Skip to main content
SpringerLink
Log in

Quantitative Redox Biology: An Approach to Understand the Role of Reactive Species in Defining the Cellular Redox Environment

  • Review Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Systems biology is now recognized as a needed approach to understand the dynamics of inter- and intra-cellular processes. Redox processes are at the foundation of nearly all aspects of biology. Free radicals, related oxidants, and antioxidants are central to the basic functioning of cells and tissues. They set the cellular redox environment and, therefore, are the key to regulation of biochemical pathways and networks, thereby influencing organism health. To understand how short-lived, quasi-stable species, such as superoxide, hydrogen peroxide, and nitric oxide, connect to the metabolome, proteome, lipidome, and genome we need absolute quantitative information on all redox active compounds as well as thermodynamic and kinetic information on their reactions, i.e., knowledge of the complete redoxome. Central to the state of the redoxome are the interactive details of the superoxide/peroxide formation and removal systems. Quantitative information is essential to establish the dynamic mathematical models needed to reveal the temporal evolution of biochemical pathways and networks. This new field of Quantitative Redox Biology will allow researchers to identify new targets for intervention to advance our efforts to achieve optimal human health.

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

Similar content being viewed by others

References

  1. Russell, R., & Superti-Furga, G. (2005). Systems biology: Understanding the biological mosaic. FEBS Letters, 579, 1771.

    Article  CAS  Google Scholar 

  2. Forman, H. J., Torres, M., Fukuto, J. (2003). Signal transduction by reactive oxygen and nitrogen species: Pathways and chemical principles. Dordrecht, The Netherlands: Kluwer Academic Publishers.

  3. Nathan, C. (2003). Specificity of a third kind: Reactive oxygen and nitrogen intermediates in cell signaling. Journal of Clinical Investigation, 111, 769–778.

    PubMed  CAS  Google Scholar 

  4. Cooper, C. E., Patel, R. P., Brookes, P. S., & Darley-Usmar, V. M. (2002). Nanotransducers in cellular redox signaling: Modification of thiols by reactive oxygen and nitrogen species. Trends in Biochemical Sciences, 27, 489–492.

    Article  PubMed  CAS  Google Scholar 

  5. Buettner, G. R. (2011). Superoxide dismutase in redox biology: The roles of superoxide and hydrogen peroxide. Anticancer Agents in Medicinal Chemistry, 11, 341–346.

    Article  CAS  Google Scholar 

  6. Schafer, F. Q., & Buettner, G. R. (2001). Redox state of the cell as viewed though the glutathione disulfide/glutathione couple. Free Radical Biology and Medicine, 30, 1191–1212.

    Article  PubMed  CAS  Google Scholar 

  7. Wagner, B. A., Venkataraman, S., & Buettner, G. R. (2011). The rate of oxygen utilization by cells. Free Radical Biology and Medicine, 51, 700–712.

    Article  PubMed  CAS  Google Scholar 

  8. Maulik, N., & Das, D. K. (2002). Redox signaling in vascular angiogenesis. Free Radical Biology and Medicine, 33, 1047–1060.

    Article  PubMed  CAS  Google Scholar 

  9. Forman, H. J., Torres, M., & Fukuto, J. (2002). Redox signaling. Molecular and Cellular Biochemistry, 234–235, 49–62.

    Article  PubMed  Google Scholar 

  10. Oh, J. I., & Kaplan, S. (2000). Redox signaling: Globalization of gene expression. EMBO Journal, 19, 4237–4247.

    Article  PubMed  CAS  Google Scholar 

  11. Sen, C. K. (2000). Cellular thiols and redox-regulated signal transduction. Current Topics in Cellular Regulation, 36, 1–30.

    Article  PubMed  CAS  Google Scholar 

  12. Rhee, S. G. (1999). Redox signaling: Hydrogen peroxide as intracellular messenger. Experimental & Molecular Medicine, 31, 53–59.

    Article  CAS  Google Scholar 

  13. Cai, J., & Jones, D. P. (1999). Mitochondrial redox signaling during apoptosis. Journal of Bioenergetics and Biomembranes, 31, 327–334.

    Article  PubMed  CAS  Google Scholar 

  14. Powis, G., Gasdaska, J. R., & Baker, A. (1997). Redox signaling and the control of cell growth and death. Advances in Pharmacology, 38, 329–359.

    Article  PubMed  CAS  Google Scholar 

  15. Sun, Y., & Oberley, L. W. (1996). Redox regulation of transcriptional activators. Free Radical Biology and Medicine, 21, 335–348.

