Neurochemical Research

, Volume 26, Issue 6, pp 739–764 | Cite as

Mitochondrial Involvement in Brain Function and Dysfunction: Relevance to Aging, Neurodegenerative Disorders and Longevity

  • V. Calabrese
  • G. Scapagnini
  • A. M. Giuffrida Stella
  • T. E. Bates
  • J. B. Clark


It is becoming increasingly evident that the mitochondrial genome may play a key role in neurodegenerative diseases. Mitochondrial dysfunction is characteristic of several neurodegenerative disorders, and evidence for mitochondria being a site of damage in neurodegenerative disorders is partially based on decreases in respiratory chain complex activities in Parkinson's disease, Alzheimer's disease, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant balance perturbation, are thought to underlie defects in energy metabolism and induce cellular degeneration. Efficient functioning of maintenance and repair process seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of genes termed vitagenes. A promising approach for the identification of critical gerontogenic processes is represented by the hormesis-like positive effect of stress. In the present review, we discuss the role of energy thresholds in brain mitochondria and their implications in neurodegeneration. We then review the evidence for the role of oxidative stress in modulating the effects of mitochondrial DNA mutations on brain age-related disorders and also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.

Oxidative stress mitochondrial diseases energy thresholds caloric restriction vitagenes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Stewart, V. C., Sharpe, M. A., Clark, J. B., and Heales, S. J. 2000. Astrocyte-derived nitric oxide causes both reversible and irreversible damage to the neuronal mitochondrial respiratory chain. J. Neurochem. 75:694–700.Google Scholar
  2. 2.
    Halliwell, B. 1999. Antioxidant defence mechanisms: From the beginning to the end (of the beginning). Free Radic. Res. 31:261–272.Google Scholar
  3. 3.
    Calabrese, V., Bates, T. E., and Giuffrida Stella, A. M. 2000. NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: The role of oxidant/antioxidant balance. Neurochem. Res. 25:1315–1341.Google Scholar
  4. 4.
    Morimoto, R. I. and Santoro, M. G. 1998. Stress-inducible response and heat shock proteins: New pharmacologic targets for cytoprotection. Nature Biotechnol. 16:833–838.Google Scholar
  5. 5.
    Calabrese, V., Testa, D., Ravagna, A., Bates, T. E., and Giuffrida Stella, A. M. 2000. HSP70 induction in the brain following ethanol administration in the rat: Regulation by glutathione redox state. Biochem. Biophys. Res. Comm. 269:397–400.Google Scholar
  6. 6.
    Calabrese, V., Copani, A., Testa, D., Ravagna, A., Spadaro, F., Tendi, E., Nicoletti, V. G., and Giuffrida Stella, A. M. 2000. Nitric oxide synthase induction in astroglial cell cultures: Effect on heat shock protein 70 synthesis and oxidant/antioxidant balance. J. Neurosci. Res. 60:613–622.Google Scholar
  7. 7.
    Motterlini, R., Foresti, R., Bassi, R., Calabrese, V., Clark, J. E., and Green, C. J. 2000. Endothelial Heme oxygenase-1 induction by hypoxia: Modulation by inducible nitric oxide synthase (iNOS) and S-nitrosothiols. J. Biol. Chem. 275:13613–13620.Google Scholar
  8. 8.
    Harman, D. 1972. Free radical theory of ageing: Dietary implications. Am. J. Clin. Nutr. 25:839–843.Google Scholar
  9. 9.
    Beckman, K. B. and Ames, B. N. 1998. Mitochondrial aging: Open questions. Ann. NY Acad. Sci. 854:118–127.Google Scholar
  10. 10.
    McHenry, L. C., Merory, J., Bass, E., Stump, D. A., Williams, R., Witcofski, R., Howard, G., and Toole, J. F. 1978. Xenon-133 inhalation method for regional cerebral blood flow measurements: Normal values and test-retest results. Stroke 9:396–399.Google Scholar
  11. 11.
    Ginsberg, M. D., Sternau, L. L., Globus, M. Y., Dietrich, W. D., and Busto, R. 1992. Therapeutic modulation of brain temperature: Relevance to ischemic brain injury. Cerebrovasc. Brain Metab. Rev. 4:189–225.Google Scholar
  12. 12.
    Altmann, B. 1894. Cited in: E. de Robertis, W. Nowinski, F. Saez (eds.), Cell Biology, W. B. Saunders, Philadelphia, 1970, pp 199–228.Google Scholar
  13. 13.
    Nass, S. and Nass, M. M. 1963. Intramitochondrial fibers and DNA Characteristics: II. Enzymatic and other hydrolytic treatments. J. Cell. Biol. 19:613–629.Google Scholar
  14. 14.
    Dujon, B. 1981. Mitochondrial genetics and functions. In: Strathern, J. N., Jones, E. W., Broach, J. R. (eds.), Molecular Biology of the yeast Saccharomyces; Life cycle, and inheritance. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 505–635.Google Scholar
  15. 15.
    Shadel, G. S. and Clayton, D. A. 1997. Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66:409–435.Google Scholar
  16. 16.
    Jang, S. H. and Jaehning, J. A. 1991. The yeast mitochondrial RNA polymerase specificity factor, MTF1, is similar to bacterial sigma factors. J. Biol. Chem. 266:22671–22677.Google Scholar
  17. 17.
    Scacco, S., Vergari, R., Scarpulla, R. C., Technikova-Dobrova, Z., Sardanelli, A., Lambo, R., Lorusso, V., and Papa, S. 2000. cAMP-dependent phosphorylation of the nuclear encoded 18-kDa (IP) subunit of respiratory complex I and activation of the complex in serum-starved mouse fibroblast cultures. J. Biol. Chem. 275:17578–17582.Google Scholar
  18. 18.
    Herzig, R. P., Scacco, S., and Scarpulla, R. C. 2000. Sequential serum-dependent activation of CREB and NRF-1 leads to enhanced mitochondrial respiration through the induction of cytochrome c. J. Biol. Chem. 275:13134–13141.Google Scholar
  19. 19.
