rani, R., Ganie, S.Y., Sheikh, T.A., Javaid, D., Qadri, S.S., Pramodh, S., Alsulimani, A., Alkhanani, M.F., Harakeh, S., Hussain, A., Haque, S., & Reshi, M.S. (2022). Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells., 11(3), 552.
13. 13. Biala, A.K., Dhingra, R., & Kirshenbaum, L.A. (2015). Mitochondrial dynamics: Orchestrating the journey to advanced age. J. Mol. Cell. Cardiol., 83, 37–43.
14. 14. Bratic, A., & Larsson, N.G. (2013). The role of mitochondria in aging. J. Clin. Investig., 123, 951–957.
15. 15. Indo, H.P., Yen, H.C., Nakanishi, I., Matsumoto, K.I., Tamura, M., Nagano, Y., Matsui, H., Gusev, O., Cornette, R., Okuda, T., Minamiyama, Y., Ichikawa, H., Suenaga, S., Oki, M., Sato, T., Ozawa, T., Clair, D.K., & Majima, H.J. (2015). A mitochondrial superoxide theory for oxidative stress diseases and aging. J. Clin. Biochem. Nutr., 56, 1–7.
16. 16. Bjelakovic, G., Nikolova, D., Gluud, C. (2014). Antioxidant supplements and mortality. Curr. Opin. Clin. Nutr. Metab. Care., 17, 40–44.
17. 17. Kushnareva, Y., Murphy, A.N., & Andreyev, A. (2002). Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem. J., 368(Pt 2), 545–553.
18. 18. Chen, Q., Vazquez, E.J., Moghaddas, S., Hoppel, C.L., & Lesnefsky, E.J. (2003). Production of reactive oxygen species by mitochondria: central role of complex III. J. Biol. Chem., 278(38), 36027–36031.
19. 19. Balaban, R.S., Nemoto, S., & Finkel, T. (2005). Mitochondria, oxidants, and aging. Cell, 120(4), 483–495.
20. 20. Van Raamsdonk, J.M., & Hekimi, S. (2010). Reactive oxygen species and aging in caenorhabditis elegans: causal or casual relationship? Antioxid Redox Signal., 13(12), 1911–1953.
21. 21. Beckman, KB, & Ames, B.N. (1998). The free radical theory of aging matures. Physiol Rev., 78(2), 547-81.
22. 22. Nguyen, G.T., Green, E.R., & Mecsas, J. (2017). Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front Cell Infect Microbiol., 7, 373.
23. 23. Lambeth, J.D. (2004). NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol., 4(3), 181-9.
24. 24. McDonnell, A.M., & Dang, C.H. (2013). Basic review of the cytochrome p450 system. J Adv Pract Oncol., 4(4), 263-8.
25. 25. Battelli, M.G., Polito, L., Bortolotti, M., & Bolognesi, A. (2016). Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme. Curr Med Chem., 23(35), 4027-4036.
26. 26. McCord, J.M., & Fridovich, I. (1969). Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem., 244(22), 6049-55.
27. 27. Shih, J.C., Chen, K., & Ridd, M.J. (1999). Monoamine oxidase: from genes to behavior. Annu Rev Neurosci., 22, 197-217.
28. 28. Lismont, C., Nordgren, M., Van Veldhoven, P.P., & Fransen, M. (2015). Redox interplay between mitochondria and peroxisomes. Front Cell Dev Biol., 3, 35.
29. 29. Yang, J., Luo, J., Tian, X., Zhao, Y., Li, Y., & Wu, X. (2024). Progress in Understanding Oxidative Stress, Aging, and Aging-Related Diseases. Antioxidants (Basel)., 13(4), 394.
30. 30. Ayala, A., Muñoz, M.F., & Argüelles, S. (2014). Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev., 2014, 360438.
31. 31. Barrera, G., Pizzimenti, S., Daga, M., Dianzani, C., Arcaro, A., Cetrangolo, G.P., Giordano, G., Cucci, M.A., Graf, M., & Gentile, F. (2018). Lipid Peroxidation-Derived Aldehydes, 4-Hydroxynonenal and Malondialdehyde in Aging-Related Disorders. Antioxidants (Basel)., 7(8), 102.
32. 32. Domínguez, R., Pateiro, M., Munekata, P.E.S., Zhang, W., Garcia-Oliveira, P., Carpena, M., Prieto, M.A., Bohrer, B., & Lorenzo, J.M. (2021). Protein Oxidation in Muscle Foods: A Comprehensive Review. Antioxidants (Basel)., 11(1), 60.
33. 33. Höhn, A., König, J., & Grune, T. (2013). Protein oxidation in aging and the removal of oxidized proteins. J Proteomics., 92, 132-59.
34. 34. Juan, C.A., Pérez de la Lastra, J.M., Plou, F.J., & Pérez-Lebeña, E. (2021). The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies. Int J Mol Sci., 22(9), 4642.
35. 35. van der Pol, A., van Gilst, W.H., Voors, A.A., & van der Meer, P. (2019). Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail., 21(4), 425-435.
36. 36. Shields, H.J., Traa, A., & Van Raamsdonk, J.M. (2021). Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies. Front Cell Dev Biol., 9, 628157.
37. 37. Lushchak, VI. (2014).Classification of oxidative stress based on its intensity.EXCLI J., 13, 922-37.
38. 38. D'Oria, R., Schipani, R., Leonardini, A., Natalicchio, A., Perrini, S., Cignarelli, A., Laviola, L., & Giorgino, F. (2020). The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor. Oxid Med Cell Longev., 2020, 5732956.
39. 39. Gaucher, C., Boudier, A., Bonetti, J., Clarot, I., Leroy, P., & Parent. M. (2018). Glutathione: Antioxidant Properties Dedicated to Nanotechnologies. Antioxidants (Basel)., 7(5), 62.
40. 40. Aramouni, K., Assaf, R., Shaito, A., Fardoun, M., Al-Asmakh, M., Sahebkar, A., & Eid, A.H. (2023). Biochemical and cellular basis of oxidative stress: Implications for disease onset. J Cell Physiol., 238(9), 1951-1963.
41. 41. Ren, X., Zou, L., Zhang, X., Branco, V., Wang, J., Carvalho, C., Holmgren, A, & Lu, J. (2017). Redox Signaling Mediated by Thioredoxin and Glutathione Systems in the Central Nervous System. Antioxid Redox Signal., 27(13), 989-1010.
42. 42. Lee, S., Kim, S.M., & Lee, RT. (2013). Thioredoxin and thioredoxin target proteins: from molecular mechanisms to functional significance. Antioxid Redox Signal., 18(10), 1165-207.
43. 43. Hanschmann, E.M., Godoy, J.R., Berndt, C., Hudemann, C., & Lillig, CH. (2013). Thioredoxins, glutaredoxins, and peroxiredoxins--molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling. Antioxid Redox Signal., 19(13), 1539-605.
44. 44. Arnhold, J. (2020). Cell and Tissue Destruction. Mechanisms, Protection, Disorders. Academic Press; London, UK: San Diego, CA, USA: Cambridge, MA, USA: Oxford, UK. Oxidation and reduction of biological material, pp. 55–97.
45. 45. Yang, B., Lin, Y., Huang, Y., Shen, Y.Q., & Chen, Q. (2024). Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases. Redox Biol., 70, 103032.
46. 46. Lee, S., Kim, S.M., & Lee, RT. (2013). Thioredoxin and thioredoxin target proteins: from molecular mechanisms to functional significance. Antioxid Redox Signal., 18(10),1165-207.
47. 47. McBean, G.J., Aslan, M., Griffiths, H.R., & Torrão, R.C. (2015). Thiol redox homeostasis in neurodegenerative disease. Redox Biol., 5, 186-194.
48. 48. Moriarty-Craige, S.E., & Jones, D.P. (2004). Extracellular thiols and thiol/disulfide redox in metabolism. Annu. Rev. Nutr., 24, 481-509.
49. 49. Kalinina, E, & Novichkova, M. (2021). Glutathione in Protein Redox Modulation through S-Glutathionylation and S-Nitrosylation. Molecules., 26(2), 435.
50. 50. Zhu, J.W., Yuan, J.F., Yang, H.M., Wang, S.T., Zhang, C.G., Sun, L.L., Yang, H., & Zhang, H. (2012). Extracellular cysteine (Cys)/cystine (CySS) redox regulates metabotropic glutamate receptor 5 activity. Biochimie., 94(3), 617-27.
51. 51. Winterbourn, CC. (2014). Are free radicals involved in thiol-based redox signaling? Free Radic Biol Med., 80, 164-70.
52. 52. Ferguson, G.D., & Bridge, W.J. (2019). The glutathione system and the related thiol network in Caenorhabditis elegans. Redox Biol., 24, 101171.
53. 53. Gorgoulis, V., Adams, P.D., Alimonti, A., Bennett, D.C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., Gil, J., Hara, E., Krizhanovsky, V., Jurk, D., Maier, A.B., Narita, M., Niedernhofer, L., Passos, J.F., Robbins, P.D., Schmitt, C.A., Sedivy, J., Vougas., K., von Zglinicki, T., Zhou, D., Serrano, M., & Demaria, M. (2019). Cellular Senescence: Defining a Path Forward. Cell., 179(4), 813-827.
54. 54. Drechsel, D.A., & Patel, M. (2010). Respiration-dependent H2O2 removal in brain mitochondria via the thioredoxin/peroxiredoxin system. J Biol Chem., 285(36), 27850-8.
55. 55. Jee, C., Vanoaica, L., Lee, J., Park, B.J., & Ahnn, J. (2005). Thioredoxin is related to life span regulation and oxidative stress response in Caenorhabditis elegans. Genes Cells., 10(12), 1203-10.
56. 56. Missirlis, F., Phillips, J.P., & Jäckle, H. (2001). Cooperative action of antioxidant defense systems in Drosophila. Curr Biol., 11(16), 1272-7.
57. 57. Pérez, VI, Lew, C.M., Cortez, L.A., Webb, C.R., Rodriguez, M., Liu, Y., Qi, W., Li, Y., Chaudhuri, A., Van Remmen, H., Richardson, A., & Ikeno, Y. (2008). Thioredoxin 2 haploinsufficiency in mice results in impaired mitochondrial function and increased oxidative stress. Free Radic Biol Med., 44(5), 882-92.
58. 58. Liu, Y., Yang, F., Li, S., Dai, J., & Deng, H. (2018). Glutaredoxin Deletion Shortens Chronological Life Span in Saccharomyces cerevisiae via ROS-Mediated Ras/PKA Activation. J Proteome Res., 17(7), 2318-2327.
59. 59. Zadrag, R., Bartosz, G., & Bilinski, T. (2008). Is the yeast a relevant model for aging of multicellular organisms? An insight from the total lifespan of Saccharomyces cerevisiae. Curr Aging Sci., 1(3), 159-65.