    Article  PubMed  CAS  Google Scholar 

  16. Menon, S. G., Sarsour, E. H., Spitz, D. R., Higashikubo, R., Sturm, M., Zhang, H., et al. (2003). Redox regulation of the G1 to S transition in the mouse embryo fibroblast cell cycle. Cancer Research, 63, 2109–2117.

    PubMed  CAS  Google Scholar 

  17. Menon, S. G., Sarsour, E. H., Kalen, A. L., Venkataraman, S., Oberley, L. W., & Goswami, P. C. (2007). Superoxide signaling mediates N-acetyl-l-cysteine induced G1 arrest: Regulatory role of manganese superoxide dismutase and cyclin D1. Cancer Research, 67, 6392–6399.

    Article  PubMed  CAS  Google Scholar 

  18. McCord, J. M., & Fridovich, I. (1968). The reduction of cytochrome c by milk xanthine oxidase. Journal of Biological Chemistry, 243, 5753–5760.

    PubMed  CAS  Google Scholar 

  19. McCord, J. M., & Fridovich, I. (1969). Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). Journal of Biological Chemistry, 244, 6049–6055.

    PubMed  CAS  Google Scholar 

  20. Oberley, L. W., Oberley, T. D., & Buettner, G. R. (1981). Cell division in normal and transformed cells: The possible role of superoxide dismutase and hydrogen peroxide. Medical Hypotheses, 7, 21–42.

    Article  PubMed  CAS  Google Scholar 

  21. Gechev, T. S., & Hille, J. (2005). Hydrogen peroxide as a signal controlling plant programmed cell death. Journal of Cell Biology, 168, 17–20.

    Article  PubMed  CAS  Google Scholar 

  22. Patel, R. P., Moellering, D., Murphy-Ullrich, J., Jo, H., Beckman, J. S., & Darley-Usmar, V. M. (2000). Cell signaling by reactive nitrogen and oxygen species in atherosclerosis. Free Radical Biology and Medicine, 28, 1780–1794.

    Article  PubMed  CAS  Google Scholar 

  23. Moriarty-Craige, S. E., & Jones, D. P. (2004). Extracellular thiols and thiol/disulfide redox in metabolism. Annual Review of Nutrition, 24, 481–509.

    Article  PubMed  CAS  Google Scholar 

  24. Menon, S. G., & Goswami, P. C. (2007). A redox cycle within the cell cycle: Ring in the old with the new. Oncogene, 26, 1101–1109.

    Article  PubMed  CAS  Google Scholar 

  25. Sarsour, E. H., Kumar, M. G., Chaudhuri, L., Kalen, A. L., & Goswami, P. C. (2009). Redox control of the cell cycle in health and disease. Antioxidants & Redox Signaling, 11, 2985–3011.

    Article  CAS  Google Scholar 

  26. Sarsour, E. H., Venkataraman, S., Kalen, A. L., Oberley, L. W., & Goswami, P. C. (2008). Manganese superoxide dismutase activity regulates transitions between quiescent and proliferative growth. Aging Cell, 7, 405–417.

    Article  PubMed  CAS  Google Scholar 

  27. Burhans, W. C., & Heintz, N. H. (2009). The cell cycle is a redox cycle: Linking phase-specific targets to cell fate. Free Radical Biology and Medicine, 47, 1282–1293.

    Article  PubMed  CAS  Google Scholar 

  28. Watson, W. H., Cai, J., & Jones, D. P. (2000). Diet and apoptosis. Annual Review of Nutrition, 20, 485–505.

    Article  PubMed  CAS  Google Scholar 

  29. Watson, W. H., Chen, Y., & Jones, D. P. (2003). Redox state of glutathione and thioredoxin in differentiation and apoptosis. Biofactors, 17, 307–314.

    Article  PubMed  CAS  Google Scholar 

  30. Jiang, S., Moriarty-Craige, S. E., Orr, M., Cai, J., Sternberg, P., Jr, & Jones, D. P. (2005). Oxidant-induced apoptosis in human retinal pigment epithelial cells: Dependence on extracellular redox state. Investigative Ophthalmology & Visual Science, 46, 1054–1061.

    Article  Google Scholar 

  31. Allen, R. G., Newton, R. K., Sohal, R. S., Shipley, G. L., & Nations, C. (1985). Alterations in superoxide dismutase, glutathione, and peroxides in the plasmodial slime mold Physarum polycephalum during differentiation. Journal of Cellular Physiology, 125, 413–419.