    Richter C. and Schweizer M. 1997. Oxidative stress in mitochondria. In Oxidative stress and the molecular biology of antioxidant defenses. Scandalios J. G., Cold Spring Harbor Laboratory Press. Planview, NY.Google Scholar
  20. 20.
    Swerdlow, R. H., Parks, J. K., Cassarino, D. S., Maguire, D. J., Maguire, R. S., Bennett, J. P., Davis, R. E., and Parker, W. D. 1997. Cybrids in Alzheimer disease: A cellular model of the disease? Neurology 49:918–925.Google Scholar
  21. 21.
    Luft, R., Ikkos, D., Palmieri, G., Ernster, L., and Afzelius, A. 1962. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: A correlated clinical, biochemical and morphological study. J. Clin. Invest. 41:1776–1804.Google Scholar
  22. 22.
    Cottrell, D. A. and Turnbull, D. M. 2000. Mitochondria and ageing. Curr. Opin. Clin. Nutr. Metab. Care 3:473–478.Google Scholar
  23. 23.
    Wallace, D. C. 1999. Mitochondrial diseases in man and mouse. Science 283:1482–1488.Google Scholar
  24. 24.
    Chomyn, A., Martinuzzi, A., Yoneda, M., Daga, A., Hurko, O., Johns, D., Lai, S. T., Nonaka, I., Angelini, C., and Attardi, G. 1992. MELAS mutations in mtDNA site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. Natl. Acad. Sci. USA 89:4221–4225.Google Scholar
  25. 25.
    Mazat, J., Rossignol, R., Malgat, M., Rocher, C., Faustin, B., and Letellier, T. 2001. What do mitochondrial diseases teach us about normal mitochondrial functions that we already knew: Threshold expression of mitochondrial defects. Biochim. Biophys. Acta 1504:20–30.Google Scholar
  26. 26.
    Letellier, T., Malgat, M., Rossignol, R., and Mazat, J. P. 1998. Metabolic control analysis and mitochondrial pathologies. Mol. Cell. Biochem. 184:409–417.Google Scholar
  27. 27.
    Davey, G. P., Peuchen, S., and Clark, J. B. 1998. Energy thresholds in brain mitochondria. J. Biol. Chem. 273:12753–12757.Google Scholar
  28. 28.
    Malgat, M., Latellier, T., Jouaville, S. L., and Mazat, J. 1995. Value of control theory in the study of cellular metabolism. Biomedical implications. J. Biol. Systems 3:165–175.Google Scholar
  29. 29.
    Rossignol, R., Letellier, T., Malgat, M., Rocher, C., and Mazat, J. P. 2000. Tissue variation in the control of oxidative phosphorylation: Implication for mitochondrial diseases. Biochem. J. 347:45–53.Google Scholar
  30. 30.
    Rossignol, R., Malgat, M., Mazat, J. P., and Letellier, T. 1999. Threshold effect and tissue specificity. Implication for mitochondrial cytopathies. J. Biol. Chem. 274:33426–33432.Google Scholar
  31. 31.
    Kirkwood, T. B. and Kowald, A. 1997. Network theory of aging. Exp. Gerontol. 32:395–399.Google Scholar
  32. 32.
    Sohal, R. S. 1997. Role of mitochondria and oxidative stress in the aging process. Pages 91–107, in Beal, M. F., Howell, N., Bodis-Wollner, I. (eds.), Mitochondria and Free Radicals in Neurodegenerative diseases, Wiley-Liss, New York.Google Scholar
  33. 33.
    Stadtman, E. R. 1992. Protein oxidation and aging. Science 257:1220–1224.Google Scholar
  34. 34.
    Stadtman, E. R. and Levine, R. L. 2000. Protein oxidation. Ann. NY Acad. Sci. 899:191–208.Google Scholar
  35. 35.
    Dyrks, T., Dyrks, E., Masters, C. L., and Beyreuther, K. 1993. Amyloidogenicity of rodent and human beta A4 sequences. FEBS Lett. 324, 231–236.Google Scholar
  36. 36.
    Smith, C. D., Carney, J. M., Tatsumo, T., Stadtman, E. R., Floyd, R. A., and Markesbery, W. R. 1992. Protein oxidation in aging brain. Ann. NY Acad. Sci. 663:110–119.Google Scholar
  37. 37.
    Smith, M. A., Perry, G., Richey, P. L., Sayre, L. M., Anderson, V. E., Beal, M. F., and Kowall, N. 1996. Oxidative damage in Alzheimer's. Nature 382:120–121.Google Scholar
  38. 38.
    Smith, M. A. and Perry, G. 1996. Alzheimer disease: Proteinprotein interaction and oxidative stress. Bol. Estud. Med. Biol. 44:5–10.Google Scholar
  39. 39.
    Mecocci, P., Beal, M. F., Cecchetti, R., Polidori, M. C., Cherubini, A., Chionne, F., Avellini, L., Romano, G., and Senin, U. 1997. Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain. Mol. Chem. Neuropathol. 31:53–64.Google Scholar
  40. 40.
    Mecocci, P., MacGarvey, U., Kaufman, A. E., Koontz, D., Shoffner, J. M., Wallace, D. C., and Beal, M. F. 1993. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann. Neurol. 34:609–616.Google Scholar
  41. 41.
    Paradies, G. and Ruggiero, F. M. 1990. Age-related changes in the activity of the pyruvate carrier and in the lipid composition in rat-heart mitochondria. Biochim. Biophys. Acta 1016:207–212.Google Scholar
  42. 42.
    Paradies, G., Petrosillo G., Gadaleta M. N., and Ruggiero, F. M. 1999. The effect of aging and acetyl-L-carnitine on the pyruvate transport and oxidation in rat heart mitochondria. FEBS Lett. 454:207–209.Google Scholar
  43. 43.
    Hagen, T. M., Yowe, D. L., Bartholomew, J. C., Wehr, C. M., Do, K. L., Park, J. Y., and Ames, B. N. 1997. Mitochondrial decay in hepatocytes from old rats: Membrane potential declines, heterogeneity and oxidants increase. Proc. Natl. Acad. Sci. USA 94:3064–3069.Google Scholar
  44. 44.
    Ozawa, T., Tanaka, M., Ikebe, S., Ohno, K., Kondo, T., and Mizuno, Y. 1990. Quantitative determination of deleted mitochondrial DNA relative to normal DNA in parkinsonian striatum by a kinetic PCR analysis. Biochem. Biophys. Res. Commun. 172:483–489.Google Scholar
  45. 45.
    Mecocci, P., MacGarvey, U., and Beal, M. F. 1994. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann. Neurol. 36:747–751.Google Scholar
  46. 46.
    Cottrell, D. A., Blakely, E. L., Johnson, M. A., Ince, P. G., Borthwick, G. M., and Turnbull, D. M. 2001. Cytochrome c oxidase deficient cells accumulate in the hippocampus and choroid plexus with age. Neurobiol. Aging 22:265–272.Google Scholar
  47. 47.
    Muller-Hocker, J. 1990. Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: An age-related alteration. J. Neurol. Sci. 100:14–21.Google Scholar
  48. 48.
    Cottrell, D. A. and Turnbull, D. M. 2000. Mitochondria and ageing. Curr. Opin. Clin. Nutr. Metab. Care 3:473–478.Google Scholar
  49. 49.
    Forster, M. J., Sohal, B. H., and Sohal, R. S. 2000. Reversible effects of long-term caloric restriction on protein oxidative damage. J. Gerontol. A. Biol. Sci. Med. Sci. 55:B522–529.Google Scholar
  50. 50.
    Feuers, R. J. 1998. The effects of dietary restriction on mitochondrial dysfunction in aging. Ann. NY Acad. Sci. 854:192–201.Google Scholar
  51. 51.
    Kristal, B. S. and Yu, B. P. 1998. Dietary restriction augments protection against induction of the mitochondrial permeability transition. Free Radic. Biol. Med. 24:1269–1277.Google Scholar
  52. 52.
    Yu, B. P. 1996. Aging and oxidative stress: Modulation by dietary restriction. Free Radic. Biol. Med. 21:651–668.Google Scholar
  53. 53.
    Hall, D. M., Oberley, T. D., Moseley, P. M., Buettner, G. R., Oberley, L. W., Weindruch, R., and Kregel, K. C. 2000. Caloric restriction improves thermotolerance and reduces hyperthermiainduced cellular damage in old rats. FASEB J. 14:78–86.Google Scholar
  54. 54.
    Lee, C. K., Klopp, R. G., Weindruch, R., and Prolla, T. A. 1999. Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390–1393.Google Scholar
  55. 55.
    Cassarino, D. S. and Bennett, J. P. 1999. An evaluation of the role of mitochondria in neurodegenerative diseases: Mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res. Brain Res. Rev. 29:1–25.Google Scholar
  56. 56.
    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.Google Scholar
  57. 57.
    Petronilli, V., Penzo, D., Scorrano, L., Bernardi, P., and Di Lisa, F. 2000. The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J. Biol. Chem. 276:2571–2575.Google Scholar
  58. 58.
    Nicholls, D., Bernardi, P., Brand, M., Halestrap, A., Lemasters, J., and Reynolds, I. 2000. Apoptosis and the laws of thermodynamics. Nat. Cell. Biol. 2:E172–173.Google Scholar
  59. 59.
    Vieira, H. L. and Kroemer, G. 1999. Pathophysiology of mitochondrial cell death control. Cell. Mol. Life Sci. 56:971–976.Google Scholar
  60. 60.
    Greenamyre, J. T., MacKenzie, G., Peng, T. L., and Stephans, S. E. 1999. Mitochondrial dysfunction in Parkinson's disease. Biochem. Soc. Symp. 66:85–97.Google Scholar
  61. 61.
    Cassarino, D. S., Parks, J. K., Parker, W. D., and Bennett, J. P. 1999. The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim. Biophys. Acta 1453:49–62.Google Scholar
  62. 62.
    Zoratti, M. and Szabo, I. 1995. The mitochondrial permeability transition. Biochim. Biophys. Acta 1241:139–176.Google Scholar
  63. 63.
    Kristal, B. S. and Dubinsky, J. M. 1997. Mitochondrial permeability transition in the central nervous system: Induction by calcium cycling-dependent and-independent pathways. J. Neurochem. 69:524–538.Google Scholar
  64. 64.
    Zamzami, N., Hirsch, T., Dallaporta, B., Petit, P. X., and Kroemer, G. 1997. Mitochondrial implication in accidental and programmed cell death: Apoptosis and necrosis. J. Bioenerg. Biomembr. 29:185–193.Google Scholar
  65. 65.
    Kannan, K. and Jain, S. K. 2000. Oxidative stress and apoptosis. Pathophysiology 7:153–163.Google Scholar
  66. 66.
    Storz, G. and Tartaglia, L. A. 1992. OxyR: A regulator of antioxidant genes. J. Nutr. 122:627–639.Google Scholar
  67. 67.
    Mattson, M., Culmsee, C., Zaifang, Yu., and Camandola, S. 2000. Roles of nuclear factor kB in neuronal survival and plasticity. J. Neurochem. 74:443–456.Google Scholar
  68. 68.
    Taylor, B. S., de Vera, M. E., Ganster, R. W., Wang, Q., Shapiro, R. A., Morris, S. M., Billiar, T. R., and Geller, D. A. 1998. Multiple NFkB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J. Biol. Chem. 273:15148–15156.Google Scholar
  69. 69.
    Mirza, A., Liu, S. L., Frizell, E., Zhu, J., Maddukuri, S., Martinez, J., Davies, P., Schwarting, R., Norton, P., and Zern, M. A. 1997. A role for tissue transglutaminase in hepatic injury and fibrogenesis, and its regulation by NF-kappaB. Am. J. Physiol. 272:281–288.Google Scholar
  70. 70.
    Zong, W. X., Edelstein, L. C., Chen, C., Bash, J., and Gelinas, C. 1999. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalphainduced apoptosis. Genes Dev. 13:382–387.Google Scholar
  71. 71.
    Mattson, M. P., Goodman, Y., Luo, H., Fu, W., and Furukawa, K. 1997. Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: Evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J. Neurosci. Res. 49:681–697.Google Scholar
  72. 72.
    Walton, M., Connor, B., Lawlor, P., Young, D., Sirimanne, E., Gluckman, P., Cole, G., and Dragunow, M. 1999. Neuronal death and survival in two models of hypoxic-ischemic brain damage. Brain Res. Brain Res. Rev. 29:137–168.Google Scholar
  73. 73.
    Matsuoka, K., Kitamura, Y., Okazaki, M., Terai, K., and Taniguchi, T. 1999. Kainic acid-induced activation of nuclear factor-kB in rat hippocampus. Exp. Brain Res. 124:215–222.Google Scholar
  74. 74.
    Yang, R., Mu, X., and Hayes, R. L. 1995. Increased cortical nuclear factor-kB DNA binding activity after traumatic brain injury in rats. Neurosci. Lett. 197:101–104.Google Scholar
  75. 75.
    Kaltschmidt, B., Uherek, M., Volk, B., Baeuerle, P. A., and Kaltschmidt, C. 1997. Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc. Natl. Acad. Sci. USA 94:2642–2647.Google Scholar
  76. 76.
    Migheli, A., Piva, R., Atzori, C., Troost, D., and Schiffer, D. 1997. c-Jun, JNK/SAPK kinases and transcription factor NFkappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 56:1314–1322.Google Scholar
  77. 77.
    Bruce-Keller, A. J., Geddes, J. W., Knapp, P. E., McFall, R. W., Keller, J. N., Holtsberg, F. W., Parthasarathy, S., Steiner, S. M., and Mattson, M. P. 1999. Anti-death properties of TNF against metabolic poisoning: Mitochondrial stabilization by MnSOD. J. Neuroimmunol. 93:53–71.Google Scholar
  78. 78.
    Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V., and Baldwin, A. S. 1998. NF-kappaB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 28:1680–1683.Google Scholar
  79. 79.
    Qin, Z. H., Wang, Y., Nakai, M., and Chase, T. N. 1998. Nuclear factor-kappa B contributes to excitotoxin-induced apoptosis in rat striatum. Mol. Pharmacol. 53:33–42.Google Scholar
  80. 80.
    Kasibhatla, S., Brunner, T., Genestier, L., Echeverri, F., Mahboubi, A., and Green, D. R. 1998. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol. Cell 4:543–551.Google Scholar
  81. 81.
    Sherman, M. Y. and Goldberg, A. L. 2001. Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32.Google Scholar
  82. 82.
    Mattson, M. P. 2000. Neuroprotective signaling and the aging brain: Take away my food and let me run. Brain Res. 2000 886:47–53.Google Scholar
  83. 83.
    Calabrese, V., Renis, M., Calderone, A., Russo, A., Reale, S., Barcellona, M. L., and Rizza, V. 1998. Stress proteins and SH-groups in oxidant-induced cell injury after chronic ethanol administration in rat. Free Rad. Biol. Med. 24:1159–1167.Google Scholar
  84. 84.
    Susuki, T., Mitake, S., and Murata, S. 1999. Presence of upstream and down-stream components of mitogen-activated protein kinase (MAPK) pathway in the PSD fraction of the rat forebrain. Brain Res. 840:36–44.Google Scholar
  85. 85.
    Ndubuisi M. I., Guo, G. G., Fried, V. A., Etlinger, J. D., and Sehgal, P. B. 1999. Cellular physiology of STAT 3: Where is the cytoplasmic monomer? J. Biol. Chem. 274:25499–25509.Google Scholar
  86. 86.
    Dell'Albani, P., Kahn, M. A., Cole, R., Condorelli, D. F., Giuffrida-Stella, A. M., and de Vellis, J. 1998. Oligodendroglial survival factors, PDGF-AA and CNTF, activate similar JAK/STAT signaling pathways. J. Neurosci. Res. 54:191–205.Google Scholar
  87. 87.
    Song, I., Kamboj, S., Xia, J., Dong, H., Liao, D., and Huganir, R. L. 1998. Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21:393–400.Google Scholar
  88. 88.
    Ohtsuka, K. and Suzuki, T. 2000. Roles of molecular chaperones in the nervous system. Brain Res. Bull. 53:141–146.Google Scholar
  89. 89.
    Kobayashi, Y., Kume, A., Li, M., Doyu, M., Hata, M., Ohtsuka, K., and Sobue, G. 2000. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem. 275:8772–8778.Google Scholar
  90. 90.
    Yenay, M. A., Giffard, R., Sapolsky, R. M., and Steinberg, G. K. 1999. The neuroprotective potential of heat shock protein (HSP70). Mol. Med. Tod. 51:525–531.Google Scholar
  91. 91.
    Takeda, A., Perry, G., Abraham, N. G., Dwyer, B. E., Kutty, R. K., Laitinen, J. T., Petersen, R. B., and Smith, M. A. 2000. Overexpression of heme oxygenase in neuronal cells, the possible interaction with Tau. J. Biol. Chem. 275:5395–5399.Google Scholar
  92. 92.
    Yenari, M. A., Fink, S. L., Sun, G. H., Chang, L. K., Patel, M. K., Kunis, D. M., Onley, D., Ho, D. Y., Sapolsky, R. M., and Steinberg, G. K. 1998. Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy. Ann. Neurol. 44:584–591.Google Scholar
  93. 93.
    Hata, R., Gass, P., Mies, G., Wiessner, C., and Hossmann, K. A. 1998. Attenuated c-fos mRNA induction after middle cerebral artery occlusion in CREB knockout mice does not modulate focal ischemic injury. J. Cereb. Blood Flow Metab. 18:1325–1335.Google Scholar
  94. 94.
    Nishimura, R. N. and Dwyer, B. E. 1995. Pharmacological induction of heat shock protein 68 synthesis in cultured rat astrocytes. J. Biol. Chem. 270:29967–29970.Google Scholar
  95. 95.
    Deckel, A. W. 2001. Nitric oxide and nitric oxide synthase in Huntington's disease. J. Neurosci. Res. 64:99–107.Google Scholar
  96. 96.
    Santoro, M. G. 2000. Heat shock and the control of the stress response. Biochem. Pharmacol. 59:55–63.Google Scholar
  97. 97.
    Baek, S. H., Kim, J. Y., Choi, J. H., Park, E. M., Han, M. Y., Kim, C. H., Ahn, Y. S., and Park, Y. M. 2000. Reduced glutathione oxidation ratio and 8-OHdG accumulation by mild ischemic pretreatment. Brain Res. 856:28–36.Google Scholar
  98. 98.
    Han, J., Cheng, F., Yang, Z., and Dryhurst G. 1999. Inhibitors of mitochondrial respiration, iron (II) and hydroxyl radical evoke release and extracellular hydrolysis of glutathione in rat striatum and substantia nigra: Potential implications to Parkinson's disease. J. Neurochem. 73:1683–1695.Google Scholar
  99. 99.
    Partridge, R. S., Monroe, S. M., Parks, J. K., Johnson, K., Parker, W. D., Eatn, G. R., and Eaton, S. S. 1994. Spin trapping of azidyl and hydroxyl radicals in azide-inhibited submitochondrial particles. Arch. Biochem. Biophys. 310:210–217.Google Scholar
  100. 100.
    Smith, T. S. and Bennet, J. P. 1997. Mitochondrial toxins in models of neurodegenerative diseases. I: In vivo brain hydroxyl radical production during systemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions. Brain Res. 765:183–188.Google Scholar
  101. 101.
    Bennett, M. C., Diamond, D. M., Stryker, S. L., Parks, J. K., and Parker, W. D. 1992. Cytochrome oxidase inhibition: A novel animal model of Alzheimer's disease. J. Geriatr. Psychiatry Neurol. 5:93–101.Google Scholar
  102. 102.
    Parks, J. K., Smith, T. S., Trimmer, P. A., Bennett, J. P. Jr., and Parker, W. D. Jr. 2001. Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J. Neurochem. 76:1050–1056.Google Scholar
  103. 103.
    Canevari, L., Clark, J. B., and Bates, T. E. 1999. beta-Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett. 457:131–134.Google Scholar
  104. 104.
    Copani, A., Condorelli, F., Caruso, A., Vancheri, C., Sala, A., Giuffrida Stella, A. M., Canonico, P. L., Nicoletti, F., and Sortino, M. A. 1999. Mitotic signaling by beta-amyloid causes neuronal death. FASEB J. 13:2225–2234.Google Scholar
  105. 105.
    Christen, Y. 2000. Oxidative stress and Alzheimer disease. Am. J. Clin. Nutr. 71:621S–629S.Google Scholar
  106. 106.
    Munch, G., Schinzel, R., Loske, C., Wong, A., Durany, N., Li, J. J., Vlassara, H., Smith, M. A., Perry, G., and Riederer, P. 1998. Alzheimer's disease. Synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. J. Neural Transm. 105:439–461.Google Scholar
  107. 107.
    Sayre, L. M., Perry, G., Harris, P. L., Liu, Y., Schubert, K. A., and Smith, M. A. 2000. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: A central role for bound transition metals. J. Neurochem. 74:270–279.Google Scholar
  108. 108.
    Bartzokis, G., Sultzer, D., Cummings, J., Holt, L. E., Hance, D. B., Henderson, V. W., and Mintz, J. 2000. In vivo evaluation of brain iron in Alzheimer disease using magnetic resonance imaging. Arch. Gen. Psychiatry 57:47–53.Google Scholar
  109. 109.
    El Khoury, J., Hickman, S. E., Thomas, C. A., Loike, J. D., and Silverstein, S. C. 1998. Microglia, scavenger receptors, and the pathogenesis of Alzheimer's disease. Neurobiol. Aging 19:S81–84.Google Scholar
  110. 110.
    Lovell, M. A., Ehmann, W. D., Mattson, M. P., and Markesbery, W. R. 1997. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease. Neurobiol. Aging 18:457–461.Google Scholar
  111. 111.
    Smith, M. A., Richey Harris, P. L. Sayre, L. M., Beckman, J. S., and Perry, G. 1997. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J. Neurosci. 17:2653–2657.Google Scholar
  112. 112.
    Schapira, A. H. V. 1999. Mitochondral involvement in Parkinson's disease, Huntington,s disease, hereditary spastic paraplegia and Friedreic's ataxia. Biochim. Biophys. Acta 1410:159–170.Google Scholar
  113. 113.
    Ilic, T. V., Jovanovic, M., Jovicic, A., and Tomovic, M. 1999. Oxidative stress indicators are elevated in de novo Parkinson's disease patients. Funct. Neurol. 14:141–147.Google Scholar
  114. 114.
    Dexter, D. T., Holley, A. E., Flitter, W. D., Slater, T. F., Wells, F. R., Daniel, S. E., Lees, A. J., Jenner, P., and Marsden, C. D. 1994. Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: An HPLC and ESR study. Mov. Disord. 9:92–97.Google Scholar
  115. 115.
    Dexter, D. T., Carayon, A., Javoy-Agid, F., Agid, Y., Wells, F. R., Daniel, S., Lees, A. J., Jenner, P., and Marsden C. D. 1991. Alterations in the levels of iron ferritin and other trace metals in Parkinson's diseases affecting the basal ganglia. Brain 114:1953–1975.Google Scholar
  116. 116.
    Li, H. and Dryhurst, G. 1997. Irreversible inhibition of mitochondrial complex I by 2-aminoethyl-3,4-dyhydro-5-hydroxy-2-benzothiazine-3-carboxylic acid (DHBT): A putative nigral endotoxin of relevance to Parkinson's disease. J. Neurochem. 69:1530–1541.Google Scholar
  117. 117.
    Spencer, J., Jenner, A., Aruoma, O., Evans, P., Jenner, P., Lees, A., Marsden, D., and Halliwell, B. 1994. Intense oxidative DNA damage promoted by L-DOPA and its metabolites. Implication for neurodegenerative diseases. FEBS Lett. 353:246–250.Google Scholar
  118. 118.
    Perry, T. L., Godin, D. V., and Hansen, S. 1982. Parkinson's disease: A disorder due to nigral glutathione deficiency? Neurosci. Lett. 33:305–310.Google Scholar
  119. 119.
    Sian, J., Dexter, D. T., and Lees, A. J. 1994. Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting the basal ganglia. Ann. Neurol. 36:348–355.Google Scholar
  120. 120.
    Hunot, S., Brugg, B., Richard, D., Michel, P. P., Muriel, M. P., Ruberg, M., Faucheux, B. A., Agid, Y., and Hirsch, E. C. 1997. Nuclear Translocation of NF-kB is increased in dopaminergic neurons of patients with Parkinson's disease. Proc. Natl. Acad. Sci. USA 94:7531–7536.Google Scholar
  121. 121.
    France-Lanord, V., Brugg, B., Michel, P. P., Agid, Y., and Ruberg, M. 1997. Mitochondrial free radical signal in ceramidedependent apoptosis: A putative mechanism for neuronal death in Parkinson's disease. J. Neurochem. 69:1612–1621.Google Scholar
  122. 122.
    Jellinger, K. A. 2000. Cell death mechanisms in Parkinson's disease. J. Neural. Transm. 107:1–29.Google Scholar
  123. 123.
    Browne, S. E. 1997. Mitochondrial dysfunction and oxidative damage in Huntington's disease. in: Flint Beal, M., Howell, N., Bodis-Wollner, I. (eds.), Mitochondria and Free Radicals in Neurodegenerative diseases, Wiley-Liss, New York.Google Scholar
  124. 124.
    Li, S. H., Lam, S., Cheng, A. L., and Li, X. J. 2000. Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Hum. Mol. Genet. 9:2859–2867.Google Scholar
  125. 125.
    Eldadah, B. A. and Faden, A. I. 2000. Caspase pathways, neuronal apoptosis, and CNS injury. J. Neurotrauma 17:811–829.Google Scholar
  126. 126.
    Andrews, T. C., Weeks, R. A., Turjanski, N., Gunn, R. N., Watkins, L. H., Sahakian, B., Hodges, J. R., Rosser, A. E., Wood, N. W., and Brooks, D. J. 1999. Huntington's disease progression. PET and clinical observations. Brain 122:2353–2363.Google Scholar
  127. 127.
    Nicoli, F., Vion-Dury, J., Maloteaux, J. M., Delwaide, C., Confort-Gouny, S., Sciaky, M., and Cozzone, P. J. 1993. CSF and serum metabolic profile of patients with Huntington's chorea: A study by high resolution proton NMR spectroscopy and HPLC. Neurosci. Lett. 154:47–51.Google Scholar
  128. 128.
    Ricklefs, R. E. 1998. Evolutionary theories of aging: Confirmation of a fundamental predicition, with implication for the genetic basis and evolution of life span. Am. Nat. 152:24–44.Google Scholar
  129. 129.
    Zwaan, B. J. 1999. The evolutionary genetics of ageing and longevity. Heredity 82:589–597.Google Scholar
  130. 130.
    Harman, D. A. 1956. A theory based on free radical and radiation chemistry. J. Gerontology 11:298–300.Google Scholar
  131. 131.
    Szilard, L. 1959. On the nature of the aging process. PNAS 45:35–45.Google Scholar
  132. 132.
    Kirkwood, T. B. 1977. Evolution of ageing. Nature 270:301–304.Google Scholar
  133. 133.
    Goto, M. 2000. Werner's syndrome: From clinics to genetics. Clin. Exp. Rheumatol. 18:760–766.Google Scholar
  134. 134.
    Rothschild, H. and Jazwinski, S. 1998. Human longevity determinant genes. J. La State Med. Soc. 150:272–274.Google Scholar
  135. 135.
    Jazwinski, S. M. 1996. Longevity, genes and aging. Science 273:54–59.Google Scholar
  136. 136.
    Verbeke, P., Clark, B. F., and Rattan, S. I. 2000. Modulating cellular aging in vitro: Hormetic effects of repeated mild heat stress on protein oxidation and glycation. Exp. Gerontol. 35:787–794.Google Scholar
  137. 137.
    Glade, M. J. 2001. Benefits from caloric restriction-is it hormesis? Nutrition 17:78–82.Google Scholar
  138. 138.
    Parsons, P. A. 2000. Caloric restriction, metabolic efficiency and hormesis. Hum. Exp. Toxicol. 19:345–347.Google Scholar
  139. 139.
    Lave, L. B. 2001. Hormesis: Implications for Public Policy Regarding Toxicants. Annu. Rev. Public Health 22:63–67.Google Scholar
  140. 140.
    Rattan, S. 1998. The nature of Gerontogenes and Vitagenes. Ann. NY Acad. Sci. 854:55–60.Google Scholar
  141. 141.
    Giuffrida Stella, A. M. 1991. Macromolecular changes in the aging brain. Pages 317–328, in: Timiras, P. S. et al., (eds.), Plasticity and Regeneration of the nervous system, Plenum Press, New York.Google Scholar
  142. 142.
    Giuffrida Stella, A. M. and Lajtha, A. 1987. Macromolecular turnover in brain during aging. Gerontology 33:136–148.Google Scholar
  143. 143.
    Lenaz, G. 1998. Role of mitochondria in oxidative stress and ageing. Biochim. Biophys. Acta 1336:53–67.Google Scholar
  144. 144.
    Nicoletti, V., Caruso, A., Tendi, E., Privitera, A., Console, A., Calabrese, V., Spadaro, F., Ravagna, A., Copani, A., and Giuffrida Stella, A. M. 1998. Effect of nitric oxide synthase induction on the expression of mitochondrial respiratory chain subunits in mixed cortical and astroglial cell cultures. Biochimie. 80:871–881.Google Scholar
  145. 145.
    Lechner, H., Agnoli, A., Benzi, G., Tucek, S., and Giuffrida Stella, A. M. 1987. Cerebral metabolism in Aging and neurological disorders. Gerontology, 33:120–270.Google Scholar
  146. 146.
    Nicoletti, V. G., Tendi, E. A., Console, A., Privitera, A., Villa, R. F., Ragusa, N., and Giuffrida-Stella, A. M. 1998. Regulation of cytochrome c oxidase and FoFl-ATPase subunits expression in rat brain during aging. Neurochem. Res. 23:55–61.Google Scholar
  147. 147.
    Acetyl-L-carnitine. 1999. Altern. Med. Rev. 4:438–441.Google Scholar
  148. 148.
    Calabrese, V. and Rizza, V. 1999. Formation of propionate after short-term ethanol treatment and its interaction with the carnitine pool in rat. Alcohol 19:169–176.Google Scholar
  149. 149.
    Boerrigter, M. E., Franceschi, C., Arrigoni-Martelli, E., Wei, J. Y., and Vijg, J. 1993. The effect of L-carnitine and acetyl-L-carnitine on the disappearance of DNA single-strand breaks in human peripheral blood lymphocytes. Carcinogenesis 14:2131–2136.Google Scholar
  150. 150.
    Calabrese V. and Rizza, V. 1999. Effects of L-carnitine on the formation of fatty acid ethyl esters in brain and peripheral organs after short-term ethanol administration in rat. Neurochem. Res. 24:79–84.Google Scholar
  151. 151.
    Calabrese, V., Scapagnini, G., Catalano, D., Dinotta, F., Bates, T. E., Calvani, M., and Giuffrida Stella, A. M. 2001. Effects of acetyl-l-carnitine on the formation of fatty acid ethyl esters in brain and peripheral organs after short-term ethanol administration in rat. Neurochemical Res. 26:167–174.Google Scholar
  152. 152.
    Pettegrew, J. W., Levine, J., and McClure, R. J. 2000. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: Relevance for its mode of action in Alzheimer's disease and geriatric depression. Mol. Psychiatry 5:616–632.Google Scholar
  153. 153.
    Thal, L. J., Calvani, M., Amato, A., and Carta, A. 2000. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 55:805–810.Google Scholar
  154. 154.
    Scarpini, E., Sacilotto, G., Baron, P., Cusini, M., and Scarlato, G. 1997. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J. Peripher. Nerv. Syst. 2:250–252.Google Scholar
  155. 155.
    Paradies, G., Ruggiero, F. M., Petrosillo, G., Gadaleta, M. N., and Quagliariello, E. 1995. Carnitine-acylcarnitine translocase activity in cardiac mitochondria from aged rats: The effect of acetyl-L-carnitine. Mech. Ageing Dev. 84:103–112.Google Scholar
  156. 156.
    Paradies, G., Ruggiero, F. M., Petrosillo, G., Gadaleta, M. N., and Quagliariello, E. 1994. Effect of aging and acetyl-L-carnitine on the activity of cytochrome oxidase and adenine nucleotide translocase in rat heart mitochondria. FEBS Lett. 350:213–215.Google Scholar
  157. 157.
    Paradies, G., Ruggiero, F. M., Gadaleta, M. N., and Quagliariello, E. 1992. The effect of aging and acetyl-L-carnitine on the activity of the phosphate carrier and on the phospholipid composition in rat heart mitochondria. Biochim. Biophys. Acta 1103:324–326.Google Scholar
  158. 158.
    Gorini, A., D'Angelo, A., and Villa, R. F. 1998. Energy metabolism of synaptosomal subpopulations from different neuronal systems of rat hippocampus: Effect of L-acetylcarnitine administration in vivo. Neurochem. Res. 23:1485–1491.Google Scholar
  159. 159.
    Calvani, M. and Arrigoni-Martelli, E. 1999. Attenuation by acetyl-L-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion. Int. J. Tissue React. 21:1–6.Google Scholar
  160. 160.
    Hagen, T. M., Wehr, C. M., and Ames, B. N. 1998. Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-carnitine and N-tert-butyl-alpha-phenyl-nitrone. Ann. NY Acad. Sci. 854:214–223.Google Scholar
  161. 161.
    Hagen, T. M., Ingersoll, R. T., Wehr, C. M., Lykkesfeldt, J., Vinarsky, V., Bartholomew, J. C., Song, M. H., and Ames, B. N. 1998. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc. Natl. Acad. Sci. USA 95:9562–9566.Google Scholar
  162. 162.
    Brooks, J. O., Yesavage, J. A., Carta, A., and Bravi, D. 1998. Acetyl-l-carnitine slows decline in younger patients with Alzheimer's disease: A reanalysis of a double-blind, placebocontrolled study using the trilinear approach. Int. Psychogeriatr. 10:193–203.Google Scholar
  163. 163.
    Pettegrew, J. W., Klunk, W. E., and Panchalingam, K. 1995. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease. Neurobiol Aging 16:1–4.Google Scholar
  164. 164.
    Fernandez, E., Pallini, R., Tamburrini, G., Lauretti, L., Tancredi, A., and La Marca, F. 1995. Effects of levo-acetylcarnitine on second motoneuron survival after axotomy. Neurol. Res. 5:373–376.Google Scholar
  165. 165.
    Foreman, P. J., Perez-Polo, J. R., Angelucci, L., Ramacci, M. T., and Taglialatela, G. 1995. Effects of acetyl-L-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 19:117–133.Google Scholar
  166. 166.
    Taglialatela, G., Caprioli, A., Giuliani, A., and Ghirardi, O. 1996. Spatial memory and NGF levels in aged rats: Natural variability and effects of acetyl-L-carnitine treatment. Exp. Gerontol. 31:577–587.Google Scholar
  167. 167.
    Butterfield, D. A. 1999. On methionine and Alzheimer's amyloid b-peptide (1–42)-induced oxidative stress. Neurobiology of Aging 20:339–342.Google Scholar
  168. 168.
    Butterfield, D. A. and Stadtman, E. R. 1997. Protein oxidation processes in aging brain. Adv. Cell Aging Gerontol. 2:161–191.Google Scholar
  169. 169.
    Varadarajan, S., Yatin, S., Aksenova, M., and Butterfield, D. A. 2000. Alzheimer's Amyloid β-peptide-associated free radical oxidative stress and neurotoxicity. J. Struct. Biol. 130:184–208.Google Scholar
  170. 170.
    Butterfield, D. A., Koppal, T., Subramaniam, R., and Yatin, S. 1999. Vitamin E as an antioxidant/free radical scavenger against amyloid β-peptide-induced oxidative stress in neocortical synaptosomal membranes and hippocampal neurons in culture: Insights into Alzheimer's disease. Rev. Neurosci. 10:141–149.Google Scholar
  171. 171.
    Koppal, T., Subramaniam, R., Drake, J., Prasad, R. P., Dhillon, H., and Butterfield, D. A. 1998. Vitamin E protects against Alzheimer's amyloid peptide (25–35)-induced changes in neocortical synaptosomal membrane lipid structure and composition. Brain Res. 786:270–273.Google Scholar
  172. 172.
    Yatin, S. M., Kink, C. D., and Butterfield, D. A. 1999. In-vitro and in-vivo oxidative stress associated with Alzheimer's amyloid β-peptide (1–42). Neurobiology of Aging 20:325–330.Google Scholar
  173. 173.
    Jen, L. S., Hart, A. J., Jen, A., Relvas, J. B., and Gentleman, S. M. 1998. Alzheimer's peptide kills cells of retina in vivo. Nature 392:140–141.Google Scholar
  174. 174.
    Gwebu, E. T., Williams, J., Mathis, D., Warden, J. A., Selassie, M., Richardson, S., and Gwebu, N. T. 1997. Cytotoxicity of β-amyloid peptide 25–35 on vascular smooth muscle cells and attenuation by vitamin E. In Vitro Cell Dev. Biol. Anim. 33:672–673.Google Scholar
  175. 175.
    Thomas, T., Thomas, G., McLendon, C., Sutton, T., and Mullan, M. 1996. β-amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168–171.Google Scholar
  176. 176.
    Zaman, Z., Roche, S., Fielden, P., Niriella, D. C., and Cayley, A. C. 1992. Plasma concentrations of vitamin A and E and carotenoids in Alzheimer's disease. Age Ageing 21:91–94.Google Scholar
  177. 177.
    Sano, M., Ernesto, C., Thomas, R. G., Klauber, M. R. Schafer, K., Grundman, M., Woodbury, P., Growdon, J., Cotman, C. W., Pfeiffer, E., Schneider, L. S., and Thal, L. J. 1997. A controlled trial of selegiline, alphatocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's disease cooperative study, N. Engl. J. Med. 336:1216–1222.Google Scholar
  178. 178.
    Peyser, C. E., Folstein, M., Chase, G. A., Starkstein, S., Brandt, J., Cockrell, J. R., Bylsma, F., Coyle, J. T., McHugh, P. R., and Folstein, S. E. 1995. Trial of d-β-tocopherol in Huntington's disease. Amer. J. Psychiatry 152:1771–1775.Google Scholar
  179. 179.
    Reider, C. R. and Paulson, G. W. 1997. Lou Gehrig and amyotrophic lateral sclerosis. Is vitamin E to be revisited? Arch. Neurol. 54:527–528.Google Scholar
  180. 180.
    Papa, S. 1996. Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications. Biochim. Biophys. Acta 1276:87–105.Google Scholar
  181. 181.
    Papa, S. and Skulachev, V. P. 1997. Reactive oxygen species,mitochondria, apoptosis and aging. Mol. Cell. Biochem. 174:305–319.Google Scholar
  182. 182.
    Papa, S., Scacco, S., Sardanelli, A. M., Vergari, R., Papa, F., Budde, S., van den Heuvel, L., and Smeitink, J. 2001. Mutation in the NDUFS4 gene of complex I abolishes cAMP-dependent activation of the complex in a child with fatal neurological syndrome. FEBS Lett. 489:259–262.Google Scholar
  183. 183.
    Hurst, R. D., Azam, S., Hurst, A., and Clark, J. B. 2001. Nitric-oxide-induced inhibition of glyceraldehyde-3-phosphate dehydrogenase may mediate reduced endothelial cell monolayer integrity in an in vitro model blood-brain barrier. Brain. Res. 894:181–188.Google Scholar
  184. 184.
    Cullingford, T. E., Bhakoo, K. K., Peuchen, S., Dolphin, C. T., and Clark, J. B. 1999. Regulation of the ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in astrocytes and meningeal fibroblasts. Implications in normal brain development and seizure neuropathologies. Adv. Exp. Med. Biol. 466:241–251.Google Scholar
  185. 185.
    Fujihara, S. M. and Nadler, S. G. 1999. Intranuclear targeted delivery of functional NF-kappaB by 70 kDa heat shock protein. EMBO J. 18:411–419.Google Scholar
  186. 186.
    Lutz, T., Westermann, B., Neupert, W., and Herrmann, J. M. 2001. The Mitochondrial Proteins Ssq1 and Jac1 are Required for the Assembly of Iron Sulfur Clusters in Mitochondria. J. Mol. Biol. 307:815–825.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • V. Calabrese
    • 1
  • G. Scapagnini
    • 1
  • A. M. Giuffrida Stella
    • 1
  • T. E. Bates
    • 2
  • J. B. Clark
    • 2
  1. 1.Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of MedicineUniversity of CataniaCatania
  2. 2.Department of Neurochemistry, Institute of NeurologyUniversity College LondonLondonU.K

Personalised recommendations