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Molecular Neurobiology

, Volume 47, Issue 1, pp 9–23 | Cite as

Molecular Mechanisms of Ischemia–Reperfusion Injury in Brain: Pivotal Role of the Mitochondrial Membrane Potential in Reactive Oxygen Species Generation

  • Thomas H. Sanderson
  • Christian A. Reynolds
  • Rita Kumar
  • Karin Przyklenk
  • Maik Hüttemann
Article

Abstract

Stroke and circulatory arrest cause interferences in blood flow to the brain that result in considerable tissue damage. The primary method to reduce or prevent neurologic damage to patients suffering from brain ischemia is prompt restoration of blood flow to the ischemic tissue. However, paradoxically, restoration of blood flow causes additional damage and exacerbates neurocognitive deficits among patients who suffer a brain ischemic event. Mitochondria play a critical role in reperfusion injury by producing excessive reactive oxygen species (ROS) thereby damaging cellular components, and initiating cell death. In this review, we summarize our current understanding of the mechanisms of mitochondrial ROS generation during reperfusion, and specifically, the role the mitochondrial membrane potential plays in the pathology of cerebral ischemia/reperfusion. Additionally, we propose a temporal model of ROS generation in which posttranslational modifications of key oxidative phosphorylation (OxPhos) proteins caused by ischemia induce a hyperactive state upon reintroduction of oxygen. Hyperactive OxPhos generates high mitochondrial membrane potentials, a condition known to generate excessive ROS. Such a state would lead to a “burst” of ROS upon reperfusion, thereby causing structural and functional damage to the mitochondria and inducing cell death signaling that eventually culminate in tissue damage. Finally, we propose that strategies aimed at modulating this maladaptive hyperpolarization of the mitochondrial membrane potential may be a novel therapeutic intervention and present specific studies demonstrating the cytoprotective effect of this treatment modality.

Keywords

Brain Reactive oxygen species Ischemia Reperfusion Mitochondria Oxidative phosphorylation 

Notes

Acknowledgments

This work was supported by the Department of Emergency Medicine, the Cardiovascular Research Institute, Wayne State University, Detroit, and grant GM089900 from the National Institutes of Health.

References

  1. 1.
    Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J (2010) Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121(7):e46–e215. doi: 10.1161/CIRCULATIONAHA.109.192667 PubMedCrossRefGoogle Scholar
  2. 2.
    Krause GS, Kumar K, White BC, Aust SD, Wiegenstein JG (1986) Ischemia, resuscitation, and reperfusion: mechanisms of tissue injury and prospects for protection. Am Heart J 111(4):768–780PubMedCrossRefGoogle Scholar
  3. 3.
    Bloom HL, Shukrullah I, Cuellar JR, Lloyd MS, Dudley SC Jr, Zafari AM (2007) Long-term survival after successful inhospital cardiac arrest resuscitation. Am Heart J 153(5):831–836. doi: 10.1016/j.ahj.2007.02.011 PubMedCrossRefGoogle Scholar
  4. 4.
    Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, Rea T, Lowe R, Brown T, Dreyer J, Davis D, Idris A, Stiell I (2008) Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 300(12):1423–1431. doi: 10.1001/jama.300.12.1423 PubMedCrossRefGoogle Scholar
  5. 5.
    Kumar K, Goosmann M, Krause GS, Nayini NR, Estrada R, Hoehner TJ, White BC, Koestner A (1987) Ultrastructural and ionic studies in global ischemic dog brain. Acta Neuropathol 73(4):393–399PubMedCrossRefGoogle Scholar
  6. 6.
    Jenkins LW, Povlishock JT, Lewelt W, Miller JD, Becker DP (1981) The role of postischemic recirculation in the development of ischemic neuronal injury following complete cerebral ischemia. Acta Neuropathol 55(3):205–220PubMedCrossRefGoogle Scholar
  7. 7.
    Ito U, Spatz M, Walker JT Jr, Klatzo I (1975) Experimental cerebral ischemia in mongolian gerbils. I. Light microscopic observations. Acta Neuropathol 32(3):209–223PubMedCrossRefGoogle Scholar
  8. 8.
    Kirino T, Sano K (1984) Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol 62(3):201–208PubMedCrossRefGoogle Scholar
  9. 9.
    Pulsinelli WA, Jacewicz M, Levy DE, Petito CK, Plum F (1997) Ischemic brain injury and the therapeutic window. Ann N Y Acad Sci 835:187–193PubMedCrossRefGoogle Scholar
  10. 10.
    Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Dodd RL, Nishi T, Maier CM, Kinouchi H, Chan PH (2003) Oxidative damage to the endoplasmic reticulum is implicated in ischemic neuronal cell death. J Cereb Blood Flow Metab 23(10):1117–1128PubMedCrossRefGoogle Scholar
  11. 11.
    Piantadosi CA, Zhang J (1996) Mitochondrial generation of reactive oxygen species after brain ischemia in the rat. Stroke 27(2):327–331, discussion 332PubMedCrossRefGoogle Scholar
  12. 12.
    Sugawara T, Chan PH (2003) Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal 5(5):597–607. doi: 10.1089/152308603770310266 PubMedCrossRefGoogle Scholar
  13. 13.
    Al-Macki N, Miller SP, Hall N, Shevell M (2009) The spectrum of abnormal neurologic outcomes subsequent to term intrapartum asphyxia. Pediatr Neurol 41(6):399–405. doi: 10.1016/j.pediatrneurol.2009.06.001 PubMedCrossRefGoogle Scholar
  14. 14.
    Vannucci RC (2000) Hypoxic-ischemic encephalopathy. Am J Perinatol 17(3):113–120. doi: 10.1055/s-2000-9293 PubMedCrossRefGoogle Scholar
  15. 15.
    Volpe JJ (1992) Brain injury in the premature infant—current concepts of pathogenesis and prevention. Biol Neonate 62(4):231–242PubMedCrossRefGoogle Scholar
  16. 16.
    Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, Pemberton PJ, Stanley FJ (1998) Intrapartum risk factors for newborn encephalopathy: the Western Australian case–control study. BMJ 317(7172):1554–1558PubMedCrossRefGoogle Scholar
  17. 17.
    Sie LT, van der Knaap MS, Oosting J, de Vries LS, Lafeber HN, Valk J (2000) MR patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia. Neuropediatrics 31(3):128–136. doi: 10.1055/s-2000-7496 PubMedCrossRefGoogle Scholar
  18. 18.
    Cowan F, Rutherford M, Groenendaal F, Eken P, Mercuri E, Bydder GM, Meiners LC, Dubowitz LM, de Vries LS (2003) Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 361(9359):736–742. doi: 10.1016/S0140-6736(03)12658-X PubMedCrossRefGoogle Scholar
  19. 19.
    Ferriero DM (2004) Neonatal brain injury. N Engl J Med 351(19):1985–1995. doi: 10.1056/NEJMra041996 PubMedCrossRefGoogle Scholar
  20. 20.
    Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21(1):2–14. doi: 10.1097/00004647-200101000-00002 PubMedCrossRefGoogle Scholar
  21. 21.
    Fiskum G, Murphy AN, Beal MF (1999) Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J Cereb Blood Flow Metab 19(4):351–369. doi: 10.1097/00004647-199904000-00001 PubMedCrossRefGoogle Scholar
  22. 22.
    Stadtman ER, Levine RL (2000) Protein oxidation. Ann N Y Acad Sci 899:191–208PubMedCrossRefGoogle Scholar
  23. 23.
    Richter C, Frei B (1988) Ca2+ release from mitochondria induced by prooxidants. Free Radic Biol Med 4(6):365–375PubMedCrossRefGoogle Scholar
  24. 24.
    Kaur H, Halliwell B (1994) Aromatic hydroxylation of phenylalanine as an assay for hydroxyl radicals. Measurement of hydroxyl radical formation from ozone and in blood from premature babies using improved HPLC methodology. Anal Biochem 220(1):11–15. doi: 10.1006/abio.1994.1291 PubMedCrossRefGoogle Scholar
  25. 25.
    LeDoux SP, Driggers WJ, Hollensworth BS, Wilson GL (1999) Repair of alkylation and oxidative damage in mitochondrial DNA. Mutat Res 434(3):149–159PubMedCrossRefGoogle Scholar
  26. 26.
    Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, Kirk M, Freeman BA (1994) Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. J Biol Chem 269(42):26066–26075PubMedGoogle Scholar
  27. 27.
    Arnold S, Kadenbach B (1999) The intramitochondrial ATP/ADP-ratio controls cytochrome c oxidase activity allosterically. FEBS Lett 443(2):105–108PubMedCrossRefGoogle Scholar
  28. 28.
    Kadenbach B, Ramzan R, Wen L, Vogt S (2010) New extension of the Mitchell theory for oxidative phosphorylation in mitochondria of living organisms. Biochim Biophys Acta 1800(3):205–212. doi: 10.1016/j.bbagen.2009.04.019 PubMedCrossRefGoogle Scholar
  29. 29.
    Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J Biol Chem 217(1):383–393PubMedGoogle Scholar
  30. 30.
    Kim N, Ripple MO, Springett R (2012) Measurement of the mitochondrial membrane potential and pH gradient from the redox poise of the hemes of the bc 1 complex. Biochem J 102(5):1194–1203Google Scholar
  31. 31.
    Nicholls DG (1974) The influence of respiration and ATP hydrolysis on the proton-electrochemical gradient across the inner membrane of rat-liver mitochondria as determined by ion distribution. Eur J Biochem 50(1):305–315PubMedCrossRefGoogle Scholar
  32. 32.
    Labajova A, Vojtiskova A, Krivakova P, Kofranek J, Drahota Z, Houstek J (2006) Evaluation of mitochondrial membrane potential using a computerized device with a tetraphenylphosphonium-selective electrode. Anal Biochem 353(1):37–42PubMedCrossRefGoogle Scholar
  33. 33.
    Cossarizza A, Ceccarelli D, Masini A (1996) Functional heterogeneity of an isolated mitochondrial population revealed by cytofluorometric analysis at the single organelle level. Exp Cell Res 222(1):84–94PubMedCrossRefGoogle Scholar
  34. 34.
    Barger JL, Brand MD, Barnes BM, Boyer BB (2003) Tissue-specific depression of mitochondrial proton leak and substrate oxidation in hibernating arctic ground squirrels. Am J Physiol Regul Integr Comp Physiol 284(5):R1306–R1313PubMedGoogle Scholar
  35. 35.
    Shears SB, Kirk CJ (1984) Characterization of a rapid cellular-fractionation technique for hepatocytes. Application in the measurement of mitochondrial membrane potential in situ. Biochem J 219(2):375–382PubMedGoogle Scholar
  36. 36.
    Brand MD, Hafner RP, Brown GC (1988) Control of respiration in non-phosphorylating mitochondria is shared between the proton leak and the respiratory chain. Biochem J 255(2):535–539PubMedGoogle Scholar
  37. 37.
    da Silva EM, Soares AM, Moreno AJ (1998) The use of the mitochondrial transmembrane electric potential as an effective biosensor in ecotoxicological research. Chemosphere 36(10):2375–2390PubMedCrossRefGoogle Scholar
  38. 38.
    Moreira PI, Santos MS, Moreno A, Oliveira C (2001) Amyloid beta-peptide promotes permeability transition pore in brain mitochondria. Biosci Rep 21(6):789–800PubMedCrossRefGoogle Scholar
  39. 39.
    Wan B, Doumen C, Duszynski J, Salama G, Vary TC, LaNoue KF (1993) Effects of cardiac work on electrical potential gradient across mitochondrial membrane in perfused rat hearts. Am J Physiol 265(2 Pt 2):H453–H460PubMedGoogle Scholar
  40. 40.
    Zhang H, Huang HM, Carson RC, Mahmood J, Thomas HM, Gibson GE (2001) Assessment of membrane potentials of mitochondrial populations in living cells. Anal Biochem 298(2):170–180PubMedCrossRefGoogle Scholar
  41. 41.
    Brand MD, Felber SM (1984) Membrane potential of mitochondria in intact lymphocytes during early mitogenic stimulation. Biochem J 217(2):453–459PubMedGoogle Scholar
  42. 42.
    Backus M, Piwnica-Worms D, Hockett D, Kronauge J, Lieberman M, Ingram P, LeFurgey A (1993) Microprobe analysis of Tc-MIBI in heart cells: calculation of mitochondrial membrane potential. Am J Physiol 265(1 Pt 1):C178–C187PubMedGoogle Scholar
  43. 43.
    Porteous WK, James AM, Sheard PW, Porteous CM, Packer MA, Hyslop SJ, Melton JV, Pang CY, Wei YH, Murphy MP (1998) Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion. Eur J Biochem 257(1):192–201PubMedCrossRefGoogle Scholar
  44. 44.
    Nicholls DG (2006) Simultaneous monitoring of ionophore- and inhibitor-mediated plasma and mitochondrial membrane potential changes in cultured neurons. J Biol Chem 281(21):14864–14874PubMedCrossRefGoogle Scholar
  45. 45.
    Hoek JB, Nicholls DG, Williamson JR (1980) Determination of the mitochondrial protonmotive force in isolated hepatocytes. J Biol Chem 255(4):1458–1464PubMedGoogle Scholar
  46. 46.
    Nobes CD, Brown GC, Olive PN, Brand MD (1990) Non-ohmic proton conductance of the mitochondrial inner membrane in hepatocytes. J Biol Chem 265(22):12903–12909PubMedGoogle Scholar
  47. 47.
    Cortese JD (1999) Rat liver GTP-binding proteins mediate changes in mitochondrial membrane potential and organelle fusion. Am J Physiol 276(3 Pt 1):C611–C620PubMedGoogle Scholar
  48. 48.
    Iwata S, Ostermeier C, Ludwig B, Michel H (1995) Structure at 2.8 Å resolution of cytochrome c oxidase from Paracoccus denitrificans. Nature 376(6542):660–669PubMedCrossRefGoogle Scholar
  49. 49.
    Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R, Yoshikawa S (1996) The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 Å. Science 272(5265):1136–1144PubMedCrossRefGoogle Scholar
  50. 50.
    Hüttemann M, Lee I, Samavati L, Yu H, Doan JW (2007) Regulation of mitochondrial oxidative phosphorylation through cell signaling. Biochim Biophys Acta 1773:1701–1720PubMedCrossRefGoogle Scholar
  51. 51.
    Picard M, Taivassalo T, Ritchie D, Wright KJ, Thomas MM, Romestaing C, Hepple RT (2011) Mitochondrial structure and function are disrupted by standard isolation methods. PLoS One 6(3):e18317. doi: doi:10.1371/journal.pone.0018317 PubMedCrossRefGoogle Scholar
  52. 52.
    Robb-Gaspers LD, Burnett P, Rutter GA, Denton RM, Rizzuto R, Thomas AP (1998) Integrating cytosolic calcium signals into mitochondrial metabolic responses. EMBO J 17(17):4987–5000PubMedCrossRefGoogle Scholar
  53. 53.
    Hopper RK, Carroll S, Aponte AM, Johnson DT, French S, Shen RF, Witzmann FA, Harris RA, Balaban RS (2006) Mitochondrial matrix phosphoproteome: effect of extra mitochondrial calcium. Biochemistry 45(8):2524–2536PubMedCrossRefGoogle Scholar
  54. 54.
    Lee I, Salomon AR, Ficarro S, Mathes I, Lottspeich F, Grossman LI, Hüttemann M (2005) cAMP-dependent tyrosine phosphorylation of subunit I inhibits cytochrome c oxidase activity. J Biol Chem 280(7):6094–6100. doi: 10.1074/jbc.M411335200 PubMedCrossRefGoogle Scholar
  55. 55.
    Bender E, Kadenbach B (2000) The allosteric ATP-inhibition of cytochrome c oxidase activity is reversibly switched on by cAMP-dependent phosphorylation. FEBS Lett 466(1):130–134PubMedCrossRefGoogle Scholar
  56. 56.
    Lee I, Salomon AR, Samavati L, Pecina P, Pecinova A, Hüttemann M (2009) Isolation of regulatory-competent, phosphorylated cytochrome c oxidase. Methods Enzymol 457:193–210PubMedCrossRefGoogle Scholar
  57. 57.
    Hüttemann M, Lee I, Pecinova A, Pecina P, Przyklenk K, Doan JW (2008) Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. J Bioenerg Biomembr 40(5):445–456PubMedCrossRefGoogle Scholar
  58. 58.
    Hüttemann M, Helling S, Sanderson TH, Sinkler C, Samavati L, Mahapatra G, Varughese A, Lu G, Liu J, Ramzan R, Vogt S, Grossman LI, Doan JW, Marcus K, Lee I (2012) Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Biochim Biophys Acta 1817(4):598–609. doi: 10.1016/j.bbabio.2011.07.001 PubMedCrossRefGoogle Scholar
  59. 59.
    Helling S, Hüttemann M, Ramzan R, Kim SH, Lee I, Muller T, Langenfeld E, Meyer HE, Kadenbach B, Vogt S, Marcus K (2012) Multiple phosphorylations of cytochrome c oxidase and their functions. Proteomics 12(7):950–959. doi: 10.1002/pmic.201100618 PubMedCrossRefGoogle Scholar
  60. 60.
    Lee I, Salomon AR, Yu K, Doan JW, Grossman LI, Hüttemann M (2006) New prospects for an old enzyme: mammalian cytochrome c is tyrosine-phosphorylated in vivo. Biochemistry 45(30):9121–9128PubMedCrossRefGoogle Scholar
  61. 61.
    Yu H, Lee I, Salomon AR, Yu K, Hüttemann M (2008) Mammalian liver cytochrome c is tyrosine-48 phosphorylated in vivo, inhibiting mitochondrial respiration. Biochim Biophys Acta 1777(7–8):1066–1071PubMedGoogle Scholar
  62. 62.
    Pecina P, Borisenko GG, Belikova NA, Tyurina YY, Pecinova A, Lee I, Samhan-Arias AK, Przyklenk K, Kagan VE, Hüttemann M (2010) Phosphomimetic substitution of cytochrome C tyrosine 48 decreases respiration and binding to cardiolipin and abolishes ability to trigger downstream caspase activation. Biochemistry 49(31):6705–6714PubMedCrossRefGoogle Scholar
  63. 63.
    Sanderson TH, Lee I, Pecina P, Kumar R, Tousignant RN, Yu K, Mahapatra G, Varughese A, Salomon AR, Hüttemann M (2012) Cytochrome c is tyrosine 97 phosphorylated by neuroprotective insulin treatment. J Neurosci Res (in press)Google Scholar
  64. 64.
    Sanderson TH, Kumar R, Sullivan JM, Krause GS (2008) Insulin blocks cytochrome c release in the reperfused brain through PI3-K signaling and by promoting Bax/Bcl-XL binding. J Neurochem 106(3):1248–1258PubMedCrossRefGoogle Scholar
  65. 65.
    Prabu SK, Anandatheerthavarada HK, Raza H, Srinivasan S, Spear JF, Avadhani NG (2006) Protein kinase A-mediated phosphorylation modulates cytochrome c oxidase function and augments hypoxia and myocardial ischemia-related injury. J Biol Chem 281(4):2061–2070PubMedCrossRefGoogle Scholar
  66. 66.
    Yu H, Lee I, Salomon AR, Yu K, Hüttemann M (2008) Mammalian liver cytochrome c is tyrosine-48 phosphorylated in vivo, inhibiting mitochondrial respiration. Biochim Biophys Acta 1777(7–8):1066–1071PubMedGoogle Scholar
  67. 67.
    Kaim G, Dimroth P (1999) ATP synthesis by F-type ATP synthase is obligatorily dependent on the transmembrane voltage. EMBO J 18(15):4118–4127PubMedCrossRefGoogle Scholar
  68. 68.
    St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277(47):44784–44790. doi: 10.1074/jbc.M207217200 PubMedCrossRefGoogle Scholar
  69. 69.
    Han D, Canali R, Rettori D, Kaplowitz N (2003) Effect of glutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria. Mol Pharmacol 64(5):1136–1144PubMedCrossRefGoogle Scholar
  70. 70.
    Kushnareva Y, Murphy AN, 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. doi: 10.1042/BJ20021121 PubMedCrossRefGoogle Scholar
  71. 71.
    Liu SS (1999) Cooperation of a “reactive oxygen cycle” with the Q cycle and the proton cycle in the respiratory chain–superoxide generating and cycling mechanisms in mitochondria. J Bioenerg Biomembr 31(4):367–376PubMedCrossRefGoogle Scholar
  72. 72.
    Rottenberg H, Covian R, Trumpower BL (2009) Membrane potential greatly enhances superoxide generation by the cytochrome bc1 complex reconstituted into phospholipid vesicles. J Biol Chem 284(29):19203–19210. doi: 10.1074/jbc.M109.017376 PubMedCrossRefGoogle Scholar
  73. 73.
    Suski JM, Lebiedzinska M, Bonora M, Pinton P, Duszynski J, Wieckowski MR (2012) Relation between mitochondrial membrane potential and ROS formation. Methods Mol Biol 810:183–205. doi: 10.1007/978-1-61779-382-0_12 PubMedCrossRefGoogle Scholar
  74. 74.
    Starkov AA, Fiskum G (2003) Regulation of brain mitochondrial H2O2 production by membrane potential and NAD(P)H redox state. J Neurochem 86(5):1101–1107PubMedCrossRefGoogle Scholar
  75. 75.
    Liu SS (2010) Mitochondrial Q cycle-derived superoxide and chemiosmotic bioenergetics. Ann N Y Acad Sci 1201:84–95. doi: 10.1111/j.1749-6632.2010.05632.x PubMedCrossRefGoogle Scholar
  76. 76.
    Korshunov SS, Skulachev VP, Starkov AA (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416(1):15–18PubMedCrossRefGoogle Scholar
  77. 77.
    Rottenberg H, Covian R, Trumpower BL (2009) Membrane potential greatly enhances superoxide generation by the cytochrome bc 1 complex reconstituted into phospholipid vesicles. J Biol Chem 284(29):19203–19210. doi: 10.1074/jbc.M109.017376 PubMedCrossRefGoogle Scholar
  78. 78.
    Kadenbach B, Arnold S, Lee I, Hüttemann M (2004) The possible role of cytochrome c oxidase in stress-induced apoptosis and degenerative diseases. Biochim Biophys Acta 1655(1–3):400–408PubMedGoogle Scholar
  79. 79.
    Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27(5):1129–1138. doi: 10.1523/JNEUROSCI.4468-06.2007 PubMedCrossRefGoogle Scholar
  80. 80.
    Liu RR, Murphy TH (2009) Reversible cyclosporin A-sensitive mitochondrial depolarization occurs within minutes of stroke onset in mouse somatosensory cortex in vivo: a two-photon imaging study. J Biol Chem 284(52):36109–36117. doi: 10.1074/jbc.M109.055301 PubMedCrossRefGoogle Scholar
  81. 81.
    Folbergrova J, Li PA, Uchino H, Smith ML, Siesjo BK (1997) Changes in the bioenergetic state of rat hippocampus during 2.5 min of ischemia, and prevention of cell damage by cyclosporin A in hyperglycemic subjects. Exp Brain Res Experimentelle Hirnforschung Experimentation Cerebrale 114(1):44–50CrossRefGoogle Scholar
  82. 82.
    Katsura K, Rodriguez de Turco EB, Folbergrova J, Bazan NG, Siesjo BK (1993) Coupling among energy failure, loss of ion homeostasis, and phospholipase A2 and C activation during ischemia. J Neurochem 61(5):1677–1684PubMedCrossRefGoogle Scholar
  83. 83.
    Domenis R, Comelli M, Bisetto E, Mavelli I (2011) Mitochondrial bioenergetic profile and responses to metabolic inhibition in human hepatocarcinoma cell lines with distinct differentiation characteristics. J Bioenerg Biomembr 43(5):493–505. doi: 10.1007/s10863-011-9380-5 PubMedCrossRefGoogle Scholar
  84. 84.
    Puka-Sundvall M, Gajkowska B, Cholewinski M, Blomgren K, Lazarewicz JW, Hagberg H (2000) Subcellular distribution of calcium and ultrastructural changes after cerebral hypoxia-ischemia in immature rats. Brain Res Dev Brain Res 125(1–2):31–41PubMedCrossRefGoogle Scholar
  85. 85.
    Ankarcrona M, Dypbukt JM, Orrenius S, Nicotera P (1996) Calcineurin and mitochondrial function in glutamate-induced neuronal cell death. FEBS Lett 394(3):321–324PubMedCrossRefGoogle Scholar
  86. 86.
    McCormack JG, Denton RM (1993) The role of intramitochondrial Ca2+ in the regulation of oxidative phosphorylation in mammalian tissues. Biochem Soc Trans 21(Pt 3):793–799PubMedGoogle Scholar
  87. 87.
    Balaban RS (2002) Cardiac energy metabolism homeostasis: role of cytosolic calcium. J Mol Cell Cardiol 34(10):1259–1271PubMedCrossRefGoogle Scholar
  88. 88.
    Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol 287(4):C817–C833. doi: 10.1152/ajpcell.00139.2004 CrossRefGoogle Scholar
  89. 89.
    Zaidan E, Sims NR (1994) The calcium content of mitochondria from brain subregions following short-term forebrain ischemia and recirculation in the rat. J Neurochem 63(5):1812–1819PubMedCrossRefGoogle Scholar
  90. 90.
    Kristian T, Pivovarova NB, Fiskum G, Andrews SB (2007) Calcium-induced precipitate formation in brain mitochondria: composition, calcium capacity, and retention. J Neurochem 102(4):1346–1356. doi: 10.1111/j.1471-4159.2007.04626.x PubMedCrossRefGoogle Scholar
  91. 91.
    Iijima T, Mishima T, Akagawa K, Iwao Y (2006) Neuroprotective effect of propofol on necrosis and apoptosis following oxygen–glucose deprivation—relationship between mitochondrial membrane potential and mode of death. Brain Res 1099(1):25–32. doi: 10.1016/j.brainres.2006.04.117 PubMedCrossRefGoogle Scholar
  92. 92.
    Choi K, Kim J, Kim GW, Choi C (2009) Oxidative stress-induced necrotic cell death via mitochondira-dependent burst of reactive oxygen species. Curr Neurovasc Res 6(4):213–222PubMedCrossRefGoogle Scholar
  93. 93.
    Kunimatsu T, Kobayashi K, Yamashita A, Yamamoto T, Lee MC (2011) Cerebral reactive oxygen species assessed by electron spin resonance spectroscopy in the initial stage of ischemia-reperfusion are not associated with hypothermic neuroprotection. J Clin Neurosci Off J Neurosurgl Soc Australas 18(4):545–548. doi: 10.1016/j.jocn.2010.07.140 Google Scholar
  94. 94.
    Fabian RH, DeWitt DS, Kent TA (1995) In vivo detection of superoxide anion production by the brain using a cytochrome c electrode. J Cereb Blood Flow Metab 15(2):242–247. doi: 10.1038/jcbfm.1995.30 PubMedCrossRefGoogle Scholar
  95. 95.
    Kudin AP, Malinska D, Kunz WS (2008) Sites of generation of reactive oxygen species in homogenates of brain tissue determined with the use of respiratory substrates and inhibitors. Biochim Biophys Acta 1777(7–8):689–695. doi: 10.1016/j.bbabio.2008.05.010 PubMedGoogle Scholar
  96. 96.
    Barja G, Herrero A (1998) Localization at complex I and mechanism of the higher free radical production of brain nonsynaptic mitochondria in the short-lived rat than in the longevous pigeon. J Bioenerg Biomembr 30(3):235–243PubMedCrossRefGoogle Scholar
  97. 97.
    Barja G (1999) Mitochondrial oxygen radical generation and leak: sites of production in states 4 and 3, organ specificity, and relation to aging and longevity. J Bioenerg Biomembr 31(4):347–366PubMedCrossRefGoogle Scholar
  98. 98.
    St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277(47):44784–44790. doi: 10.1074/jbc.M207217200 PubMedCrossRefGoogle Scholar
  99. 99.
    Sims NR, Pulsinelli WA (1987) Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat. J Neurochem 49(5):1367–1374PubMedCrossRefGoogle Scholar
  100. 100.
    Sims NR (1991) Selective impairment of respiration in mitochondria isolated from brain subregions following transient forebrain ischemia in the rat. J Neurochem 56(6):1836–1844PubMedCrossRefGoogle Scholar
  101. 101.
    Racay P, Tatarkova Z, Chomova M, Hatok J, Kaplan P, Dobrota D (2009) Mitochondrial calcium transport and mitochondrial dysfunction after global brain ischemia in rat hippocampus. Neurochem Res 34(8):1469–1478. doi: 10.1007/s11064-009-9934-7 PubMedCrossRefGoogle Scholar
  102. 102.
    Chomova M, Tatarkova Z, Dobrota D, Racay P (2012) Ischemia-induced inhibition of mitochondrial complex I in rat brain: effect of permeabilization method and electron acceptor. Neurochem Res. doi: 10.1007/s11064-011-0689-6
  103. 103.
    Zhang Y, Marcillat O, Giulivi C, Ernster L, Davies KJ (1990) The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J Biol Chem 265(27):16330–16336PubMedGoogle Scholar
  104. 104.
    Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, Chan PH (1998) Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci 18(1):205–213PubMedGoogle Scholar
  105. 105.
    Friberg H, Wieloch T, Castilho RF (2002) Mitochondrial oxidative stress after global brain ischemia in rats. Neurosci Lett 334(2):111–114PubMedCrossRefGoogle Scholar
  106. 106.
    Shinzawa-Itoh K, Aoyama H, Muramoto K, Terada H, Kurauchi T, Tadehara Y, Yamasaki A, Sugimura T, Kurono S, Tsujimoto K, Mizushima T, Yamashita E, Tsukihara T, Yoshikawa S (2007) Structures and physiological roles of 13 integral lipids of bovine heart cytochrome c oxidase. EMBO J 26(6):1713–1725. doi: 10.1038/sj.emboj.7601618 PubMedCrossRefGoogle Scholar
  107. 107.
    Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY, Tyurin VA, Jiang J, Stoyanovsky DA, Wipf P, Kochanek PM, Greenberger JS, Pitt B, Shvedova AA, Borisenko G (2009) Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic Biol Med 46(11):1439–1453PubMedCrossRefGoogle Scholar
  108. 108.
    Kim J, Minkler PE, Salomon RG, Anderson VE, Hoppel CL (2011) Cardiolipin: characterization of distinct oxidized molecular species. J Lipid Res 52(1):125–135. doi: 10.1194/jlr.M010520 PubMedCrossRefGoogle Scholar
  109. 109.
    Robinson NC (1993) Functional binding of cardiolipin to cytochrome c oxidase. J Bioenerg Biomembr 25(2):153–163PubMedCrossRefGoogle Scholar
  110. 110.
    Petrosillo G, Di Venosa N, Moro N, Colantuono G, Paradies V, Tiravanti E, Federici A, Ruggiero FM, Paradies G (2011) In vivo hyperoxic preconditioning protects against rat-heart ischemia/reperfusion injury by inhibiting mitochondrial permeability transition pore opening and cytochrome c release. Free Radic Biol Med 50(3):477–483. doi: 10.1016/j.freeradbiomed.2010.11.030 PubMedCrossRefGoogle Scholar
  111. 111.
    Paradies G, Petrosillo G, Paradies V, Ruggiero FM (2010) Oxidative stress, mitochondrial bioenergetics, and cardiolipin in aging. Free Radic Biol Med 48(10):1286–1295. doi: 10.1016/j.freeradbiomed.2010.02.020 PubMedCrossRefGoogle Scholar
  112. 112.
    Petrosillo G, Matera M, Moro N, Ruggiero FM, Paradies G (2009) Mitochondrial complex I dysfunction in rat heart with aging: critical role of reactive oxygen species and cardiolipin. Free Radic Biol Med 46(1):88–94. doi: 10.1016/j.freeradbiomed.2008.09.031 PubMedCrossRefGoogle Scholar
  113. 113.
    Petrosillo G, Ruggiero FM, Pistolese M, Paradies G (2004) Ca2+-induced reactive oxygen species production promotes cytochrome c release from rat liver mitochondria via mitochondrial permeability transition (MPT)-dependent and MPT-independent mechanisms: role of cardiolipin. J Biol Chem 279(51):53103–53108. doi: 10.1074/jbc.M407500200 PubMedCrossRefGoogle Scholar
  114. 114.
    Garcia Fernandez M, Troiano L, Moretti L, Nasi M, Pinti M, Salvioli S, Dobrucki J, Cossarizza A (2002) Early changes in intramitochondrial cardiolipin distribution during apoptosis. Cell Growth Differ Mol Biol J Am Assoc Cancer Res 13(9):449–455Google Scholar
  115. 115.
    Kagan VE, Tyurin VA, Jiang J, Tyurina YY, Ritov VB, Amoscato AA, Osipov AN, Belikova NA, Kapralov AA, Kini V, Vlasova II, Zhao Q, Zou M, Di P, Svistunenko DA, Kurnikov IV, Borisenko GG (2005) Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol 1(4):223–232. doi: 10.1038/nchembio727 PubMedCrossRefGoogle Scholar
  116. 116.
    Northington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ (2001) Early neurodegeneration after hypoxia-ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol Dis 8(2):207–219. doi: 10.1006/nbdi.2000.0371 PubMedCrossRefGoogle Scholar
  117. 117.
    Leist M, Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2(8):589–598. doi: 10.1038/35085008 PubMedCrossRefGoogle Scholar
  118. 118.
    Hetz C, Vitte PA, Bombrun A, Rostovtseva TK, Montessuit S, Hiver A, Schwarz MK, Church DJ, Korsmeyer SJ, Martinou JC, Antonsson B (2005) Bax channel inhibitors prevent mitochondrion-mediated apoptosis and protect neurons in a model of global brain ischemia. J Biol Chem 280(52):42960–42970PubMedCrossRefGoogle Scholar
  119. 119.
    Cao G, Xing J, Xiao X, Liou AK, Gao Y, Yin XM, Clark RS, Graham SH, Chen J (2007) Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci 27(35):9278–9293. doi: 10.1523/JNEUROSCI.2826-07.2007 PubMedCrossRefGoogle Scholar
  120. 120.
    Sugawara T, Fujimura M, Morita-Fujimura Y, Kawase M, Chan PH (1999) Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. J Neurosci 19(22):RC39PubMedGoogle Scholar
  121. 121.
    Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8(3):705–711PubMedCrossRefGoogle Scholar
  122. 122.
    Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 15(6):691–699PubMedCrossRefGoogle Scholar
  123. 123.
    Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S (2002) Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci USA 99(3):1259–1263. doi: 10.1073/pnas.241655498 PubMedCrossRefGoogle Scholar
  124. 124.
    Berezhna S, Wohlrab H, Champion PM (2003) Resonance Raman investigations of cytochrome c conformational change upon interaction with the membranes of intact and Ca2+-exposed mitochondria. Biochemistry 42(20):6149–6158. doi: 10.1021/bi027387y PubMedCrossRefGoogle Scholar
  125. 125.
    Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326(Pt 1):1–16PubMedGoogle Scholar
  126. 126.
    Blomgren K, Zhu C, Wang X, Karlsson JO, Leverin AL, Bahr BA, Mallard C, Hagberg H (2001) Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia: a mechanism of “pathological apoptosis”? J Biol Chem 276(13):10191–10198. doi: 10.1074/jbc.M007807200 PubMedCrossRefGoogle Scholar
  127. 127.
    Cheng Y, Deshmukh M, D’Costa A, Demaro JA, Gidday JM, Shah A, Sun Y, Jacquin MF, Johnson EM, Holtzman DM (1998) Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. J Clin Invest 101(9):1992–1999. doi: 10.1172/JCI2169 PubMedCrossRefGoogle Scholar
  128. 128.
    Zhu C, Wang X, Cheng X, Qiu L, Xu F, Simbruner G, Blomgren K (2004) Post-ischemic hypothermia-induced tissue protection and diminished apoptosis after neonatal cerebral hypoxia-ischemia. Brain Res 996(1):67–75PubMedCrossRefGoogle Scholar
  129. 129.
    Chan PH, Kawase M, Murakami K, Chen SF, Li Y, Calagui B, Reola L, Carlson E, Epstein CJ (1998) Overexpression of SOD1 in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion. J Neurosci 18(20):8292–8299PubMedGoogle Scholar
  130. 130.
    Fujimura M, Morita-Fujimura Y, Noshita N, Sugawara T, Kawase M, Chan PH (2000) The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice. J Neurosci 20(8):2817–2824PubMedGoogle Scholar
  131. 131.
    Christophe M, Nicolas S (2006) Mitochondria: a target for neuroprotective interventions in cerebral ischemia–reperfusion. Curr Pharm Des 12(6):739–757PubMedCrossRefGoogle Scholar
  132. 132.
    Niizuma K, Endo H, Chan PH (2009) Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem 109(Suppl 1):133–138PubMedCrossRefGoogle Scholar
  133. 133.
    Chan PH, Kinouchi H, Epstein CJ, Carlson E, Chen SF, Imaizumi S, Yang GY (1993) Role of superoxide dismutase in ischemic brain injury: reduction of edema and infarction in transgenic mice following focal cerebral ischemia. Prog Brain Res 96:97–104PubMedCrossRefGoogle Scholar
  134. 134.
    Chan PH, Longar S, Fishman RA (1987) Protective effects of liposome-entrapped superoxide dismutase on posttraumatic brain edema. Ann Neurol 21(6):540–547. doi: 10.1002/ana.410210604 PubMedCrossRefGoogle Scholar
  135. 135.
    He YY, Hsu CY, Ezrin AM, Miller MS (1993) Polyethylene glycol-conjugated superoxide dismutase in focal cerebral ischemia–reperfusion. Am J Physiol 265(1 Pt 2):H252–H256PubMedGoogle Scholar
  136. 136.
    Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC, Ashwood T, Wasiewski WW, Emeribe U (2007) NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 357(6):562–571. doi: 10.1056/NEJMoa070240 PubMedCrossRefGoogle Scholar
  137. 137.
    Weigl M, Tenze G, Steinlechner B, Skhirtladze K, Reining G, Bernardo M, Pedicelli E, Dworschak M (2005) A systematic review of currently available pharmacological neuroprotective agents as a sole intervention before anticipated or induced cardiac arrest. Resuscitation 65(1):21–39. doi: 10.1016/j.resuscitation.2004.11.004 PubMedCrossRefGoogle Scholar
  138. 138.
    Iijima T, Mishima T, Akagawa K, Iwao Y (2003) Mitochondrial hyperpolarization after transient oxygen-glucose deprivation and subsequent apoptosis in cultured rat hippocampal neurons. Brain Res 993(1–2):140–145PubMedCrossRefGoogle Scholar
  139. 139.
    Pandya JD, Pauly JR, Sullivan PG (2009) The optimal dosage and window of opportunity to maintain mitochondrial homeostasis following traumatic brain injury using the uncoupler FCCP. Exp Neurol 218(2):381–389. doi: 10.1016/j.expneurol.2009.05.023 PubMedCrossRefGoogle Scholar
  140. 140.
    Brennan JP, Southworth R, Medina RA, Davidson SM, Duchen MR, Shattock MJ (2006) Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation. Cardiovasc Res 72(2):313–321. doi: 10.1016/j.cardiores.2006.07.019 PubMedCrossRefGoogle Scholar
  141. 141.
    Haines BA, Mehta SL, Pratt SM, Warden CH, Li PA (2010) Deletion of mitochondrial uncoupling protein-2 increases ischemic brain damage after transient focal ischemia by altering gene expression patterns and enhancing inflammatory cytokines. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 30(11):1825–1833. doi: 10.1038/jcbfm.2010.52 CrossRefGoogle Scholar
  142. 142.
    Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF, Melcher T, Gonzalez-Zulueta M, Nikolich K, Wieloch T (2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 9(8):1062–1068. doi: 10.1038/nm903 PubMedCrossRefGoogle Scholar
  143. 143.
    Teshima Y, Akao M, Jones SP, Marban E (2003) Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res 93(3):192–200. doi: 10.1161/01.RES.0000085581.60197.4D PubMedCrossRefGoogle Scholar
  144. 144.
    Han YH, Kim SH, Kim SZ, Park WH (2009) Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) as an O2· generator induces apoptosis via the depletion of intracellular GSH contents in Calu-6 cells. Lung Cancer 63(2):201–209. doi: 10.1016/j.lungcan.2008.05.005 PubMedCrossRefGoogle Scholar
  145. 145.
    Dave KR, DeFazio RA, Raval AP, Torraco A, Saul I, Barrientos A, Perez-Pinzon MA (2008) Ischemic preconditioning targets the respiration of synaptic mitochondria via protein kinase C epsilon. J Neurosci 28(16):4172–4182. doi: 10.1523/JNEUROSCI.5471-07.2008 PubMedCrossRefGoogle Scholar
  146. 146.
    Liu Y, Chen L, Xu X, Vicaut E, Sercombe R (2009) Both ischemic preconditioning and ghrelin administration protect hippocampus from ischemia/reperfusion and upregulate uncoupling protein-2. BMC Physiol 9:17. doi: 10.1186/1472-6793-9-17 PubMedCrossRefGoogle Scholar
  147. 147.
    Samavati L, Lee I, Mathes I, Lottspeich F, Hüttemann M (2008) Tumor necrosis factor α inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem 283(30):21134–21144PubMedCrossRefGoogle Scholar
  148. 148.
    Sanderson TH, Kumar R, Murariu-Dobrin AC, Page AB, Krause GS, Sullivan JM (2009) Insulin activates the PI3K-Akt survival pathway in vulnerable neurons following global brain ischemia. Neurol Res 31(9):947–958. doi: 10.1179/174313209X382449 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Thomas H. Sanderson
    • 1
    • 2
    • 3
  • Christian A. Reynolds
    • 1
    • 2
    • 3
  • Rita Kumar
    • 1
    • 2
    • 3
  • Karin Przyklenk
    • 1
    • 2
    • 3
  • Maik Hüttemann
    • 1
    • 4
  1. 1.Cardiovascular Research InstituteWayne State University School of MedicineDetroitUSA
  2. 2.Department of Emergency MedicineWayne State University School of MedicineDetroitUSA
  3. 3.Department of PhysiologyWayne State University School of MedicineDetroitUSA
  4. 4.Center for Molecular Medicine and GeneticsWayne State University School of MedicineDetroitUSA

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