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Cell Biochemistry and Biophysics

, Volume 77, Issue 1, pp 89–98 | Cite as

Low-Temperature EPR Spectroscopy as a Probe-Free Technique for Monitoring Oxidants Formed in Tumor Cells and Tissues: Implications in Drug Resistance and OXPHOS-Targeted Therapies

  • Balaraman KalyanaramanEmail author
  • Gang Cheng
  • Jacek Zielonka
  • Brian BennettEmail author
Original Paper
  • 174 Downloads

Abstract

Oxidants formed from oxidative and nitrative metabolism include reactive oxygen species (ROS) such as superoxide, hydrogen peroxide/lipid hydroperoxides and reactive nitrogen species (RNS) (e.g., peroxynitrite [ONOO] and nitrogen dioxide), and reactive halogenated species (e.g., hypochlorous acid [HOCl]). Increasingly, ROS and RNS are implicated in tumorigenesis as well as tumor growth, progression, and metastasis. Recently, ROS were implicated in drug resistance, metabolic reprogramming, and T-cell metabolism in immunotherapy. Mostly, fluorescent probes have been used in cell culture systems. The identity of species is obtained by LC–MS analyses of diagnostic marker products. However, extrapolation of these assays to cancer xenografts is difficult if not impossible. Thus, development of a probe-free assay for monitoring and assessing oxidant formation in tumor cells and tumor xenografts is critical and timely. Here, we describe the use of ex vivo electron paramagnetic resonance (EPR) spectroscopy at cryogenic temperatures as a uniquely useful probe-free technique for assessing intracellular oxidation and oxidants via EPR signals from redox centers, particularly iron-sulfur clusters, in mitochondrial and cytosolic redox proteins. Examples of cancer cells subjected to inhibition of mitochondrial oxidative phosphorylation are presented. This ex vivo methodology can be readily extended to monitor oxidant formation in tumor tissues isolated from mice and humans.

Keywords

Electron paramagnetic resonance Reactive oxygen species Oxidative phosphorylation Mitochondrial targeting 

Notes

Acknowledgements

This research was supported by NIH NCI U01 CA178960 to B.K., NIH NCI R01 CA208648 to B.K., the Quadracci Endowment to B.K., and an MCW Cancer Center award to B.K. and B.B. EPR was supported by an NSF Major Research Instrumentation award (CHE-1532168 to B.B.) and by Bruker BioSpin.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Wang, H., Gao, Z., Liu, X., Agarwal, P., Zhao, S., Conroy, D. W., Ji, G., Yu, J., Jaroniec, C. P., Liu, Z., Lu, X., Li, X., & He, X. (2018). Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance. Nature Communications, 9, 562.CrossRefGoogle Scholar
  2. 2.
    Wangpaichitr, M., Kandemir, H., Li, Y.Y., Wu, C., Nguyen, D., Feun, L.G., Kuo, M.T., & Savaraj, N. (2017). Relationship of metabolic alterations and PD-L1 expression in cisplatin resistant lung cancer. Cell and Developmental Biology, 6, pii:183.Google Scholar
  3. 3.
    Wangpaichitr, M., Wu, C., Li, Y. Y., Nguyen, D. J. M., Kandemir, H., Shah, S., Chen, S., Feun, L. G., Prince, J. S., Kuo, M. T., & Savaraj, N. (2017). Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer. Oncotarget, 8, 49275–49292.CrossRefGoogle Scholar
  4. 4.
    Vazquez, F., Lim, J. H., Chim, H., Bhalla, K., Girnun, G., Pierce, K., Clish, C. B., Granter, S. R., Widlund, H. R., Spiegelman, B. M., & Puigserver, P. (2013). PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell, 23, 287–301.CrossRefGoogle Scholar
  5. 5.
    Holmstrom, K. M., & Finkel, T. (2014). Cellular mechanisms and physiological consequences of redox-dependent signalling. Nature Reviews Molecular Cell Biology, 15, 411–421.CrossRefGoogle Scholar
  6. 6.