    Article  PubMed  CAS  Google Scholar 

  32. Schafer, F. Q., & Buettner, G. R. (2003). Redox state and redox environment in biology. In H. J. Forman, M. Torres, & J. Fukuto (Eds.), Signal transduction by reactive oxygen, nitrogen species: Pathways, chemical principles (pp. 1–14). Dordrecht, The Netherlands: Kluwer Academic Publishers.

    Google Scholar 

  33. Nkabyo, Y. S., Ziegler, T. R., Gu, L. H., Watson, W. H., & Jones, D. P. (2002). Glutathione and thioredoxin redox during differentiation in human colon epithelial (Caco-2) cells. American Journal of Physiology–Gastrointestinal & Liver Physiology, 283, G1352–G1359.

    CAS  Google Scholar 

  34. Mannery, Y. O., Ziegler, T. R., Park, Y., & Jones, D. P. (2010). Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans. Journal of Pharmacology and Experimental Therapeutics, 333, 939–947.

    Article  PubMed  CAS  Google Scholar 

  35. Iyer, S. S., Accardi, C. J., Ziegler, T. R., Blanco, R. A., Ritzenthaler, J. D., Rojas, M., et al. (2009). Cysteine redox potential determines pro-inflammatory IL-1beta levels. PLoS One, 4(3), e5017.

    Article  PubMed  Google Scholar 

  36. Jones, D. P., & Liang, Y. (2009). Measuring the poise of thiol/disulfide couples in vivo. Free Radical Biology and Medicine, 47(10), 1329–1338.

    Article  PubMed  CAS  Google Scholar 

  37. Shyntum, Y., Iyer, S. S., Tian, J., Hao, L., Mannery, Y. O., Jones, D. P., et al. (2009). Dietary sulfur amino acid supplementation reduces small bowel thiol/disulfide redox state and stimulates ileal mucosal growth after massive small bowel resection in rats. Journal of Nutrition, 139(12), 2272–2278.

    Article  PubMed  CAS  Google Scholar 

  38. Antunes, F., Salvador, A., Marinho, H. S., Alves, R., & Pinto, R. E. (1996). Lipid peroxidation in mitochondrial inner membranes. I. An integrative kinetic model. Free Radical Biology and Medicine, 21(7), 917–943.

    Article  PubMed  CAS  Google Scholar 

  39. Marinho, H. S., Antunes, F., & Pinto, R. E. (1997). Role of glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase in the reduction of lysophospholipid hydroperoxides. Free Radical Biology and Medicine, 22(5), 871–883.

    Article  PubMed  CAS  Google Scholar 

  40. Johnson, R. M., Ho, Y. S., Yu, D. Y., Kuypers, F. A., Ravindranath, Y., & Goyette, G. W. (2010). The effects of disruption of genes for peroxiredoxin-2, glutathione peroxidase-1, and catalase on erythrocyte oxidative metabolism. Free Radical Biology and Medicine, 48(4), 519–525.

    Article  PubMed  CAS  Google Scholar 

  41. Adimora, N. J., Jones, D. P., & Kemp, M. L. (2010). A model of redox kinetics implicates the thiol proteome in cellular hydrogen peroxide responses. Antioxidants & Redox Signaling, 2010, 731–743.

    Article  Google Scholar 

  42. Jones, D. P. (2006). Disruption of mitochondrial redox circuitry in oxidative stress. Chemico-Biological Interactions, 163(1–2), 38–53.

    Article  PubMed  CAS  Google Scholar 

  43. Wang, M., Kirk, J. S., Venkataraman, S., Domann, F. E., Zhang, H. J., Schafer, F. Q., et al. (2005). Manganese superoxide dismutase suppresses hypoxic induction of hypoxia inducible factor-1α and vascular endothelial growth factor. Oncogene, 24, 8154–8166.

    PubMed  CAS  Google Scholar 

  44. Kaewpila, S., Venkataraman, S., Buettner, G. R., & Oberley, L. W. (2008). Manganese superoxide dismutase modulates hypoxia inducible factor-1α induction via superoxide. Cancer Research, 68(8), 2781–2788.

    Article  PubMed  CAS  Google Scholar 

  45. Buettner, G. R., Ng, C. F., Wang, W., Rodgers, V. G. J., & Schafer, F. Q. (2006). A new paradigm: Manganese superoxide dismutase influences the production of H2O2 in cells and thereby their biological state. Free Radical Biology and Medicine, 41, 1338–1350.

    Article  PubMed  CAS  Google Scholar 

  46. Song, Y., & Buettner, G. R. (2010). Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide. Free Radical Biology and Medicine, 49, 919–962.

