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Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage

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Abstract

Ischemic stroke and neonatal hypoxic-ischemic encephalopathy are two of the leading causes of disability in adults and infants. The energy demands of the brain are provided by mitochondrial oxidative phosphorylation. Ischemia/reperfusion (I/R) affects the production of ATP in brain mitochondria, leading to energy failure and death of the affected tissue. Among the enzymes of the mitochondrial respiratory chain, mitochondrial complex I is the most sensitive to I/R; however, the mechanisms of its inhibition are poorly understood. This article reviews some of the existing data on the mitochondria impairment during I/R and proposes two distinct mechanisms of complex I damage emerging from recent studies. One mechanism is a reversible dissociation of natural flavin mononucleotide cofactor from the enzyme I after ischemia. Another mechanism is a modification of critical cysteine residue of complex I involved into the active/deactive conformational transition of the enzyme. I describe potential effects of these two processes in the development of mitochondrial I/R injury and briefly discuss possible neuroprotective strategies to ameliorate I/R brain injury.

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Abbreviations

A/D transition:

active/deactive transition

FAD:

flavin adenine dinucleotide

FMN/FMNH2 :

oxidized/reduced flavin mononucleotide

HI:

hypoxia-ischemia

I/R:

ischemia/reperfusion

MCAO:

middle cerebral artery occlusion

Q:

ubiquinone

RET:

reverse electron transfer

ROS:

reactive oxygen species

TCA:

tricarboxylic acid (cycle)

References

  1. Lee, A. C., Kozuki, N., Blencowe, H., Vos, T., Bahalim, A., Darmstadt, G. L., Niermeyer, S., Ellis, M., Robertson, N. J., Cousens, S., and Lawn, J. E. (2013) Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990, Pediatr. Res., 74, 50–72, doi: https://doi.org/10.1038/pr.2013.206.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Roger, V. L., Go, A. S., Lloyd-Jones, D. M., Benjamin, E. J., Berry, J. D., Borden, W. B., Bravata, D. M., Dai, S., Ford, E. S., Fox, C. S., Fullerton, H. J., Gillespie, C., Hailpern, S. M., Heit, J. A., Howard, V. J., Kissela, B. M., Kittner, S. J., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Makuc, D. M., Marcus, G. M., Marelli, A., Matchar, D. B., Moy, C. S., Mozaffarian, D., Mussolino, M. E., Nichol, G., Paynter, N. P., Soliman, E. Z., Sorlie, P. D., Sotoodehnia, N., Turan, T. N., Virani, S. S., Wong, N. D., Woo, D., Turner, M. B., and American Heart Association Statistics Committee and Stroke Statistics Subcommittee. (2012) Heart disease and stroke statistics — 2012 update: a report from the American Heart Association, Circulation, 125, e2–e220.

    Article  PubMed  Google Scholar 

  3. Siesjo, B. K., Elmer, E., Janelidze, S., Keep, M., Kristian, T., Ouyang, Y. B., and Uchino, H. (1999) Role and mechanisms of secondary mitochondrial failure, Acta Neurochir. Suppl., 73, 7–13.

    CAS  PubMed  Google Scholar 

  4. Vannucci, R. C., Towfighi, J., and Vannucci, S. J. (2004) Secondary energy failure after cerebral hypoxia-ischemia in the immature rat, J. Cereb. Blood Flow Metab., 24, 1090–1097.

    Article  CAS  PubMed  Google Scholar 

  5. Hertz, L. (2008) Bioenergetics of cerebral ischemia: a cellular perspective, Neuropharmacology, 55, 289–309, doi: https://doi.org/10.1016/j.neuropharm.2008.05.023.

    Article  CAS  PubMed  Google Scholar 

  6. Sims, N. R., and Muyderman, H. (2010) Mitochondria, oxidative metabolism and cell death in stroke, Biochim. Biophys. Acta, 1802, 80–91, doi: https://doi.org/10.1016/j.bbadis.2009.09.003.

    Article  CAS  PubMed  Google Scholar 

  7. Mracek, T., Drahota, Z., and Houstek, J. (2013) The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues, Biochim. Biophys. Acta, 1827, 401–410, doi: https://doi.org/10.1016/j.bbabio.2012.11.014.

    Article  CAS  PubMed  Google Scholar 

  8. Watmough, N. J., and Frerman, F E. (2010) The electron transfer favoprotein:ubiquinone oxidoreductases, Biochim. Biophys. Acta, 1797, 1910–1916, doi: https://doi.org/10.1016/j.bbabio.2010.10.007.

    Article  CAS  PubMed  Google Scholar 

  9. Galkin, A. S., Grivennikova, V. G., and Vinogradov, A. D. (1999) H+/2e− stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles, FEBS Lett., 451, 157–161.

    Article  CAS  PubMed  Google Scholar 

  10. Hirst, J. (2013) Mitochondrial complex I, Annu. Rev. Biochem., 82, 551–575.

    Article  CAS  PubMed  Google Scholar 

  11. Brandt, U. (2006) Energy converting NADH:quinone oxidoreductases, Annu. Rev. Biochem., 75, 69–92.

    Article  CAS  PubMed  Google Scholar 

  12. Burbaev, D. S., Moroz, I. A., Kotlyar, A. B., Sled, V. D., and Vinogradov, A. D. (1989) Ubisemiquinone in the NADH-ubiquinone reductase region of the mitochondrial respiratory chain, FEBS Lett., 254, 47–51.

    Article  CAS  Google Scholar 

  13. De Jong, A. M., and Albracht, S. P. (1994) Ubisemiquinones as obligatory intermediates in the electron transfer from NADH to ubiquinone, Eur. J. Biochem., 222, 975–982.

    Article  CAS  PubMed  Google Scholar 

  14. Cabrera-Orefice, A., Yoga, E. G., Wirth, C., Siegmund, K., Zwicker, K., Guerrero-Castillo, S., Zickermann, V., Hunte, C., and Brandt, U. (2018) Locking loop movement in the ubiquinone pocket of complex I disengages the proton pumps, Nat. Commun., 9, 4500, doi: https://doi.org/10.1038/s41467-018-06955-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vinogradov, A. D., Gavrikova, E. V., Grivennikova, V. G., Zharova, T. V., and Zakharova, N. V. (1999) Catalytic properties of mitochondrial NADH-ubiquinone reductase (Complex I), Biochemistry (Moscow), 64, 136–152.

    CAS  Google Scholar 

  16. Chance, B., and Hollunger, G. (1960) Energy-linked reduction of mitochondrial pyridine nucleotide, Nature, 185, 666–672.

    Article  CAS  PubMed  Google Scholar 

  17. Klingenberg, M., and Slenczka, W. (1959) Pyridine nucleotide in liver mitochondria. An analysis of their redox relationships, Biochemische Zeitschrift, 331, 486–517.

    CAS  PubMed  Google Scholar 

  18. Folbergrova, J., Ljunggren, B., Norberg, K., and Siesjo, B. K. (1974) Influence of complete ischemia on glycolytic metabolites, citric acid cycle intermediates, and associated amino acids in the rat cerebral cortex, Brain Res., 80, 265–279, doi: https://doi.org/10.1016/0006-8993(74)90690-8.

    Article  CAS  PubMed  Google Scholar 

  19. Solberg, R., Enot, D., Deigner, H. P., Koal, T., Scholl-Burgi, S., Saugstad, O. D., and Keller, M. (2010) Metabolomic analyses of plasma reveals new insights into asphyxia and resuscitation in pigs, PLoS One, 5, e9606, doi: https://doi.org/10.1371/journal.pone.0009606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Benzi, G., Arrigoni, E., Marzatico, F., and Villa, R. F. (1979) Influence of some biological pyrimidines on the succinate cycle during and after cerebral ischemia, Biochem. Pharmacol., 28, 2545–2550.

    Article  CAS  PubMed  Google Scholar 

  21. Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijevic, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N., Smith, A. C., Eyassu, F., Shirley, R., Hu, C. H., Dare, A. J., James, A. M., Rogatti, S., Hartley, R. C., Eaton, S., Costa, A. S., Brookes, P. S., Davidson, S. M., Duchen, M. R., Saeb-Parsy, K., Shattock, M. J., Robinson, A. J., Work, L. M., Frezza, C., Krieg, T., and Murphy, M. P. (2014) Ischemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature, 515, 431–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sahni, P. V., Zhang, J., Sosunov, S., Galkin, A., Niatsetskaya, Z., Starkov, A., Brookes, P. S., and Ten, V. S. (2017) Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice, Pediatr. Res., 83, 491–497, doi: https://doi.org/10.1038/pr.2017.277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hinkle, P. C., Butow, R. A., Racker, E., and Chance, B. (1967) Partial resolution of the enzymes catalyzing oxidative phosphorylation. XV. Reverse electron transfer in the flavin-cytochrome beta region of the respiratory chain of beef heart submitochondrial particles, J. Biol. Chem., 242, 5169–5173.

    CAS  PubMed  Google Scholar 

  24. Turrens, J. F., and Boveris, A. (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria, Biochem. J., 191, 421–427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Grivennikova, V. G., and Vinogradov, A. D. (2006) Generation of superoxide by the mitochondrial complex I, Biochim. Biophys. Acta, 1757, 553–561.

    Article  CAS  PubMed  Google Scholar 

  26. Pryde, K. R., and Hirst, J. (2011) Superoxide is produced by the reduced flavin in mitochondrial complex I: a single, unified mechanism that applies during both forward and reverse electron transfer, J. Biol. Chem., 286, 18056–18065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Niatsetskaya, Z. V., Sosunov, S. A., Matsiukevich, D., Utkina-Sosunova, I. V., Ratner, V. I., Starkov, A. A., and Ten, V. S. (2012) The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice, J. Neurosci., 32, 3235–3244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Quinlan, C. L., Perevoshchikova, I. V., Hey-Mogensen, M., Orr, A. L., and Brand, M. D. (2013) Sites of reactive oxygen species generation by mitochondria oxidizing different substrates, Redox. Biol., 1, 304–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stepanova, A., Konrad, C., Manfredi, G., Springett, R., Ten, V., and Galkin, A. (2018) The dependence of brain mitochondria reactive oxygen species production on oxygen level is linear, except when inhibited by antimycin A, J. Neurochem., 148, 731–745, doi: https://doi.org/10.1111/jnc.14654.

    Article  CAS  Google Scholar 

  30. Kudin, A. P., Bimpong-Buta, N. Y., Vielhaber, S., Elger, C. E., and Kunz, W. S. (2004) Characterization of superoxide-producing sites in isolated brain mitochondria, J. Biol. Chem., 279, 4127–4135.

    Article  CAS  PubMed  Google Scholar 

  31. Vinogradov, A. D., and Grivennikova, V. G. (2005) Generation of superoxide-radical by the NADH:ubiquinone oxidoreductase of heart mitochondria, Biochemistry (Moscow), 70, 120–127.

    Article  CAS  Google Scholar 

  32. Galkin, A., and Brandt, U. (2005) Superoxide radical formation by pure complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica, J. Biol. Chem., 280, 30129–30135.

    Article  CAS  PubMed  Google Scholar 

  33. Kussmaul, L., and Hirst, J. (2006) The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria, Proc. Natl. Acad. Sci. USA, 103, 7607–7612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stepanova, A., Kahl, A., Konrad, C., Ten, V., Starkov, A. S., and Galkin, A. (2017) Reverse electron transfer results in a loss of flavin from mitochondrial complex I: potential mechanism for brain ischemia reperfusion injury, J. Cereb. Blood Flow Metab., 37, 3649–3658, doi: https://doi.org/10.1177/0271678X17730242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kotlyar, A. B., and Vinogradov, A. D. (1990) Slow active/inactive transition of the mitochondrial NADH-ubiquinone reductase, Biochim. Biophys. Acta, 1019, 151–158.

    Article  CAS  PubMed  Google Scholar 

  36. Maklashina, E. O., Sled, V. D., and Vinogradov, A. D. (1994) Hysteresis behavior of complex I from bovine heart mitochondria: kinetic and thermodynamic parameters of retarded reverse transition from the inactive to active state, Biochemistry (Moscow), 59, 946–957.

    CAS  Google Scholar 

  37. Gavrikova, E. V., and Vinogradov, A. D. (1999) Active/deactive state transition of the mitochondrial complex I as revealed by specific sulfhydryl group labeling, FEBS Lett., 455, 36–40.

    Article  CAS  PubMed  Google Scholar 

  38. Grivennikova, V. G., Kapustin, A. N., and Vinogradov, A. D. (2001) Catalytic activity of NADH-ubiquinone oxidoreductase (complex I) in intact mitochondria. evidence for the slow active/inactive transition, J. Biol. Chem., 276, 9038–9044.

    Article  CAS  PubMed  Google Scholar 

  39. Roberts, P. G., and Hirst, J. (2012) The deactive form of respiratory complex I from mammalian mitochondria is a Na+/H+ antiporter, J. Biol. Chem., 287, 34743–34751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Galkin, A., Meyer, B., Wittig, I., Karas, M., Schagger, H., Vinogradov, A., and Brandt, U. (2008) Identification of the mitochondrial ND3 subunit as a structural component involved in the active/deactive enzyme transition of respiratory complex I, J. Biol. Chem., 283, 20907–20913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Galkin, A., and Moncada, S. (2007) S-nitrosation of mitochondrial complex I depends on its structural conformation, J. Biol. Chem., 282, 37448–37453.

    Article  CAS  PubMed  Google Scholar 

  42. Maklashina, E., Kotlyar, A. B., and Cecchini, G. (2003) Active/de-active transition of respiratory complex I in bacteria, fungi, and animals, Biochim. Biophys. Acta, 1606, 95–103.

    Article  CAS  PubMed  Google Scholar 

  43. Matsuzaki, S., and Humphries, K. M. (2015) Selective inhibition of deactivated mitochondrial complex I by biguanides, Biochemistry, 54, 2011–2021.

    Article  CAS  PubMed  Google Scholar 

  44. Babot, M., Labarbuta, P., Birch, A., Kee, S., Fuszard, M., Botting, C. H., Wittig, I., Heide, H., and Galkin, A. (2014) ND3, ND1 and 39 kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I, Biochim. Biophys. Acta, 1837, 929–939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Galkin, A., Abramov, A. Y., Frakich, N., Duchen, M. R., and Moncada, S. (2009) Lack of oxygen deactivates mitochondrial complex I: implications for ischemic injury? J. Biol. Chem., 284, 36055–36061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Maklashina, E., Sher, Y., Zhou, H. Z., Gray, M. O., Karliner, J. S., and Cecchini, G. (2002) Effect of anoxia/reperfusion on the reversible active/de-active transition of NADH-ubiquinone oxidoreductase (complex I) in rat heart, Biochim. Biophys. Acta, 1556, 6–12.

    Article  CAS  PubMed  Google Scholar 

  47. Gorenkova, N., Robinson, E., Grieve, D., and Galkin, A. (2013) Conformational change of mitochondrial complex I increases ROS sensitivity during ischaemia, Antioxid. Redox. Signal., 19, 1459–1468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chouchani, E. T., Methner, C., Nadtochiy, S. M., Logan, A., Pell, V. R., Ding, S., James, A. M., Cocheme, H. M., Reinhold, J., Lilley, K. S., Partridge, L., Fearnley, I. M., Robinson, A. J., Hartley, R. C., Smith, R. A., Krieg, T., Brookes, P. S., and Murphy, M. P. (2013) Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I, Nat. Med., 19, 753–759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stepanova, A., Konrad, C., Guerrero-Castillo, S., Manfredi, G., Vannucci, S., Arnold, S., and Galkin, A. (2019) Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain, J. Cereb. Blood Flow Metab., 39, 1790–1802, doi: https://doi.org/10.1177/0271678X18770331, Epub 2018, Apr 9.

    Article  CAS  PubMed  Google Scholar 

  50. Kim, M., Stepanova, A., Niatsetskaya, Z., Sosunov, S., Arndt, S., Murphy, M. P., Galkin, A., and Ten, V. S. (2018) Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury, Free Radic. Biol. Med., 124, 517–524, doi: https://doi.org/10.1016/j.freeradbiomed.2018.06.040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hernansanz-Agustin, P., Ramos, E., Navarro, E., Parada, E., Sanchez-Lopez, N., Pelaez-Aguado, L., Cabrera-Garcia, J. D., Tello, D., Buendia, I., Marina, A., Egea, J., Lopez, M. G., Bogdanova, A., and Martinez-Ruiz, A. (2017) Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia, Redox Biol., 12, 1040–1051, doi: https://doi.org/10.1016/j.redox.2017.04.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lopez-Fabuel, I., Le Douce, J., Logan, A., James, A. M., Bonvento, G., Murphy, M. P., Almeida, A., and Bolanos, J. P. (2016) Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes, Proc. Natl. Acad. Sci. USA, 113, 13063–13068, doi: https://doi.org/10.1073/pnas.1613701113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vinogradov, A. D., and Grivennikova, V. G. (2001) The mitochondrial complex I: progress in understanding of catalytic properties, IUBMB Life, 52, 129–134.

    Article  CAS  PubMed  Google Scholar 

  54. Babot, M., Birch, A., Labarbuta, P., and Galkin, A. (2014) Characterisation of the active/de-active transition of mitochondrial complex I, Biochim. Biophys. Acta, 1837, 1083–1092, doi: https://doi.org/10.1016/j.bbabio.2014.02.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Drose, S., Stepanova, A., and Galkin, A. (2016) Ischemic A/D transition of mitochondrial complex I and its role in ROS generation, Biochim. Biophys. Acta, 1857, 946–957, doi: https://doi.org/10.1016/j.bbabio.2015.12.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kotlyar, A. B., Sled, V. D., and Vinogradov, A. D. (1992) Effect of Ca2+ ions on the slow active/inactive transition of the mitochondrial NADH-ubiquinone reductase, Biochim. Biophys. Acta, 1098, 144–150.

    Article  CAS  PubMed  Google Scholar 

  57. Babot, M., and Galkin, A. (2013) Molecular mechanism and physiological role of active-deactive transition of mitochondrial complex I, Biochem. Soc. Trans., 41, 1325–1330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Loskovich, M. V., Grivennikova, V. G., Cecchini, G., and Vinogradov, A. D. (2005) Inhibitory effect of palmitate on the mitochondrial NADH:ubiquinone oxidoreductase (complex I) as related to the active-de-active enzyme transition, Biochem. J., 387, 677–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Stepanova, A., Valls, A., and Galkin, A. (2015) Effect of monovalent cations on the kinetics of hypoxic conformational change of mitochondrial complex I, Biochim. Biophys. Acta, 1847, 1085–1092, doi: https://doi.org/10.1016/j.bbabio.2015.05.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ciano, M., Fuszard, M., Heide, H., Botting, C. H., and Galkin, A. (2013) Conformation-specific crosslinking of mitochondrial complex I, FEBS Lett., 587, 867–872.

    Article  CAS  PubMed  Google Scholar 

  61. Blaza, J. N., Vinothkumar, K. R., and Hirst, J. (2018) Structure of the deactive state of mammalian respiratory complex I, Structure, 26, 312–319e3, doi: https://doi.org/10.1016/j.str.2017.12.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Parey, K., Brandt, U., Xie, H., Mills, D. J., Siegmund, K., Vonck, J., Kuhlbrandt, W., and Zickermann, V. (2018) Cryo-EM structure of respiratory complex I at work, Elife, 7, doi: https://doi.org/10.7554/eLife.39213.

  63. Agip, A. A., Blaza, J. N., Bridges, H. R., Viscomi, C., Rawson, S., Muench, S. P., and Hirst, J. (2018) Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states, Nat. Struct. Mol. Biol., 25, 548–556, doi: https://doi.org/10.1038/s41594-018-0073-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fiedorczuk, K., Letts, J. A., Degliesposti, G., Kaszuba, K., Skehel, M., and Sazanov, L. A. (2016) Atomic structure of the entire mammalian mitochondrial complex I, Nature, 537, 644–648, doi: https://doi.org/10.1038/nature19794.

    Article  CAS  PubMed  Google Scholar 

  65. Zhu, J., Vinothkumar, K. R., and Hirst, J. (2016) Structure of mammalian respiratory complex I, Nature, 536, 354–358, doi: https://doi.org/10.1038/nature19095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zickermann, V., Wirth, C., Nasiri, H., Siegmund, K., Schwalbe, H., Hunte, C., and Brandt, U. (2015) Mechanistic insight from the crystal structure of mitochondrial complex I, Science, 347, 44–49.

    Article  CAS  PubMed  Google Scholar 

  67. Koopman, W. J., Willems, P. H., and Smeitink, J. A. (2012) Monogenic mitochondrial disorders, N. Engl. J. Med., 366, 1132–1141, doi: https://doi.org/10.1056/NEJMra1012478.

    Article  CAS  PubMed  Google Scholar 

  68. Stefanatos, R., and Sanz, A. (2011) Mitochondrial complex I: a central regulator of the aging process, Cell Cycle, 10, 1528–1532.

    Article  CAS  PubMed  Google Scholar 

  69. Breuer, M. E., Koopman, W. J., Koene, S., Nooteboom, M., Rodenburg, R. J., Willems, P. H., and Smeitink, J. A. (2013) The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases, Neurobiol. Dis., 51, 27–34, doi: https://doi.org/10.1016/j.nbd.2012.03.007.

    Article  CAS  PubMed  Google Scholar 

  70. Ndubuizu, O., and LaManna, J. C. (2007) Brain tissue oxygen concentration measurements, Antioxid. Redox. Signal., 9, 1207–1219.

    Article  CAS  PubMed  Google Scholar 

  71. Madsen, P. L., Holm, S., Herning, M., and Lassen, N. A. (1993) Average blood flow and oxygen uptake in the human brain during resting wakefulness: a critical appraisal of the Kety-Schmidt technique, J. Cereb. Blood Flow Metab., 13, 646–655, doi: https://doi.org/10.1038/jcbfm.1993.83.

    Article  CAS  PubMed  Google Scholar 

  72. Reneau, D. D., Guilbeau, E. J., and Null, R. E. (1977) Oxygen dynamics in brain, Microvasc. Res., 13, 337–344.

    Article  CAS  PubMed  Google Scholar 

  73. Lowry, O. H., Passonneau, J. V., Hasselberger, F. X., and Schulz, D. W. (1964) Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain, J. Biol. Chem., 239, 18–30.

    CAS  PubMed  Google Scholar 

  74. Hillered, L., Siesjo, B. K., and Arfors, K. E. (1984) Mitochondrial response to transient forebrain ischemia and recirculation in the rat, J. Cereb. Blood Flow Metab., 4, 438–446, doi: https://doi.org/10.1038/jcbfm.1984.63.

    Article  CAS  PubMed  Google Scholar 

  75. Kristian, T. (2004) Metabolic stages, mitochondria and calcium in hypoxic/ischemic brain damage, Cell Calcium, 36, 221–233, doi: https://doi.org/10.1016/j.ceca.2004.02.016.

    Article  CAS  PubMed  Google Scholar 

  76. Sugawara, T., Lewen, A., Noshita, N., Gasche, Y., and Chan, P. H. (2002) Effects of global ischemia duration on neuronal, astroglial, oligodendroglial, and microglial reactions in the vulnerable hippocampal CA1 subregion in rats, J. Neurotrauma, 19, 85–98, doi: https://doi.org/10.1089/089771502753460268.

    Article  PubMed  Google Scholar 

  77. Astrup, J., Siesjo, B. K., and Symon, L. (1981) Thresholds in cerebral ischemia — the ischemic penumbra, Stroke, 12, 723–725.

    Article  CAS  PubMed  Google Scholar 

  78. Becker, N. H. (1961) The cytochemistry of anoxic and anoxioischemic encephalopathy in rats. II. Alterations in neuronal mitochondria indentified by diphosphopyridine and triphosphopyridine nucleotide diaphorases, Am. J. Pathol., 38, 587–597.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Def Webster, H., and Ames, A. (1965) Reversible and irreversible changes in the fine structure of nervous tissue during oxygen and glucose deprivation, J. Cell Biol., 26, 885–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zeman, W. (1963) Histochemical and metabolic changes in brain tissue after hypoxaemia, in Selective Vulnerability of the Brain in Hypoxemia (Schade, J. P., and McMenemey, W. H., eds.) Blackwell Publishing Co, London, pp. 327–348.

    Google Scholar 

  81. Ozawa, K., Seta, K., Araki, H., and Handa, H. (1967) The effect of ischemia on mitochondrial metabolism, J. Biochem., 61, 512–514.

    Article  CAS  PubMed  Google Scholar 

  82. Ozawa, K., Itada, N., Kuno, S., Seta, K., and Handa, H. (1966) Biochemical studies on brain swelling. II. Influence of brain swelling and ischemia on the formation of an endogenous inhibitor in mitochondria, Folia Psychiatr. Neurol. Jpn., 20, 73–84.

    CAS  PubMed  Google Scholar 

  83. Schutz, H., Silverstein, P. R., Vapalahti, M., Bruce, D. A., Mela, L., and Langfitt, T. W. (1973) Brain mitochondrial function after ischemia and hypoxia. I. Ischemia induced by increased intracranial pressure, Arch. Neurol., 29, 408–416.

    Article  CAS  PubMed  Google Scholar 

  84. Ljunggren, B., Schutz, H., and Siesjo, B. K. (1974) Changes in energy state and acid-base parameters of the rat brain during complete compression ischemia, Brain Res., 73, 277–289, doi: 0006-8993(74)91049-X.

    Article  CAS  PubMed  Google Scholar 

  85. Ginsberg, M. D., Mela, L., Wrobel-Kuhl, K., and Reivich, M. (1977) Mitochondrial metabolism following bilateral cerebral ischemia in the gerbil, Ann. Neurol., 1, 519–527, doi: https://doi.org/10.1002/ana.410010603.

    Article  CAS  PubMed  Google Scholar 

  86. Rehncrona, S., Mela, L., and Siesjo, B. K. (1979) Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia, Stroke, 10, 437–446.

    Article  CAS  PubMed  Google Scholar 

  87. Nordstrom, C. H., Rehncrona, S., and Siesjo, B. K. (1978) Effects of phenobarbital in cerebral ischemia. Part II: Restitution of cerebral energy state, as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after pronounced incomplete ischemia, Stroke, 9, 335–343.

    Article  CAS  PubMed  Google Scholar 

  88. Sims, N. R., and Pulsinelli, W. A. (1987) Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat, J. Neurochem., 49, 1367–1374.

    Article  CAS  PubMed  Google Scholar 

  89. Sims, N. R. (1991) Selective impairment of respiration in mitochondria isolated from brain subregions following transient forebrain ischemia in the rat, J. Neurochem., 56, 1836–1844.

    Article  CAS  PubMed  Google Scholar 

  90. Herculano-Houzel, S., Ribeiro, P., Campos, L., Valotta da Silva, A., Torres, L. B., Catania, K. C., and Kaas, J. H. (2011) Updated neuronal scaling rules for the brains of Glires (rodents/lagomorphs), Brain Behav. Evol., 78, 302–314, doi: https://doi.org/10.1159/000330825.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Panov, A., Orynbayeva, Z., Vavilin, V., and Lyakhovich, V. (2014) Fatty acids in energy metabolism of the central nervous system, Biomed. Res. Int., 2014, 472459, doi: https://doi.org/10.1155/2014/472459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tretter, L., Takacs, K., Hegedus, V., and Adam-Vizi, V. (2007) Characteristics of alpha-glycerophosphate-evoked H2O2 generation in brain mitochondria, J. Neurochem., 100, 650–663.

    Article  CAS  PubMed  Google Scholar 

  93. Kahl, A., Stepanova, A., Konrad, C., Anderson, C., Manfredi, G., Zhou, P., Iadecola, C., and Galkin, A. (2018) Critical role of flavin and glutathione in complex I-mediated bioenergetic failure in brain ischemia/reperfusion injury, Stroke, 49, 1223–1231, doi: https://doi.org/10.1161/STROKEAHA.117.019687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Linn, F., Paschen, W., Ophoff, B. G., and Hossmann, K. A. (1987) Mitochondrial respiration during recirculation after prolonged ischemia in cat brain, Exp. Neurol., 96, 321–333.

    Article  CAS  PubMed  Google Scholar 

  95. Almeida, A., Allen, K. L., Bates, T. E., and Clark, J. B. (1995) Effect of reperfusion following cerebral ischaemia on the activity of the mitochondrial respiratory chain in the gerbil brain, J. Neurochem., 65, 1698–1703.

    Article  CAS  PubMed  Google Scholar 

  96. Allen, K. L., Almeida, A., Bates, T. E., and Clark, J. B. (1995) Changes of respiratory chain activity in mitochondrial and synaptosomal fractions isolated from the gerbil brain after graded ischaemia, J. Neurochem., 64, 2222–2229.

    Article  CAS  PubMed  Google Scholar 

  97. Yoshimoto, T., Kristian, T., Hu, B., Ouyang, Y. B., and Siesjo, B. K. (2002) Effect of NXY-059 on secondary mitochondrial dysfunction after transient focal ischemia; comparison with cyclosporin A, Brain Res., 932, 99–109.

    Article  CAS  PubMed  Google Scholar 

  98. Tsukada, H., Ohba, H., Nishiyama, S., Kanazawa, M., Kakiuchi, T., and Harada, N. (2014) PET imaging of ischemia-induced impairment of mitochondrial complex I function in monkey brain, J. Cereb. Blood Flow Metab., 34, 708–714, doi: https://doi.org/10.1038/jcbfm.2014.5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Stepanova, A., Sosunov, S., Niatsetskaya, Z., Konrad, C., Starkov, A. A., Manfredi, G., Wittig, I., Ten, V., and Galkin, A. (2019) Redox-dependent loss of flavin by mitochondrial complex I in brain ischemia/reperfusion injury, Antioxid. Redox Signal., doi: https://doi.org/10.1089/ars.2018.7693.

  100. Rao, N. A., Felton, S. P., Huennekens, F. M., and Mackler, B. (1963) Flavin mononucleotide: the coenzyme of reduced diphosphopyridine nucleotide dehydrogenase, J. Biol. Chem., 238, 449–455.

    CAS  PubMed  Google Scholar 

  101. Yoshida, S., Abe, K., Busto, R., Watson, B. D., Kogure, K., and Ginsberg, M. D. (1982) Influence of transient ischemia on lipid-soluble antioxidants, free fatty acids and energy metabolites in rat brain, Brain Res., 245, 307–316.

    Article  CAS  PubMed  Google Scholar 

  102. Deutsch, J., Kalderon, B., Purdon, A. D., and Rapoport, S. I. (2000) Evaluation of brain long-chain acylcarnitines during cerebral ischemia, Lipids, 35, 693–696.

    Article  CAS  PubMed  Google Scholar 

  103. Nguyen, N. H., Gonzalez, S. V., and Hassel, B. (2007) Formation of glycerol from glucose in rat brain and cultured brain cells. Augmentation with kainate or ischemia, J. Neurochem., 101, 1694–1700, doi: https://doi.org/10.1111/j.1471-4159.2006.04433.x.

    Article  CAS  PubMed  Google Scholar 

  104. Massey, V. (1994) Activation of molecular oxygen by flavins and flavoproteins, J. Biol. Chem., 269, 22459–22462.

    CAS  PubMed  Google Scholar 

  105. Gibson, Q. H., Massey, V., and Atherton, N. M. (1962) The nature of compounds present in mixtures of oxidized and reduced flavin mononucleotides, Biochem. J., 85, 369–383.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Barile, M., Brizio, C., Valenti, D., De Virgilio, C., and Passarella, S. (2000) The riboflavin/FAD cycle in rat liver mitochondria, Eur. J. Biochem., 267, 4888–4900.

    Article  CAS  PubMed  Google Scholar 

  107. Sled, V. D., and Vinogradov, A. D. (1993) Reductive inactivation of the mitochondrial three subunit NADH dehydrogenase, Biochim. Biophys. Acta, 1143, 199–203.

    Article  CAS  PubMed  Google Scholar 

  108. Gostimskaya, I. S., Grivennikova, V. G., Cecchini, G., and Vinogradov, A. D. (2007) Reversible dissociation of flavin mononucleotide from the mammalian membrane-bound NADH:ubiquinone oxidoreductase (complex I), FEBS Lett., 581, 5803–5806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Holt, P. J., Efremov, R. G., Nakamaru-Ogiso, E., and Sazanov, L. A. (2016) Reversible FMN dissociation from Escherichia coli respiratory complex I, Biochim. Biophys. Acta, 1857, 1777–1785, doi: https://doi.org/10.1016/j.bbabio.2016.08.008.

    Article  CAS  PubMed  Google Scholar 

  110. Gariballa, S., and Ullegaddi, R. (2007) Riboflavin status in acute ischaemic stroke, Eur. J. Clin. Nutr., 61, 1237–1240, doi: https://doi.org/10.1038/sj.ejcn.1602666.

    Article  CAS  PubMed  Google Scholar 

  111. Da Silva-Candal, A., Perez-Diaz, A., Santamaria, M., Correa-Paz, C., Rodriguez-Yanez, M., Arda, A., Perez-Mato, M., Iglesias-Rey, R., Brea, J., Azuaje, J., Sotelo, E., Sobrino, T., Loza, M. I., Castillo, J., and Campos, F. (2018) Clinical validation of blood/brain glutamate grabbing in acute ischemic stroke, Ann. Neurol., 84, 260–273, doi: https://doi.org/10.1002/ana.25286.

    Article  CAS  PubMed  Google Scholar 

  112. Kalogeris, T., Bao, Y., and Korthuis, R. J. (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning, Redox Biol., 2, 702–714, doi: https://doi.org/10.1016/j.redox.2014.05.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cao, W., Carney, J. M., Duchon, A., Floyd, R. A., and Chevion, M. (1988) Oxygen free radical involvement in ischemia and reperfusion injury to brain, Neurosci. Lett., 88, 233–238.

    Article  CAS  PubMed  Google Scholar 

  114. Anderson, M. F., and Sims, N. R. (2002) The effects of focal ischemia and reperfusion on the glutathione content of mitochondria from rat brain subregions, J. Neurochem., 81, 541–549.

    Article  CAS  PubMed  Google Scholar 

  115. Mizui, T., Kinouchi, H., and Chan, P. H. (1992) Depletion of brain glutathione by buthionine sulfoximine enhances cerebral ischemic injury in rats, Am. J. Physiol., 262, H313–317.

    CAS  PubMed  Google Scholar 

  116. Folbergrova, J., Zhao, Q., Katsura, K., and Siesjo, B. K. (1995) N-tert-Butyl-alpha-phenylnitrone improves recovery of brain energy state in rats following transient focal ischemia, Proc. Natl. Acad. Sci. USA, 92, 5057–5061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Khan, M., Sekhon, B., Jatana, M., Giri, S., Gilg, A. G., Sekhon, C., Singh, I., and Singh, A. K. (2004) Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke, J. Neurosci. Res., 76, 519–527, doi: https://doi.org/10.1002/jnr.20087.

    Article  CAS  PubMed  Google Scholar 

  118. Anderson, M. F., Nilsson, M., Eriksson, P. S., and Sims, N. R. (2004) Glutathione monoethyl ester provides neuroprotection in a rat model of stroke, Neurosci. Lett., 354, 163–165.

    Article  CAS  PubMed  Google Scholar 

  119. Prime, T. A., Blaikie, F. H., Evans, C., Nadtochiy, S. M., James, A. M., Dahm, C. C., Vitturi, D. A., Patel, R. P., Hiley, C. R., Abakumova, I., Requejo, R., Chouchani, E. T., Hurd, T. R., Garvey, J. F., Taylor, C. T., Brookes, P. S., Smith, R. A., and Murphy, M. P. (2009) A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury, Proc. Natl. Acad. Sci. USA, 106, 10764–10769.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Stepanova, A., Shurubor, Y., Valsecchi, F., Manfredi, G., and Galkin, A. (2016) Differential susceptibility of mitochondrial complex II to inhibition by oxaloacetate in brain and heart, Biochim. Biophys. Acta, 1857, 1561–1568, doi: https://doi.org/10.1016/j.bbabio.2016.06.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kang, P. T., Chen, C. L., Lin, P., Zhang, L., Zweier, J. L., and Chen, Y. R. (2018) Mitochondrial complex I in the post-ischemic heart: reperfusion-mediated oxidative injury and protein cysteine sulfonation, J. Mol. Cell. Cardiol., 121, 190–204, doi: https://doi.org/10.1016/j.yjmcc.2018.07.244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I am grateful to Dr. Anna Stepanova and Dr. Vadim Ten for critical reading of the manuscript. I also wish to thank Dr. Vera Grivennikova for the help with the Russian version of this review and valuable discussions. Thanks are due to Nicole Sayles for her help in the preparation of the review.

Funding

The work in the author’s laboratory was supported by the NIH grant NS-100850 and MRC UK grants G1100051 and MR/L007339/1.

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  1. Division of Neonatology, Department of Pediatrics, Columbia University William Black Building, NY, 10032, New York, USA

    A. Galkin

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This article does not contain any studies with human participants or animals.

Published in Russian in Biokhimiya, 2019, Vol. 84, No. 11, pp. 1743–1758.

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Galkin, A. Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage. Biochemistry Moscow 84, 1411–1423 (2019). https://doi.org/10.1134/S0006297919110154

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