Mitochondrial Medicine for Aging and Neurodegenerative Diseases

Abstract

Mitochondria are key cytoplasmic organelles, responsible for generating cellular energy, regulating intracellular calcium levels, altering the reduction-oxidation potential of cells, and regulating cell death. Increasing evidence suggests that mitochondria play a central role in aging and in neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Freidriech ataxia. Further, several lines of evidence suggest that mitochondrial dysfunction is an early event in most late-onset neurodegenerative diseases. Biochemical and animal model studies of inherited neurodegenerative diseases have revealed that mutant proteins of these diseases are associated with mitochondria. Mutant proteins are reported to block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins and disrupt the electron transport chain, induce free radicals, cause mitochondrial dysfunction, and, ultimately, damage neurons. This article discusses critical issues of mitochondria causing dysfunction in aging and neurodegenerative diseases, and discusses the potential of developing mitochondrial medicine, particularly mitochondrially targeted antioxidants, to treat aging and neurodegenerative diseases.

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Abbreviations

Aß:

Amyloid beta

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

APP:

Amyloid precursor protein

ATP:

Adenosine triphosphate

CR:

Caloric restricted

ETC:

Electron transport chain

FRDA:

Freidriech ataxia

H2O2 :

Hydrogen peroxide

HD:

Huntington’s disease

mtDNA:

Mitochondrial DNA

PGC-1α:

Peroxisome proliferator-activated receptor- coactivator

O 2 :

Superoxide radical

OXPHOS:

Oxidative phosphorylation

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

SS peptide:

Szeto-Schiller peptide

References

  1. Abe, Y., Hashimoto, Y., Tomita, Y., Terashita, K., Aiso, S., Tajima, H., et al. (2004). Cytotoxic mechanisms by M239 V presenilin 2, a little-analyzed Alzheimer’s disease-causative mutant. Journal of Neuroscience Research, 77, 583–595. doi:10.1002/jnr.20163.

    PubMed  CAS  Google Scholar 

  2. Abeliovich, A., & Beal, M. F. (2006). Parkinsonism genes: Culprits and clues. Journal of Neurochemistry, 99, 1062–1072. doi:10.1111/j.1471-4159.2006.04102.x.

    PubMed  CAS  Google Scholar 

  3. Afifi, A. K., Aleu, F. P., Goodgold, J., & MacKay, B. (1966). Ultrastructure of atrophic muscle in amyotrophic lateral sclerosis. Neurology, 16, 475–481.

    PubMed  CAS  Google Scholar 

  4. Anandatheerthavarada, H. K., Biswas, G., Robin, M. A., & Avadhani, N. G. (2003). Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. Journal of Cell Biology, 161, 41–54. doi:10.1083/jcb.200207030.

    PubMed  CAS  Google Scholar 

  5. Andersen, J. K. (2004). Iron dysregulation and Parkinson’s disease. Journal of Alzheimer’s Disease, 6, S47–S52.

    PubMed  CAS  Google Scholar 

  6. Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H., Coulson, A. R., Drouin, J., et al. (1981). Sequence and organization of the human mitochondrial genome. Nature, 290, 457–465. doi:10.1038/290457a0.

    PubMed  CAS  Google Scholar 

  7. Anekonda, T. (2006). Resveratrol––a boon for treating Alzheimer’s disease? Brain Research Reviews, 52, 316–326. doi:10.1016/j.brainresrev.2006.04.004.

    PubMed  CAS  Google Scholar 

  8. Anekonda, T. S., & Reddy, P. H. (2006). Neuronal protection by sirtuins in Alzheimer’s disease. Journal of Neurochemistry, 96, 305–313. doi:10.1111/j.1471-4159.2005.03492.x.

    PubMed  CAS  Google Scholar 

  9. Ankarcrona, M., & Hultenby, K. (2002). Presenilin-1 is located in rat mitochondria. Biochemical and Biophysical Research Communications, 295, 766–770. doi:10.1016/S0006-291X(02)00735-0.

    PubMed  CAS  Google Scholar 

  10. Barsoum, M. J., Yuan, H., Gerencser, A. A., et al. (2006). Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO Journal, 25, 3900–3911. doi:10.1038/sj.emboj.7601253.

    PubMed  CAS  Google Scholar 

  11. Bates, G. P. (2005). History of genetic disease: The molecular genetics of Huntington disease––a history. Nature Reviews. Genetics, 6, 766–773. doi:10.1038/nrg1686.

    PubMed  CAS  Google Scholar 

  12. Beal, M. F. (2005). Mitochondria take center stage in aging and neurodegeneration. Annals of Neurology, 58, 495–505. doi:10.1002/ana.20624.

    PubMed  CAS  Google Scholar 

  13. Behbahani, H., Shabalina, I. G., Wiehager, B., et al. (2006). Differential role of Presenilin-1 and -2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts. Journal of Neuroscience Research, 84, 891–902. doi:10.1002/jnr.20990.

    PubMed  CAS  Google Scholar 

  14. Beilina, A., Van Der Brug, M., Ahmad, R., Kesavapany, S., Miller, D. W., Petsko, G. A., et al. (2005). Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proceedings of the National Academy of Sciences of the United States of America, 102, 5703–5708. doi:10.1073/pnas.0500617102.

    PubMed  CAS  Google Scholar 

  15. Benard, G., Bellance, N., James, D., Parrone, P., Fernandez, H., Letellier, T., et al. (2007). Mitochondrial bioenergetics and structural network organization. Journal of Cell Science, 120, 838–848. doi:10.1242/jcs.03381.

    PubMed  CAS  Google Scholar 

  16. Bergemalm, D., Jonsson, P. A., Graffmo, K. S., Andersen, P. M., Brannstrom, T., Rehnmark, A., et al. (2006). Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models. Journal of Neuroscience, 26, 4147–4154. doi:10.1523/JNEUROSCI.5461-05.2006.

    PubMed  CAS  Google Scholar 

  17. Blander, G., & Guarente, L. (2004). The Sir2 family of protein deacetylases. Annual Review of Biochemistry, 73, 417–435. doi:10.1146/annurev.biochem.73.011303.073651.

    PubMed  CAS  Google Scholar 

  18. Boillee, S., Vande Velde, C., & Cleveland, D. W. (2006). ALS: A disease of motor neurons and their nonneuronal neighbors. Neuron, 52, 39–59. doi:10.1016/j.neuron.2006.09.018.

    PubMed  CAS  Google Scholar 

  19. Bonifati, V., Rizzu, P., van Baren, M. J., et al. (2003). Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science, 299, 256–259. doi:10.1126/science.1077209.

    PubMed  CAS  Google Scholar 

  20. Bossy-Wetzel, E., Barsoum, M. J., Godzik, A., Schwarzenbacher, R., & Lipton, S. A. (2003). Mitochondrial fission in apoptosis, neurodegeneration and aging. Current Opinion in Cell Biology, 15, 706–716. doi:10.1016/j.ceb.2003.10.015.

    PubMed  CAS  Google Scholar 

  21. Boyd-Kimball, D., Sultana, R., Abdul, H. M., & Butterfield, D. A. (2005a). Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1–42)-mediated oxidative stress and neurotoxicity: Implications for Alzheimer’s disease. Journal of Neuroscience Research, 79, 700–706. doi:10.1002/jnr.20394.

    PubMed  CAS  Google Scholar 

  22. Boyd-Kimball, D., Sultana, R., Poon, H. F., Mohmmad-Abdul, H., Lynn, B. C., Klein, J. B., et al. (2005b). Gamma-glutamylcysteine ethyl ester protection of proteins from Abeta(1-42)-mediated oxidative stress in neuronal cell culture: A proteomics approach. Journal of Neuroscience Research, 79, 707–713. doi:10.1002/jnr.20393.

    PubMed  CAS  Google Scholar 

  23. Bozner, P., Grishko, V., LeDoux, S. P., Wilson, G. L., Chyan, Y. C., & Pappolla, M. A. (1997). The amyloid beta protein induces oxidative damage of mitochondrial DNA. Journal of Neuropathology and Experimental Neurology, 56, 1356–1362. doi:10.1097/00005072-199712000-00010.

    PubMed  CAS  Google Scholar 

  24. Browne, S. E., & Beal, M. F. (2004). The energetics of Huntington’s disease. Neurochemical Research, 29, 531–546. doi:10.1023/B:NERE.0000014824.04728.dd.

    PubMed  CAS  Google Scholar 

  25. Browne, S. E., & Beal, M. F. (2006). Oxidative damage in Huntington’s disease pathogenesis. Antioxidants Redox Signaling, 8, 2061–2073. doi:10.1089/ars.2006.8.2061.

    PubMed  CAS  Google Scholar 

  26. Browne, S. E., Bowling, A. C., MacGarvey, U., Baik, M. J., Berger, S. C., Muqit, M. M., et al. (1997). Oxidative damage and metabolic dysfunction in Huntington’s disease: Selective vulnerability of the basal ganglia. Annals of Neurology, 41, 646–653. doi:10.1002/ana.410410514.

    PubMed  CAS  Google Scholar 

  27. Bruijn, L. I., Houseweart, M. K., Kato, S., Anderson, K. L., Anderson, S. D., Ohama, E., et al. (1998). Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science, 281, 1851–1854. doi:10.1126/science.281.5384.1851.

    PubMed  CAS  Google Scholar 

  28. Campuzano, V., Montermini, L., Molto, M. D., et al. (1996). Friedreich’s ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science, 271, 1423–1427. doi:10.1126/science.271.5254.1423.

    PubMed  CAS  Google Scholar 

  29. Canet-Avilés, R. M., Wilson, M. A., Miller, D. W., Ahmad, R., McLendon, C., Bandyopadhyay, S., et al. (2004). The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proceedings of the National Academy of Sciences of the United States of America, 101, 9103–9108.

    PubMed  Google Scholar 

  30. Caspersen, C., Wang, N., Yao, J., Sosunov, A., Chen, X., Lustbader, J. W., et al. (2005). Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB Journal, 19, 2040–2041.

    PubMed  CAS  Google Scholar 

  31. Chan, D. C. (2006). Mitochondrial fusion and fission in mammals. Annual Review of Cell and Developmental Biology, 22, 79–99. doi:10.1146/annurev.cellbio.22.010305.104638.

    PubMed  CAS  Google Scholar 

  32. Chan, S. L., Furukawa, K., & Mattson, M. P. (2002). Presenilins and APP in neuritic and synaptic plasticity: Implications for the pathogenesis of Alzheimer’s disease. Neuromolecular Medicine, 2, 167–196. doi:10.1385/NMM:2:2:167.

    PubMed  CAS  Google Scholar 

  33. Chang, S., Ran, M. A. T., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y. (2005). Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 102, 18694–18689 doi:10.1073/pnas.0508254102.

  34. Chang, D. T., & Reynolds, I. J. (2006). Mitochondrial trafficking and morphology in healthy and injured neurons. Progress in Neurobiology, 80, 241–268. doi:10.1016/j.pneurobio.2006.09.003.

    PubMed  CAS  Google Scholar 

  35. Chang, D. T., Rintoul, G. L., Pandipati, S., & Reynolds, I. J. (2006). Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiology of Disease, 22, 388–400. doi:10.1016/j.nbd.2005.12.007.

    PubMed  CAS  Google Scholar 

  36. Chen, X., Liang, H., Van Remmen, H., Vijg, J., & Richradson, A. (2004). Catalase transgenic mice: Characterization and sensitivity to oxidative stress. Archives of Biochemistry and Biophysics, 422, 197–210. doi:10.1016/j.abb.2003.12.023.

    PubMed  CAS  Google Scholar 

  37. Cho, S., Szeto, H. H., Kim, E., Kim, H., Tolhurst, A. T., & Pinto, J. T. (2007a). A novel cell-permeable antioxidant peptide, SS31, attenuates ischemic brain injury by down-regulating CD36. Journal of Biological Chemistry, 282, 4634–4642. doi:10.1074/jbc.M609388200.

    PubMed  CAS  Google Scholar 

  38. Cho, J., Won, K., Wu, D., Soong, Y., Liu, S., Szeto, H. H., et al. (2007b). Potent mitochondria-targeted peptides reduce myocardial infarction in rats. Coronary Artery Disease, 18, 215–220. doi:10.1097/01.mca.0000236285.71683.b6.

    PubMed  Google Scholar 

  39. Chung, M. J., & Suh, Y. L. (2002). Ultrastructural changes of mitochondria in the skeletal muscle of patients with amyotrophic lateral sclerosis. Ultrastructural Pathology, 26, 3–7. doi:10.1080/01913120252934260.

    PubMed  Google Scholar 

  40. Cocheme, H. M., Kelso, G. F., James, A. M. Ross, M. F., Trnka, J., Mahendrian, T., Asin-Cayuela, J., Blaike, F. H., Manas, A. R., Porteous, C. M., Adlam, V. J., Smith, R. A. & Murphy, M. P. (2007). Mitochondrial targeting of quinones: Therapeutic implications. Mitochondrion (Suppl:S94–S102) doi:10.1016/j.mito.2007.02.007.

  41. Cooper, J. M., Mann, V. M., & Schapira, A. H. (1992). Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: Effect of ageing. Journal of the Neurological Sciences, 113, 91–98. doi:10.1016/0022-510X(92)90270-U.

    PubMed  CAS  Google Scholar 

  42. Copeland, W. C. (2008). Inherited mitochondrial diseases of DNA replication. Annual Review of Medicine, 59, 131–146. doi:10.1146/annurev.med.59.053006.104646.

    PubMed  CAS  Google Scholar 

  43. Corral-Debrinski, M., Horton, T., Lott, M. T., Shoffner, J. M., McKee, A. C., Beal, M. F., et al. (1994). Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics, 23, 471–476. doi:10.1006/geno.1994.1525.

    PubMed  CAS  Google Scholar 

  44. Crouch, P. J., Blake, R., Duce, J. A., et al. (2005). Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1–42. Journal of Neuroscience, 25, 672–679. doi:10.1523/JNEUROSCI.4276-04.2005.

    PubMed  CAS  Google Scholar 

  45. Cui, L., Jeong, H., Borovecki, F., Parkhurst, C. N., Tanese, N., & Krainc, D. (2006). Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell, 127, 59–69. doi:10.1016/j.cell.2006.09.015.

    PubMed  CAS  Google Scholar 

  46. Deng, H. X., Shi, Y., Furukawa, Y., Zhai, H., et al. (2006). Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proceedings of the National Academy of Sciences of the United States of America, 103, 7142–7147. doi:10.1073/pnas.0602046103.

    PubMed  CAS  Google Scholar 

  47. Derossi, D., Calvet, S., Trembleau, A., Brunissen, A., Chassaing, G., & Prochiantz, A. (1996). Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. Journal of Biological Chemistry, 271, 18188–18193. doi:10.1074/jbc.271.30.18188.

    PubMed  CAS  Google Scholar 

  48. Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G., & Anandatheerthavarada, H. K. (2006). Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. Journal of Neuroscience, 26, 9057–9068. doi:10.1523/JNEUROSCI.1469-06.2006.

    PubMed  CAS  Google Scholar 

  49. Devi, L., Raghavendran, V., Prabhu, B. M., Avadhani, N. G., & Anandatheerthavarada, H. K. (2008). Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. Journal of Biological Chemistry, 283, 9089–9100. doi:10.1074/jbc.M710012200.

    PubMed  CAS  Google Scholar 

  50. Dhanasekaran, A., Kotamraju, S., Kalivendi, S. V., Matsunaga, T., Shang, T., Keszler, A., Jpseph, J., & Kalyanaraman, B. (2004). Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. Jounal of Biological Chemistry, 279, 37575–37587.

    CAS  Google Scholar 

  51. Ding, Q., Cecarini, V., & Keller, J. N. (2007). Interplay between protein synthesis and degradation in the CNS: Physiological and pathological implications. Trends in Neurosciences, 30, 31–36. doi:10.1016/j.tins.2006.11.003.

    PubMed  CAS  Google Scholar 

  52. Drin, G., Cottin, S., Blanc, E., Rees, A. R., & Temsamani, J. (2003). Studies on the internalization mechanism of cationic cell-penetrating peptides. Journal of Biological Chemistry, 278, 31192–31201. doi:10.1074/jbc.M303938200.

    PubMed  CAS  Google Scholar 

  53. Dupuis, L., di Scala, F., Rene, F., de Tapia, M., Oudart, H., Pradat, P. F., et al. (2003). Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. FASEB Journal, 17, 2091–2093.

    PubMed  CAS  Google Scholar 

  54. Farrer, M., Stone, J., Mata, I. F., Lincoln, S., Kachergus, J., Hulihan, M., et al. (2005). LRRK2 mutations in Parkinson disease. Neurology, 65, 738–740. doi:10.1212/01.WNL.0000169023.51764.b0.

    PubMed  CAS  Google Scholar 

  55. Fromenty, B., Grimbert, S., Mansouri, A., Beaugrand, M., Erlinger, S., Rotug, A., et al. (1995). Hepatic mitochondrial DNA deletion in alcoholics: Association with microvesicular steatosis. Gastroenterology, 108, 193–200. doi:10.1016/0016-5085(95)90024-1.

    PubMed  CAS  Google Scholar 

  56. Folstein, S. E. (1990). Huntington’s Disease. Baltimore: Johns Hopkins University Press.

    Google Scholar 

  57. Fukui, H., & Moraes, C. T. (2007). Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates. Human Molecular Genetics, 16, 783–797. doi:10.1093/hmg/ddm023.

    PubMed  CAS  Google Scholar 

  58. Furukawa, Y., Fu, R., Deng, H. X., Siddique, T., & O’Halloran, T. V. (2006). Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice. Proceedings of the National Academy of Sciences of the United States of America, 103, 7148–7153. doi:10.1073/pnas.0602048103.

    PubMed  CAS  Google Scholar 

  59. Galluzzi, L., Larochette, N., Zamzami, N., & Kroemer, G. (2006). Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene, 25, 4812–4830. doi:10.1038/sj.onc.1209598.

    PubMed  CAS  Google Scholar 

  60. Galter, D., Westerlund, M., Carmine, A., Lindqvist, E., Sydow, O., & Olson, L. (2006). LRRK2 expression linked to dopamine-innervated areas. Annals of Neurology, 59, 714–719. doi:10.1002/ana.20808.

    PubMed  CAS  Google Scholar 

  61. Gandhi, S., & Wood, N. W. (2005). Molecular pathogenesis of Parkinson’s disease. Human Molecular Genetics, 14, 2749–2755.

    Google Scholar 

  62. Gibson, G. E., Sheu, K. F., & Blass, J. P. (1998). Abnormalities of mitochondrial enzymes in Alzheimer disease. Journal of Neural Transmission, 105, 855–870. doi:10.1007/s007020050099.

    PubMed  CAS  Google Scholar 

  63. Gilks, W. P., Abou-Sleiman, P. M., Gandhi, S., Jain, S., et al. (2005). A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet, 365, 415–416.

    PubMed  CAS  Google Scholar 

  64. Guarente, L. (2000). Sir2 links chromatin silencing, metabolism, and aging. Genes and Development, 14, 1021–1026.

    PubMed  CAS  Google Scholar 

  65. Guo, Q., Sebastian, L., Sopher, B. L., Miller, M. W., Ware, C. B., Martin, G. M., et al. (1999). Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: Central roles of superoxide production and caspase activation. Journal of Neurochemistry, 72, 1019–1029. doi:10.1046/j.1471-4159.1999.0721019.x.

    PubMed  CAS  Google Scholar 

  66. Guo, Q., Sopher, B. L., Furukawa, K., Pham, D. G., Robinson, N., Martin, G. M., et al. (1997). Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: Involvement of calcium and oxyradicals. Journal of Neuroscience, 17, 4212–4222.

    PubMed  CAS  Google Scholar 

  67. Gurney, M. E., Pu, H., Chiu, A. Y., et al. (1994). Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science, 264, 1772–1775. doi:10.1126/science.8209258.

    PubMed  CAS  Google Scholar 

  68. Hansson, C. A., Frykman, S., Farmery, M. R., et al. (2004). Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. Journal of Biological Chemistry, 279, 51654–51660. doi:10.1074/jbc.M404500200.

    PubMed  CAS  Google Scholar 

  69. Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 297, 353–356. doi:10.1126/science.1072994.

    PubMed  CAS  Google Scholar 

  70. Hausse, A. O., Aggoun, Y., Bonnet, D., Sidi, D., Munnich, A., Rotig, A., et al. (2002). Idebenone and reduced cardiac hypertrophy in Friedreich’s ataxia. Heart, 87, 346–349. doi:10.1136/heart.87.4.346.

    PubMed  CAS  Google Scholar 

  71. Hervias, I., Beal, M. F., & Manfredi, G. (2006). Mitochondrial dysfunction and amyotrophic lateral sclerosis. Muscle and Nerve, 33, 598–608. doi:10.1002/mus.20489.

    PubMed  CAS  Google Scholar 

  72. Higgins, C. M., Jung, C., & Xu, Z. (2003). ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neuroscience, 4, 16. doi:10.1186/1471-2202-4-16.

    PubMed  Google Scholar 

  73. Hirai, K., Aliev, G., Nunomura, A., et al. (2001). Mitochondrial abnormalities in Alzheimer’s disease. Journal of Neuroscience, 21, 3017–3023.

    PubMed  CAS  Google Scholar 

  74. Hirano, A., Donnenfeld, H., Sasaki, S., & