Mitochondrial Dysfunction in Oxidative Stress, Excitotoxicity, and Apoptosis

  • Anna-Liisa Nieminen
  • Aaron M. Byrne
  • Kaisa M. Heiskanen


Green Fluorescent Protein Mitochondrial Permeability Transition Mitochondrial Permeability Transition Pore Green Fluorescent Protein Fluorescence Pyridine Nucleotide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bellomo, G., Fulceri, R., Albano, E., Gamberucci, A., Pompella, A., Parola, M., and Benedetti, A., 1991, A Ca2+-dependent and independent mitochondrial damage in hepatocellular injury, Cell Calcium 12:335–341.CrossRefPubMedGoogle Scholar
  2. Bernardi, P., Broekemeier, K. M., and Pfeiffer, D. R., 1994, Recent progress on regulation of the mitochondrial permeability transition pore, a cyclosporin-sensitive pore in the inner mitochondrial membrane, J. Bioenerg. Biomembr. 26:509–517.CrossRefPubMedGoogle Scholar
  3. Beutner, G., Ruck, A., Riede, B., Welte, W., and Brdiczka, D., 1996, Complexes between kinases, mitochondrial porin, and adenylate translocator in rat brain resemble the permeability transition pore, FEBS Lett. 396:189–195.CrossRefPubMedGoogle Scholar
  4. Broekemeier, K. M., Schmid, P. C., Schmid, H.H. O., and Pfeiffer, D. R., 1985, Effects of phospholipase A2 inhibitors on ruthenium red-induced Ca2+ release from mitochondria, J. Biol. Chem. 260:105–113.PubMedGoogle Scholar
  5. Brustovetsky, N., and Klingenberg, M., 1996, Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+, Biochemistry 35:8483–8488.CrossRefPubMedGoogle Scholar
  6. Byrne, A. M., Lemasters, J. J., and Nieminen, A.-L., 1999, Contribution of increased mitochondrial free Ca2+ to the tert-butylhydroperoxide-induced mitochondrial permeability transition in rat hepatocytes, Hepatology 29:1523–1531.CrossRefPubMedGoogle Scholar
  7. Chacon, E., Ulrich, R., and Acosta, D., 1992, A digitized-fluorescence-imaging study of mitochondrial Ca2+ increase by doxorubicin in cardiac myocytes, Biochem. J. 281:871–878.PubMedGoogle Scholar
  8. Chacon, E., Reece, J. M., Nieminen, A.-L., Zahrebelski, G., Herman, B., and Lemasters, J. J., 1994, Distribution of electrical potential, pH, free Ca2+, and volume inside cultured adult rabbit cardiac myocytes during chemical hypoxia: A multiparameter digitized confocal microscopic study, Biophys. J. 66:942–952.PubMedGoogle Scholar
  9. Chacon, E., Ohata, H., Harper, I. S., Trollinger, D. R., and Lemasters, J. J., 1996, Mitochondrial free calcium transients during excitation-contraction coupling in rabbit cardiac myocytes, FEBS Lett. 382:31–36.CrossRefPubMedGoogle Scholar
  10. Chance, B., Sies, H., and Boveris, A., 1979, Hydroperoxide metabolism in mammalian organs, Physiol. Rev. 59:527–605.PubMedGoogle Scholar
  11. Choi, D. W., 1988, Glutamate neurotoxicity and diseases of the nervous system, Neuron 1:623–634.CrossRefPubMedGoogle Scholar
  12. Constantini, P., Chernyak, B. V., Petronilli, V., and Bernardi, P., 1996, Modulation of the mitochondrial permeability transition pore by pyridine nucleotides and dithiol oxidation at two separate sites, J. Biol. Chem. 271:6746–6751.Google Scholar
  13. Cortese, J. D., and Hackenbrock, C. R., 1993, Motional dynamics of functional cytochrome c delivered by low pH fusion into the intermembrane space of intact mitochondria, Biochim. Biophys. Acta 1142:194–202.PubMedGoogle Scholar
  14. Cotgreave, I. A., Moldeus, P., and Orrenius, S., 1988, Host biochemical defense mechanisms against prooxidants, Annu. Rev. Pharmacol. Toxicol. 28:189–212.CrossRefPubMedGoogle Scholar
  15. Crompton, M., Capano, M., and Carafoli, E., 1976, A kinetic study of the energy-linked influx of Ca2+ into heart mitochondria, Eur. J. Biochem 69:429–343.Google Scholar
  16. Crompton, M., Ellinger, H., and Costi, A., 1988, Inhibition of cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress, Biochem. J. 255:357–360.PubMedGoogle Scholar
  17. Cross, D. E., Halliwell, B., Borish, E. T., Pryor, W. A., Ames, B. A., Saul, R. S., McCord, J. M., and Harman, D., 1987, Oxygen radicals and human disease, Ann. Intern. Med. 107:526–545.PubMedGoogle Scholar
  18. Dawson, T. L., Gores, G. J., Nieminen, A.-L., Herman, B., and Lemasters, J. J., 1993, Subcellular sites of toxic oxygen species generation during reductive stress in rat hepatocytes. Am. J. Physiol. 264:C961–C967.PubMedGoogle Scholar
  19. Denton, R. M., Richards, D. A., and Chen, J.G., 1978, Calcium ions and the regulation of NAD+-linked isocitrate dehydrogenase from the mitochondria of rat heart and other tissues. Bio chem. J. 176:899–906.Google Scholar
  20. DiMonte, D., Sandy, D. M. S., Blank, L., and Smith, M. T., 1988, Fructose prevents l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-induced ATP depletion and toxicity in isolated hepatocytes, Biochem, Biophys. Res. Commun. 153:734–740.CrossRefGoogle Scholar
  21. Dugan, L. L., Sensi, S. L., Canzoniero, L. M. T., Handran, S. D., Rothman, S. M., Lin, T.-S., Gold-berg, M. P., and Choi, D.W., 1995, Mitochondrial production of active oxygen species in cortical neurons following exposure to N-methyl-D-aspartate, J. Neurosci. 15:6377–6388.PubMedGoogle Scholar
  22. Ehrenberg, B. V, Montana, V, Wei, M.-D., Wuskell, J. P., and Loew, L. M., 1988, Memrane potential can be determined in individual cells from the nernstian distribution of cationic dyes, Biophys. J. 53:785–794.PubMedGoogle Scholar
  23. Flohe, L., and Schlegel, W., 1971, Glutathion-peroxidase, Hoppe-Seylers Z. Physiol. Chem. 352:1401–1410.PubMedGoogle Scholar
  24. Fournier, N., Ducet, G., and Crevat, A., 1987, Action of cyclosporin on mitochondrial calcium fluxes, J. Bioenerg. Biomembr. 19:297–303.CrossRefPubMedGoogle Scholar
  25. Gores, G. J., Flarsheim, C. E., Dawson, T. L., Nieminen, A.-L., Herman, B., and Lemasters, J. J., 1989, Swelling, reductive stress, and cell death during chemical hypoxia in hepatocytes. Am. J. Physiol. 257:C347–C354.PubMedGoogle Scholar
  26. Hackenbrock, C.R., 1968, Chemical and physical fixation of isolated mitochondria in low-energy and high energy states, Proc. Natl. Acad. Sci. USA 61:598–605.PubMedGoogle Scholar
  27. Hajnoczky, G., Robb-Gaspers, L. D., Seitz, M. B., and Thomas, A. P., 1995, Decoding of cytosolic calcium oscillations in the mitochondria, Cell 82:415–424.CrossRefPubMedGoogle Scholar
  28. Halestrap, A. P., and Davidson, A. M., 1990, Inhibition of Ca2+-inducedlarge-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding tomitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase, Biochem. J. 268:153–160.PubMedGoogle Scholar
  29. Hansford, R.G., 1981, Effectof micromolar concentrations of free Ca2+ ions on pyruvate dehydrogenase interconversion in intact rat heart mitochondria, Biochem. J. 194:721–732.PubMedGoogle Scholar
  30. Hartley, D. M., Kurth, M. C., Bjerkness, L., Weiss, J. H., and Choi, D. W., 1993, Glutamate receptor-induced accumulation in cortical cell culture correlates with subsequent neuronal degeneration, J. Neurosci. 13:1993–2000.PubMedGoogle Scholar
  31. Haworth, R. A., and Hunter, D. R., 1979, The Ca2+-induced membrane transition in mitochondria: II. Nature of the Ca2+ trigger site, Arch. Biochem. Biophys. 195:460–467.CrossRefPubMedGoogle Scholar
  32. Heiskanen, K. M., Bhat, M. B., Wang, H.-W., Ma, J., and Nieminen, A.-L., 1999, Mitochondrial depolarization accompanies cytochrome c release during apoptosis in PC6 cells, J. Biol. Chem. 274:5654–5658.CrossRefPubMedGoogle Scholar
  33. Hunter, D.R., and Haworth, R.A., 1979a, The Ca2+-inducedmembrane transition inmitochondria:I. The protective mechanisms, Arch, Biochem. Biophys. 195:453–459.Google Scholar
  34. Hunter, D.R., and Haworth, R.A., 1979b, The Ca2+-inducedmembranetransition inmitochondria: III. Transitional Ca2+ release. Arch. Biochem.Biophys. 195:468–477.PubMedGoogle Scholar
  35. Hunter, D. R., Haworth, R. A., and Southard, J. H., 1976, The relationship between permeability, configuration, and function in calcium treated mitochondria, J. Biol. Chem. 251:5069–5077.PubMedGoogle Scholar
  36. Imberti, R., Nieminen, A.-L., Herman, B., and Lemasters, J. J., 1990, Mitochondrial inhibition and uncoupling preceding lethal injury to rat hepatocytes by t-butyl hydroperoxide: Protection by fructose, oligomycin, cyclosporin A, and trifluoperazine, Hepatology 12:933.Google Scholar
  37. Imberti, R., Nieminen, A.-L., Herman, B., and Lemasters, J. J., 1992, Synergism of cyclosporin A and phospholipase inhibitors in protection against lethal injury to rat hepatocytes from oxidant chemicals, Res. Commun. Chem. Pathol. Pharmacol. 78:27–38.PubMedGoogle Scholar
  38. Imberti, R., Nieminen, A.-L., Herman, B., and Lemasters, J. J., 1993, Mitochondrial and glycolytic dysfunction in lethal injury to hepatocytes by t-butylhydroperoxide: Protection by fructose, cyclosporin A, and trifluoperazine, J. Pharmacol. Exp. Therap. 265:392–400.Google Scholar
  39. Kawanishi, T., Nieminen, A.-L., Herman, B., and Lemasters, J. J., 1991, Suppression of Ca2+ oscillations in cultured rat hepatocytes by chemical hypoxia, J. Biol. Chem. 266:20062–20069.PubMedGoogle Scholar
  40. Kinnally, K. W., Campo, M. L., and Tedeschi, H., 1989, Mitochondrial channel activity studied by patch-clamping mitoplasts, J. Bioenerg. Biomembr. 21:497–506.CrossRefPubMedGoogle Scholar
  41. Kluck, R. M., Bossy-Wetzel, E., Green, D. R., Newmeyer, D. D., 1997, The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis, Science 275:1132–1136.CrossRefPubMedGoogle Scholar
  42. Kowaltowski, A. J., Castilho, R. F., and Vercesi, A. E., 1996, Opening of the mitochondrial permeability transition pore by uncoupling or inorganic phosphate in the presence of Ca2+ is dependent on mitochondrial-generated reactive oxygen species, FEBS Lett. 378:150–152.CrossRefPubMedGoogle Scholar
  43. Lee, C. P., and Ernster, L., 1964, Equilibrium studies of the energy-dependent and non-energy-dependent pyridine nucleotide transhydrogenase reactions, Biochim. Biophys, Ada 81:187–190.Google Scholar
  44. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., and Wang, X., 1997, Cytochrome c and dATP-dependent formation of apaf-1/caspase-9 complex initiates an apoptotic protease cascade, Cell 91:479–489.CrossRefPubMedGoogle Scholar
  45. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X., 1996, Induction of apoptosis in cell-free extracts: Requirement for dATP and cytochrome c. Cell, 86:147–157.PubMedGoogle Scholar
  46. Lohret, T. A., Murphy, R. C., Drgon, T., and Kinnally, K. W., 1996, Activity of the mitochondrial multiple conductance channel is independent of the adenine nucleotide translocator, J. Biol. Chem. 271:4846–4849.PubMedGoogle Scholar
  47. Lotscher, H. R., Winterhalter, K. H., Carafoli, E., and Richter, C., 1980, Hydroperoxide-induced loss of pyridine nucleotides and releases of calcium from rat liver mitochondria, J. Biol. Chem. 255:9325–9330.PubMedGoogle Scholar
  48. Marchetti, P., Susin, S. A., Decaudin, D., Gamen, S., and Castedo, M., 1996, Apoptosis-associated derangement of mitochondrial function in cells lacking mitochondrial DNA, Cancer Res. 56:2033–2038.PubMedGoogle Scholar
  49. Marzo, I., Brenner, C., Zamzami, N., Jurgensmeier, J. M., Susin, S. A., Vieira, H. L. A., Prevost, M.-C., Xie, Z., Matsuyama, S., Reed, J. C., and Kroemer, G., 1998, Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031.CrossRefPubMedGoogle Scholar
  50. McCormack, J. G., and Denton, R. M., 1979, The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex, Biochem. J. 180:533–544.PubMedGoogle Scholar
  51. Nieminen, A.-L., Gores, G. J., Dawson, T. L., Herman, B., and Lemasters, J. J., 1990a, Toxic injury from mercuric chloride in rat hepatocytes, J. Biol. Chem. 265:2399–2408.PubMedGoogle Scholar
  52. Nieminen, A.-L., Dawson, T. L., Gores, G. J., Kawanishi, T., Herman, B., and Lemasters, J. J., 1990b, Protection by acidotic pH and fructose against lethal injury to rat hepatocytes from mitochondrial inhibition, ionophores, and oxidant chemicals, Biochem. Biophys. Res. Commun. 167:600–606.CrossRefPubMedGoogle Scholar
  53. Nieminen, A.-L., Saylor, A. K., Herman, B., and Lemasters, J. J., 1994, ATP depletion rather than mitochondrial depolarization mediates hepatocyte killing after metabolic inhibition, Am. J. Physiol. 267:C67–C74.PubMedGoogle Scholar
  54. Nieminen, A.-L., Saylor, A. K., Tesfai, S. A., Herman, B., and Lemasters, J. J., 1995, Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide, Biochem. J. 307:99–106.PubMedGoogle Scholar
  55. Nieminen, A.-L., Petrie, T. G., Lemasters, J. J., and Selman, W. R., 1996, Cyclosporin A delays mitochondrial depolarization induced by N-methyl-D-aspartate in cortical neurons: Evidence of the mitochondrial permeability transition, Neuroscience 75:993–997.PubMedGoogle Scholar
  56. Nieminen, A.-L., Byrne, A. M., Herman, B., and Lemasters, J. J., 1997, Mitochondrial permeability transition in hepatocytes induced by t-BuOOH:NAD(P)H and reactive oxygen species. Am. J. Physiol. 272:C1286–C1294.PubMedGoogle Scholar
  57. Peng, T.I., Jou, M. J., Sheu, S. S., and Greenamyre, J.T., 1998, Visualization of NMDA receptorinduced mitochondrial calcium accumulation in striatal neurons, Exp. Neurol. 149:1–12.CrossRefPubMedGoogle Scholar
  58. Petronilli, V, Szabo, I, and Zoratti, M., 1989, The inner mitochondrial membrane contains ionconducting channels similar to those found in bacteria, FEBS Lett. 259:137–143.CrossRefPubMedGoogle Scholar
  59. Pivovarova, N. B., Hongpaisan, J., Andrews, S. B., and Friel, D. D., 1999, Depolarization-induced mitochondrial Ca accumulation in sympathetic neurons: Spatial and temporal characteristics, J. Neurosci. 19:6372–6384.PubMedGoogle Scholar
  60. Puskin, J. S., Gunter, T. E., Gunter, K. K., and Russell, P. R., 1976, Evidence of more than one Ca2+ transport mechanism in mitochondria, Biochemistry 15:3834–3842.CrossRefPubMedGoogle Scholar
  61. Qian, T., Herman, B., and Lemasters, J. J., 1999, The mitochondrial permeability transition mediates both necrotic and apoptotic death of hepatocytes exposed to Br-A23187, Toxicol. Appl. Pharmacol. 154:117–125.CrossRefPubMedGoogle Scholar
  62. Reynolds, I, and Hastings, T. G., 1995, Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation, J. Neurosci. 15:3318–3327.PubMedGoogle Scholar
  63. Rizzuto, R., Simpson, A. W. M., and Pozzan, T., 1992, Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin, Nature 358:325–327.CrossRefPubMedGoogle Scholar
  64. Rothman, S. M., and Olney, J. W., 1987, Excitotoxicity and the NMDA receptor, Trends Neurosci. 10:299–302.CrossRefGoogle Scholar
  65. Ruck, A., Dolber, M., Wallimann, T., and Brdiczka, D., 1998, Reconstituted adenine nucleotide translocase forms a channel for small molecules comparable to the mitochondrial permeability transition pore, FEBS Lett. 426:97–101.PubMedGoogle Scholar
  66. Schinder, A. F., Olson, E., Spitzer, N. C., and Montal, M., 1996, Mitochondrial dysfunction is a primary event in glutamate neurotoxicity, J. Neurosci. 16:6125–6133.PubMedGoogle Scholar
  67. Shimizu, S., Narita, M., and Tsujimoto, Y., 1999, Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC, Nature 399:483–487.PubMedGoogle Scholar
  68. Sies, H., Gerstenecker, C., Menzel, H., and Flohe, L., 1972, Oxidation in the NADP system and release of GSSG from hemoglobin-free perfused rat liver during peroxidatic oxidation of glutathione by hydroperoxidase, FEBS Lett. 27:171–175.CrossRefPubMedGoogle Scholar
  69. Susin, S. A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Geuskens, M., and Kroemer, G., 1996, Bcl-2 inhibits the mitochondrial release of an apoptogenic protease, J. Exp. Med. 184:1331–1342.CrossRefPubMedGoogle Scholar
  70. Susin, S. A., Zamzami, N., Castedo, M., Daugas, E., Wang, H.-G., Geley, S., Fassy, F., Reed, J. C., and Kroemer, G., 1997, The central executioner of apoptosis: Multiple links between protease activation and mitochondria in Fas/Apo-l/CD95-and ceramide-induced apoptosis, J. Exp. Med. 186:25–37.CrossRefPubMedGoogle Scholar
  71. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Constantini, P., Loeffler, M., Larochette, N., Goodlett, D. R., Aebersold, R., Siderovski, D. P., Penninger, J. M., and Kroemer, G., 1999, Molecular characterization of mitochondrial apoptosis-inducing factor, Nature 397:441–446.PubMedGoogle Scholar
  72. Szabò, I., and Zoratti, M., 1991, The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A, J. Biol. Chem. 266:3376–3379.PubMedGoogle Scholar
  73. Thomas, C. E., and Reed, D. J., 1988, Effect of extracellular Ca++ omission on isolated hepatocytes: II. Loss of mitochondrial membrane potential and protection by inhibitors of uniport Ca++ transduction, J. Pharmacol. Exp. Therap. 245:501–507.Google Scholar
  74. Thor, H., Smith, M. T, Hartzell, P., Bellomo, G., Jewell, S. A., and Orrenius, S., 1982, The metabolism of menadione (2-methyl-l, 4-naphthoquinone) by isolated hepatocytes, J. Biol. Chem. 257:6612–6615.Google Scholar
  75. Trollinger, D. R., Cascio, W. E., and Lemasters, J. J., 1997, Selective loading of Rhod-2 into mitochondria shows mitochondrial Ca2+ transients during the contractile cycle in adult rabbit cardiac myocytes, Biochem. Biophys. Res. Commun. 236:738–742.CrossRefPubMedGoogle Scholar
  76. Trump, B. F, Goldblatt, P. J., and Stowell, R. E., 1965, Studies of necrosis in vitro of mouse hepatic parenchymal cells: Ultrastructural alterations in endoplasmic reticulum, Golgi apparatus, plasma membrane, and lipid droplets, Lab. Invest. 14:2000–2028.PubMedGoogle Scholar
  77. Vanderkooi, J., Erecinska, M., and Chance, B., 1973, Cytochrome c interaction with membranes: I. Use of a fluorescent chromophore in the study of cytochrome c interaction with artificial membranes, Arch. Biochem. Biophys. 154:219–229.CrossRefPubMedGoogle Scholar
  78. Vlessis, A. A., 1990, NADH-linked substrate dependence of peroxide-induced respiratory inhibition and calcium efflux in isolated renal mitochondria, J. Biol. Chem. 265:1448–1453.PubMedGoogle Scholar
  79. White, R. J., and Reynolds, I. J., 1996, Mitochondrial depolarization in glutamate-stimulated neurons: An early signal specific to excitotoxin exposure, J. Neurosci. 16:5688–5697.PubMedGoogle Scholar
  80. Wu, E. Y., Smith, M. T., Bellomo, G., and DiMonte, D., 1990, Relationships between transmembrane potential, ATP concentration, and cytotoxicity in isolated rat hepatocytes, Arch. Biochem. Biophys. 282:358–362.CrossRefPubMedGoogle Scholar
  81. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T.-I., Jones, D. P., and Wang, X., 1997, Prevention of apoptosis by bcl-2: Release of cytochrome c from mitochondria blocked, Science 275:1129–1132.CrossRefPubMedGoogle Scholar
  82. Zahrebelski, G., Nieminen, A.-L, Al-Ghoul, K., Qian, T., Herman, B., and Lemasters, J. J., 1995, Progression of subcellular changes during chemical hypoxia to cultured rat hepatocytes: A laser scanning confocal microscopy study, Hepatology 21:1361–1372.CrossRefPubMedGoogle Scholar
  83. Zoratti, M, and Szabò, I., 1995, The mitochondrial permeability transition, Biochim.Biophys. Acta 1241:139–176.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Anna-Liisa Nieminen
    • 1
  • Aaron M. Byrne
    • 1
  • Kaisa M. Heiskanen
    • 1
  1. 1.Department of Anatomy, School of MedicineCase Western Reserve UniversityCleveland

Personalised recommendations