    Article  PubMed  CAS  Google Scholar 

  47. Funahashi, A., Tanimura, N., Morohashi, M., & Kitano, H. (2003). CellDesigner: A process diagram editor for gene-regulatory and biochemical networks. BIOSILICO, 1, 159–162.

    Article  Google Scholar 

  48. Funahashi, A., Matsuoka, Y., Jouraku, A., Morohashi, M., Kikuchi, N., & Kitano, H. (2008). CellDesigner 3.5: A versatile modeling tool for biochemical networks. Proceedings of the IEEE, 96(8), 1254–1265. doi:10.1109/JPROC.2008.925458.

    Article  Google Scholar 

  49. Aloy, P., & Russel, E. B. (2005). Structure-based systems biology: A zoom lens for the cell. FEBS Letters, 579, 1854–1858.

    Article  PubMed  CAS  Google Scholar 

  50. Takahashi, K., Vel Arjunan, S. N., & Tomita, M. (2005). Space in systems biology signaling pathways—towards intracellular molecular crowding in silico. FEBS Letters, 579, 1783–1788.

    Article  PubMed  CAS  Google Scholar 

  51. Apic, G., Ignjatovic, T., Boyer, S., & Russel, R. B. (2005). Illuminating drug discovery with biological pathways. FEBS Letters, 579, 1872–1877.

    Article  PubMed  CAS  Google Scholar 

  52. O’Brien, P. J. (1991). Molecular mechanisms of quinone cytotoxicity. Chemico-Biological Interactions, 80, 1–41.

    Article  PubMed  Google Scholar 

  53. Chen, Q., Espey, M. G., Sun, A. Y., Lee, J. H., Krishna, M. C., Shacter, E., et al. (2007). Ascorbic acid in pharmacologic concentrations: A pro-drug for selective delivery of ascorbate radical and hydrogen peroxide to extracellular fluid in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104, 8749–8754.

    Article  PubMed  CAS  Google Scholar 

  54. Du, J., Martin, S. M., Levine, M., Wagner, B. A., Buettner, G. R., Wang, S. H., et al. (2010). Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clinical Cancer Research, 16(2), 509–520.

    Article  PubMed  CAS  Google Scholar 

  55. Brigelius-Flohe, R. (1999). Tissue-specific functions of individual glutathione peroxidases. Free Radical Biology and Medicine, 27, 951–965.

    Article  PubMed  CAS  Google Scholar 

  56. Watson, W. H., Yang, X., Choi, Y. E., Jones, D. P., & Kehrer, J. P. (2004). Thioredoxin and its role in toxicology. Toxicological Sciences, 78, 3–14.

    Article  PubMed  CAS  Google Scholar 

  57. Nordberg, J., & Arner, E. S. (2001). Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radical Biology and Medicine, 31, 1287–1312.

    Article  PubMed  CAS  Google Scholar 

  58. Powis, G., & Montfort, W. R. (2001). Properties and biological activities of thioredoxins. Annual Review of Pharmacology and Toxicology, 41, 261–295.

    Article  PubMed  CAS  Google Scholar 

  59. Manevich, Y., Reddy, K. S., Shuvaeva, T., Feinstein, S. I., & Fisher, A. B. (2007). Structure and phospholipase function of peroxiredoxin 6: Identification of the catalytic triad and its role in phospholipid substrate binding. Journal of Lipid Research, 48(10), 2306–23018.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by Grants R01GM073929 from the NIGMS and P42ES013661 from the NIEHS. The content is solely the responsibility of the authors and does not represent views of the NIGMS, NIEHS, or the NIH. The University of Iowa ESR Facility provided invaluable support.

Author information

Authors and Affiliations

  1. Free Radical and Radiation Biology & ESR Facility, Med Labs B180, The University of Iowa, Iowa City, IA, 52242-1181, USA

    Garry R. Buettner & Brett A. Wagner

  2. Bourns College of Engineering, Bioengineering, University of California Riverside, Riverside, CA, USA

    Victor G. J. Rodgers

Authors
  1. Garry R. Buettner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brett A. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor G. J. Rodgers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Garry R. Buettner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buettner, G.R., Wagner, B.A. & Rodgers, V.G.J. Quantitative Redox Biology: An Approach to Understand the Role of Reactive Species in Defining the Cellular Redox Environment. Cell Biochem Biophys 67, 477–483 (2013). https://doi.org/10.1007/s12013-011-9320-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-011-9320-3

Keywords

Search

Navigation