    Durand, N., & Storz, P. (2017). Targeting reactive oxygen species in development and progression of pancreatic cancer. Expert Review of Anticancer Therapy, 17, 19–31.CrossRefGoogle Scholar
  7. 7.
    Gorrini, C., Harris, I. S., & Mak, T. W. (2013). Modulation of oxidative stress as an anticancer strategy. Nature Reviews Drug Discovery, 12, 931–947.CrossRefGoogle Scholar
  8. 8.
    Chio, I. I. C., & Tuveson, D. A. (2017). ROS in cancer: the burning question. Trends in Molecular Medicine, 23, 411–429.CrossRefGoogle Scholar
  9. 9.
    Idelchik, M., Begley, U., Begley, T. J., & Melendez, J. A. (2017). Mitochondrial ROS control of cancer. Seminars in Cancer Biology, 47, 57–66.CrossRefGoogle Scholar
  10. 10.
    Wang, J., & Yi, J. (2008). Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biology & Therapy, 7, 1875–1884.CrossRefGoogle Scholar
  11. 11.
    Caino, M. C., & Altieri, D. C. (2016). Molecular pathways: mitochondrial reprogramming in tumor progression and therapy. Clinical Cancer Research, 22, 540–545.CrossRefGoogle Scholar
  12. 12.
    Ren, Y. J., Wang, X. H., Ji, C., Guan, Y. D., Lu, X. J., Liu, X. R., Zhang, H. H., Guo, L. C., Xu, Q. H., Zhu, W. D., Ming, Z. J., Yang, J. M., Cheng, Y., & Zhang, Y. (2017). Silencing of NAC1 expression induces cancer cells oxidative stress in hypoxia and potentiates the therapeutic activity of elesclomol. Frontiers in Pharmacology, 8, 804.CrossRefGoogle Scholar
  13. 13.
    Ren, T., Zhang, H., Wang, J., Zhu, J., Jin, M., Wu, Y., Guo, X., Ji, L., Huang, Q., Zhang, H., Yang, H., & Xing, J. (2017). MCU-dependent mitochondrial Ca(2+) inhibits NAD(+)/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells. Oncogene, 36, 5897–5909.CrossRefGoogle Scholar
  14. 14.
    Tao, R., Coleman, M. C., Pennington, J. D., Ozden, O., Park, S. H., Jiang, H., Kim, H. S., Flynn, C. R., Hill, S., Hayes McDonald, W., Olivier, A. K., Spitz, D. R., & Gius, D. (2010). Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Molecular Cell, 40, 893–904.CrossRefGoogle Scholar
  15. 15.
    Torrens-Mas, M., Oliver, J., Roca, P., & Sastre-Serra, J. (2017). SIRT3: oncogene and tumor suppressor in cancer. Cancers, 9, 90.CrossRefGoogle Scholar
  16. 16.
    Bell, E. L., Emerling, B. M., Ricoult, S. J., & Guarente, L. (2011). SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene, 30, 2986–2996.CrossRefGoogle Scholar
  17. 17.
    Patel, S. A., & Minn, A. J. (2018). Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity, 48, 417–433.CrossRefGoogle Scholar
  18. 18.
    Chamoto, K., Chowdhury, P. S., Kumar, A., Sonomura, K., Matsuda, F., Fagarasan, S., & Honjo, T. (2017). Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proceedings of the National Academy of Sciences of the United States of America, 114, E761–E770.CrossRefGoogle Scholar
  19. 19.
    Scharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R. E., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016). The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity, 45, 374–388.CrossRefGoogle Scholar
  20. 20.
    Zhang, Y., & Ertl, H. C. (2016). Aging: T cell metabolism within tumors. Aging (Albany Nyomda), 8, 1163–1164.CrossRefGoogle Scholar
  21. 21.
    Cheng, G., Zielonka, M., Dranka, B., Kumar, S.N., Myers, C.R., Bennett, B., Garces, A.M., Dias Duarte Machado, L.G., Thiebaut, D., Ouari, O., Hardy, M., Zielonka, J., & Kalyanaraman, B. (2018). Detection of mitochondria-generated reactive oxygen species in cells using multiple probes and methods: Potentials, pitfalls, and the future. The Journal of Biological Chemistry, 293, 10363–10380.CrossRefGoogle Scholar
  22. 22.
    Kalyanaraman, B., Darley-Usmar, V., Davies, K. J., Dennery, P. A., Forman, H. J., Grisham, M. B., Mann, G. E., Moore, K., Roberts, 2nd, L. J., & Ischiropoulos, H. (2012). Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radical Biology and Medicine, 52, 1–6.CrossRefGoogle Scholar
  23. 23.
    Kalyanaraman, B., Dranka, B. P., Hardy, M., Michalski, R., & Zielonka, J. (2014). HPLC-based monitoring of products formed from hydroethidine-based fluorogenic probes—the ultimate approach for intra- and extracellular superoxide detection. Biochimica et Biophysica Acta, 1840, 739–744.CrossRefGoogle Scholar
  24. 24.
    Dikalov, S. I., & Harrison, D. G. (2014). Methods for detection of mitochondrial and cellular reactive oxygen species. Antioxidants & Redox Signaling, 20, 372–382.CrossRefGoogle Scholar
  25. 25.
    Zielonka, J., Lambeth, J. D., & Kalyanaraman, B. (2013). On the use of L-012, a luminol-based chemiluminescent probe, for detecting superoxide and identifying inhibitors of NADPH oxidase: a reevaluation. Free Radical Biology and Medicine, 65, 1310–1314.CrossRefGoogle Scholar
  26. 26.
    Zielonka, J., Srinivasan, S., Hardy, M., Ouari, O., Lopez, M., Vasquez-Vivar, J., Avadhani, N. G., & Kalyanaraman, B. (2008). Cytochrome c-mediated oxidation of hydroethidine and mito-hydroethidine in mitochondria: identification of homo- and heterodimers. Free Radical Biology and Medicine, 44, 835–846.CrossRefGoogle Scholar
  27. 27.
    Zielonka, J., Vasquez-Vivar, J., & Kalyanaraman, B. (2008). Detection of 2-hydroxyethidium in cellular systems: a unique marker product of superoxide and hydroethidine. Nature Protocols, 3, 8–21.CrossRefGoogle Scholar
  28. 28.
    Zhao, H., Kalivendi, S., Zhang, H., Joseph, J., Nithipatikom, K., Vasquez-Vivar, J., & Kalyanaraman, B. (2003). Superoxide reacts with hydroethidine but forms a fluorescent product that is distinctly different from ethidium: potential implications in intracellular fluorescence detection of superoxide. Free Radical Biology and Medicine, 34, 1359–1368.CrossRefGoogle Scholar
  29. 29.
    Zhao, H., Joseph, J., Fales, H. M., Sokoloski, E. A., Levine, R. L., Vasquez-Vivar, J., & Kalyanaraman, B. (2005). Detection and characterization of the product of hydroethidine and intracellular superoxide by HPLC and limitations of fluorescence. Proceedings of the National Academy of Sciences of the United States of America, 102, 5727–5732.CrossRefGoogle Scholar
  30. 30.
    Zielonka, J., & Kalyanaraman, B. (2010). Hydroethidine- and MitoSOX-derived red fluorescence is not a reliable indicator of intracellular superoxide formation: another inconvenient truth. Free Radical Biology and Medicine, 48, 983–1001.CrossRefGoogle Scholar
  31. 31.
    Kalyanaraman, B., Cheng, G., Hardy, M., Ouari, O., Bennett, B., & Zielonka, J. (2018). Teaching the basics of reactive oxygen species and their relevance to cancer biology: mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies. Redox Biology, 15, 347–362.CrossRefGoogle Scholar
  32. 32.
    Dhanasekaran, A., Kotamraju, S., Karunakaran, C., Kalivendi, S. V., Thomas, S., Joseph, J., & Kalyanaraman, B. (2005). Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: role of mitochondrial superoxide. Free Radical Biology and Medicine, 39, 567–583.CrossRefGoogle Scholar
  33. 33.
    Cheng, G., Zielonka, J., McAllister, D., Hardy, M., Ouari, O., Joseph, J., Dwinell, M. B., & Kalyanaraman, B. (2015). Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: role of mitochondrial bioenergetics and energy-sensing mechanism. Cancer Letters, 365, 96–106.CrossRefGoogle Scholar
  34. 34.
    Hawkins, C. L., & Davies, M. J. (2014). Detection and characterisation of radicals in biological materials using EPR methodology. Biochimica et Biophysica Acta, 1840, 708–721.CrossRefGoogle Scholar
  35. 35.
    Griendling, K. K., Touyz, R. M., Zweier, J. L., Dikalov, S., Chilian, W., Chen, Y. R., Harrison, D. G., & Bhatnagar, A. (2016). Measurement of reactive oxygen species, reactive nitrogen species, and redox-dependent signaling in the cardiovascular system: a scientific statement from the American Heart Association. Circulation Research, 119, e39–75.CrossRefGoogle Scholar
  36. 36.
    Davies, M. J. (2016). Detection and characterisation of radicals using electron paramagnetic resonance (EPR) spin trapping and related methods. Methods, 109, 21–30.CrossRefGoogle Scholar
  37. 37.
    Sikora, A., Zielonka, J., Lopez, M., Joseph, J., & Kalyanaraman, B. (2009). Direct oxidation of boronates by peroxynitrite: mechanism and implications in fluorescence imaging of peroxynitrite. Free Radical Biology and Medicine, 47, 1401–1407.CrossRefGoogle Scholar
  38. 38.
    Sikora, A., Zielonka, J., Lopez, M., Dybala-Defratyka, A., Joseph, J., Marcinek, A., & Kalyanaraman, B. (2011). Reaction between peroxynitrite and boronates: EPR spin-trapping, HPLC Analyses, and quantum mechanical study of the free radical pathway. Chemical Research in Toxicology, 24, 687–697.CrossRefGoogle Scholar
  39. 39.
    Zielonka, J., Sikora, A., Joseph, J., & Kalyanaraman, B. (2010). Peroxynitrite is the major species formed from different flux ratios of co-generated nitric oxide and superoxide: direct reaction with boronate-based fluorescent probe. The Journal of Biological Chemistry, 285, 14210–14216.CrossRefGoogle Scholar
  40. 40.
    Zielonka, J., Zielonka, M., VerPlank, L., Cheng, G., Hardy, M., Ouari, O., Ayhan, M. M., Podsiadly, R., Sikora, A., Lambeth, J. D., & Kalyanaraman, B. (2016). Mitigation of NADPH oxidase 2 activity as a strategy to inhibit peroxynitrite formation. The Journal of Biological Chemistry, 291, 7029–7044.CrossRefGoogle Scholar
  41. 41.
    Lippert, A. R., Van de Bittner, G. C., & Chang, C. J. (2011). Boronate oxidation as a bioorthogonal reaction approach for studying the chemistry of hydrogen peroxide in living systems. Accounts of Chemical Research, 44, 793–804.CrossRefGoogle Scholar
  42. 42.
    Orme-Johnson, N. R., Hansen, R. E., & Beinert, H. (1974). Electron paramagnetic resonance-detectable electron acceptors in beef heart mitochondria. The Journal of Biological Chemistry, 249, 1928–1939.Google Scholar
  43. 43.
    Beinert, H. (1978). EPR spectroscopy of components of the mitochondrial electron-transfer system. Methods Enzymology, 54, 133–150.CrossRefGoogle Scholar
  44. 44.
    Bennett, B., Helbling, D., Meng, H., Jarzembowski, J., Geurts, A. M., Friederich, M. W., Van Hove, J. L., Lawlor, M. W., & Dimmock, D. P. (2016). Potentially diagnostic electron paramagnetic resonance spectra elucidate the underlying mechanism of mitochondrial dysfunction in the deoxyguanosine kinase deficient rat model of a genetic mitochondrial DNA depletion syndrome. Free Radical Biology and Medicine, 92, 141–151.CrossRefGoogle Scholar
  45. 45.
    Kennedy, M. C., Antholine, W. E., & Beinert, H. (1997). An EPR investigation of the products of the reaction of cytosolic and mitochondrial aconitases with nitric oxide. The Journal of Biological Chemistry, 272, 20340–20347.CrossRefGoogle Scholar
  46. 46.
    Siebers, E.M., Choi, M.J., Tinklenberg, J.A., Beatka, M.J., Ayres, S., Meng, H., Helbling, D.C., Takizawa, A., Bennett, B., Garces, A.M., Dias Duarte Machado, L.G., Dimmock, D., Dwinell, M.R., Geurts, A.M., & Lawlor, M.W. (2018). Sdha+/- rats display minimal muscle pathology without significant behavioral or biochemical abnormalities. Journal of Neuropathology & Experimental Neurology.Google Scholar
  47. 47.
    Langley, M., Ghosh, A., Charli, A., Sarkar, S., Ay, M., Luo, J., Zielonka, J., Brenza, T., Bennett, B., Jin, H., Ghaisas, S., Schlichtmann, B., Kim, D., Anantharam, V., Kanthasamy, A., Narasimhan, B., Kalyanaraman, B., & Kanthasamy, A. G. (2017). Mito-apocynin prevents mitochondrial dysfunction, microglial activation, oxidative damage, and progressive neurodegeneration in MitoPark transgenic mice. Antioxidants & Redox Signaling, 27, 1048–1066.CrossRefGoogle Scholar
  48. 48.
    Sethumadhavan, S., Whitsett, J., Bennett, B., Ionova, I. A., Pieper, G. M., & Vasquez-Vivar, J. (2016). Increasing tetrahydrobiopterin in cardiomyocytes adversely affects cardiac redox state and mitochondrial function independently of changes in NO production. Free Radical Biology and Medicine, 93, 1–11.CrossRefGoogle Scholar
  49. 49.
    Haddy, A., & Smith, G. (1999). Transition metal and organic radical components of carp liver tissue observed by electron paramagnetic resonance spectroscopy. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 123, 407–415.CrossRefGoogle Scholar
  50. 50.
    Aasa, R., Albracht, S. P. J., Falk, K.-E., Lanne, B., & Vänngård, T. (1976). EPR signals from cytochrome c oxidase. Biochimica et Biophysica Acta (BBA) - Enzymology, 422, 260–272.CrossRefGoogle Scholar
  51. 51.
    Kroneck, P. M., Antholine, W. E., Kastrau, D. H., Buse, G., Steffens, G. C., & Zumft, W. G. (1990). Multifrequency EPR evidence for a bimetallic center at the CuA site in cytochrome c oxidase. FEBS Letters, 268, 274–276.CrossRefGoogle Scholar
  52. 52.
    Chandran, K., Aggarwal, D., Migrino, R. Q., Joseph, J., McAllister, D., Konorev, E. A., Antholine, W. E., Zielonka, J., Srinivasan, S., Avadhani, N. G., & Kalyanaraman, B. (2009). Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophysical Journal, 96, 1388–1398.CrossRefGoogle Scholar
  53. 53.
    Hagen, W. R. (1982). EPR of non-kramers doublets in biological systems: Characterization of an S=2 system in oxidized cytochrome c oxidase. Biochimica et Biophysica Acta, 708, 82–98.CrossRefGoogle Scholar
  54. 54.
    Cooper, C. E., & Salerno, J. C. (1992). Characterization of a novel g’=2.95 EPR signal from the binuclear center of mitochondrial cytochrome c oxidase. The Journal of Biological Chemistry, 267, 280–285.Google Scholar
  55. 55.
    Beinert, H., Ackrell, B. A., Kearney, E. B., & Singer, T. P. (1975). Iron-sulfur components of succinate dehydrogenase: stoichiometry and kinetic behavior in activated preparations. European Journal of Biochemistry, 54, 185–194.CrossRefGoogle Scholar
  56. 56.
    Maguire, J. J., Johnson, M. K., Morningstar, J. E., Ackrell, B. A., & Kearney, E. B. (1985). Electron paramagnetic resonance studies of mammalian succinate dehydrogenase. Detection of the tetranuclear cluster S2. The Journal of Biological Chemistry, 260, 10909–10912.Google Scholar
  57. 57.
    Johnson, M. K., Morningstar, J. E., Bennett, D. E., Ackrell, B. A., & Kearney, E. B. (1985). Magnetic circular dichroism studies of succinate dehydrogenase. Evidence for [2Fe-2S], [3Fe-xS], and [4Fe-4S] centers in reconstitutively active enzyme. The Journal of Biological Chemistry, 260, 7368–7378.Google Scholar
  58. 58.
    Salerno, J. C., & Ohnishi, T. (1980). Studies on the stabilized ubisemiquinone species in the succinate-cytochrome c reductase segment of the intact mitochondrial membrane system. The Biochemical Journal, 192, 769–781.CrossRefGoogle Scholar
  59. 59.
    Rieske, J. S., MacLennan, D. H., & Coleman, R. (1964). Isolation and properties of an iron-protein from the (reduced coenzyme Q)-cytochrome C reductase complex of the respiratory chain. Biochemical and Biophysical Research Communications, 15, 338–344.CrossRefGoogle Scholar
  60. 60.
    Trumpower, B. L., & Edwards, C. A. (1979). Purification of a reconstitutively active iron-sulfur protein (oxidation factor) from succinate. cytochrome c reductase complex of bovine heart mitochondria. The Journal of Biological Chemistry, 254, 8697–8706.Google Scholar
  61. 61.
    Siedow, J. N., Power, S., de la Rosa, F. F., & Palmer, G. (1978). The preparation and characterization of highly purified, enzymically active complex III from baker’s yeast. The Journal of Biological Chemistry, 253, 2392–2399.Google Scholar
  62. 62.
    Medvedev, E. S., Couch, V. A., & Stuchebrukhov, A. A. (2010). Determination of the intrinsic redox potentials of FeS centers of respiratory complex I from experimental titration curves. Biochimica et Biophysica Acta, 1797, 1665–1671.CrossRefGoogle Scholar
  63. 63.
    Ohnishi, T., & Nakamaru-Ogiso, E. (2008). Were there any “misassignments” among iron-sulfur clusters N4, N5 and N6b in NADH-quinone oxidoreductase (complex I)? Biochimica et Biophysica Acta, 1777, 703–710.CrossRefGoogle Scholar
  64. 64.
    Yakovlev, G., Reda, T., & Hirst, J. (2007). Reevaluating the relationship between EPR spectra and enzyme structure for the iron sulfur clusters in NADH:quinone oxidoreductase. Proceedings of the National Academy of Sciences of the United States of America, 104, 12720–12725.CrossRefGoogle Scholar
  65. 65.
    Torii, K., Iizuka, T., & Ogura, Y. (1970). Magnetic susceptibility and EPR measurements of catalase and its derivatives. A thermal equilibrium between the high- and low-spin states in the catalase-azide compound. Journal of Biochemistry, 68, 837–841.CrossRefGoogle Scholar
  66. 66.
    Bomba, M., Camagna, A., Cannistraro, S., Indovina, P. L., & Samoggia, P. (1977). EPR study of serum ceruloplasmin and iron transferrin in myocardial infarction. Physiological Chemistry and Physics, 9, 175–180.Google Scholar
  67. 67.
    Harris, D. C. (1977). Different metal-binding properties of the two sites of human transferrin. Biochemistry, 16, 560–564.CrossRefGoogle Scholar
  68. 68.
    Dunne, J., Caron, A., Menu, P., Alayash, A. I., Buehler, P. W., Wilson, M. T., Silaghi-Dumitrescu, R., Faivre, B., & Cooper, C. E. (2006). Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo. The Biochemical Journal, 399, 513–524.CrossRefGoogle Scholar
  69. 69.
    Kumar, P., Bulk, M., Webb, A., van der Weerd, L., Oosterkamp, T. H., Huber, M., & Bossoni, L. (2016). A novel approach to quantify different iron forms in ex-vivo human brain tissue. Scientific Reports, 6, 38916.CrossRefGoogle Scholar
  70. 70.
    Ghosh, A., Chandran, K., Kalivendi, S. V., Joseph, J., Antholine, W. E., Hillard, C. J., Kanthasamy, A., Kanthasamy, A., & Kalyanaraman, B. (2010). Neuroprotection by a mitochondria-targeted drug in a Parkinson’s disease model. Free Radical Biology and Medicine, 49, 1674–1684.CrossRefGoogle Scholar
  71. 71.
    Unden, G., & Bongaerts, J. (1997). Alternative respiratory pathways of Escherichia coli: energetics and transcriptional regulation in response to electron acceptors. Biochimica et Biophysica Acta, 1320, 217–234.CrossRefGoogle Scholar
  72. 72.
    Hausladen, A., & Fridovich, I. (1994). Superoxide and peroxynitrite inactivate aconitases, but nitric oxide does not. The Journal of Biological Chemistry, 269, 29405–29408.Google Scholar
  73. 73.
    Vasquez-Vivar, J., Kalyanaraman, B., & Kennedy, M. C. (2000). Mitochondrial aconitase is a source of hydroxyl radical. An electron spin resonance investigation. The Journal of Biological Chemistry, 275, 14064–14069.CrossRefGoogle Scholar
  74. 74.
    Tortora, V., Quijano, C., Freeman, B., Radi, R., & Castro, L. (2007). Mitochondrial aconitase reaction with nitric oxide, S-nitrosoglutathione, and peroxynitrite: mechanisms and relative contributions to aconitase inactivation. Free Radical Biology and Medicine, 42, 1075–1088.CrossRefGoogle Scholar
  75. 75.
    Bulteau, A. L., Ikeda-Saito, M., & Szweda, L. I. (2003). Redox-dependent modulation of aconitase activity in intact mitochondria. Biochemistry, 42, 14846–14855.CrossRefGoogle Scholar
  76. 76.
    Selvaratnam, J., & Robaire, B. (2016). Overexpression of catalase in mice reduces age-related oxidative stress and maintains sperm production. Experimental Gerontology, 84, 12–20.CrossRefGoogle Scholar
  77. 77.
    Schriner, S. E., Linford, N. J., Martin, G. M., Treuting, P., Ogburn, C. E., Emond, M., Coskun, P. E., Ladiges, W., Wolf, N., Van Remmen, H., Wallace, D. C., & Rabinovitch, P. S. (2005). Extension of murine life span by overexpression of catalase targeted to mitochondria. Science, 308, 1909–1911.CrossRefGoogle Scholar
  78. 78.
    Meilhac, O., Zhou, M., Santanam, N., & Parthasarathy, S. (2000). Lipid peroxides induce expression of catalase in cultured vascular cells. Journal of Lipid Research, 41, 1205–1213.Google Scholar
  79. 79.
    Bai, J., Rodriguez, A. M., Melendez, J. A., & Cederbaum, A. I. (1999). Overexpression of catalase in cytosolic or mitochondrial compartment protects HepG2 cells against oxidative injury. The Journal of Biological Chemistry, 274, 26217–26224.CrossRefGoogle Scholar
  80. 80.
    Koter, M., & Leyko, W. (1983). ESR study of beta-irradiated erythrocyte membranes. Studia Biophysica, 96, 1–9.Google Scholar
  81. 81.
    Vanin, A. F. (2018). EPR characterization of dinitrosyl iron complexes with thiol-containing ligands as an approach to their identification in biological objects: an overview. Cell Biochemistry and Biophysics, 76, 3–17.CrossRefGoogle Scholar
  82. 82.
    Pieper, G.M., Halligan, N.L.N., Hilton, G., Konorev, E.A., Felix, C.C., Roza, A.M., Adams, M.B., & Griffith, O.W. (2003). Non-heme iron protein: a potential target of nitric oxide in acute cardiac allograft rejection. Proceedings of the National Academy of Sciences of the United States of America, 100, 3125–3130.Google Scholar
  83. 83.
    Doi, K., Akaike, T., Horie, H., Noguchi, Y., Fujii, S., Beppu, T., Ogawa, M., & Maeda, H. (1996). Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth. Cancer, 77, 1598–1604.CrossRefGoogle Scholar
  84. 84.
    Pearce, L. L., Martinez-Bosch, S., Manzano, E. L., Winnica, D. E., Epperly, M. W., & Peterson, J. (2009). The resistance of electron-transport chain Fe-S clusters to oxidative damage during the reaction of peroxynitrite with mitochondrial complex II and rat-heart pericardium. Nitric Oxide, 20, 135–142.CrossRefGoogle Scholar
  85. 85.
    Dei Zotti, F., Lobysheva, I. I., & Balligand, J. L. (2018). Nitrosyl-hemoglobin formation in rodent and human venous erythrocytes reflects NO formation from the vasculature in vivo. PLoS ONE, 13, e0200352.CrossRefGoogle Scholar
  86. 86.
    Cheng, G., Zielonka, J., Ouari, O., Lopez, M., McAllister, D., Boyle, K., Barrios, C. S., Weber, J. J., Johnson, B. D., Hardy, M., Dwinell, M. B., & Kalyanaraman, B. (2016). Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Research, 76, 3904–3915.CrossRefGoogle Scholar
  87. 87.
    Xia, D., Yu, C. A., Kim, H., Xia, J. Z., Kachurin, A. M., Zhang, L., Yu, L., & Deisenhofer, J. (1997). Crystal structure of the cytochrome bc1 complex from bovine heart mitochondria. Science, 277, 60–66.CrossRefGoogle Scholar
  88. 88.
    Zhang, Z., Huang, L., Shulmeister, V. M., Chi, Y. I., Kim, K. K., Hung, L. W., Crofts, A. R., Berry, E. A., & Kim, S. H. (1998). Electron transfer by domain movement in cytochrome bc1. Nature, 392, 677–684.CrossRefGoogle Scholar
  89. 89.
    Iwata, S., Lee, J. W., Okada, K., Lee, J. K., Iwata, M., Rasmussen, B., Link, T. A., Ramaswamy, S., & Jap, B. K. (1998). Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science, 281, 64–71.CrossRefGoogle Scholar
  90. 90.
    Zielonka, J., Joseph, J., Sikora, A., Hardy, M., Ouari, O., Vasquez-Vivar, J., Cheng, G., Lopez, M., & Kalyanaraman, B. (2017). Mitochondria-targeted triphenylphosphonium-based compounds: Syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chemical Reviews, 117, 10043–10120.CrossRefGoogle Scholar
  91. 91.
    Pan, J., Lee, Y., Cheng, G., Zielonka, J., Zhang, Q., Bajzikova, M., Xiong, D., Tsaih, S.-W., Hardy, M., Flister, M., Olsen, C. M., Wang, Y., Vang, O., Neuzil, J., Myers, C. R., Kalyanaraman, B., & You, M. (2018). Mitochondria-targeted honokiol confers a striking inhibitory effect on lung cancer via inhibiting complex I activity. iScience, 3, 192–207.CrossRefGoogle Scholar
  92. 92.
    Boudreau, A., Purkey, H. E., Hitz, A., Robarge, K., Peterson, D., Labadie, S., Kwong, M., Hong, R., Gao, M., Del Nagro, C., Pusapati, R., Ma, S., Salphati, L., Pang, J., Zhou, A., Lai, T., Li, Y., Chen, Z., Wei, B., Yen, I., Sideris, S., McCleland, M., Firestein, R., Corson, L., Vanderbilt, A., Williams, S., Daemen, A., Belvin, M., Eigenbrot, C., Jackson, P. K., Malek, S., Hatzivassiliou, G., Sampath, D., Evangelista, M., & O’Brien, T. (2016). Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nature Chemical Biology, 12, 779–786.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiophysicsMedical College of WisconsinMilwaukeeUSA
  2. 2.Free Radical Research CenterMedical College of WisconsinMilwaukeeUSA
  3. 3.Cancer CenterMedical College of WisconsinMilwaukeeUSA
  4. 4.Department of PhysicsMarquette UniversityMilwaukeeUSA

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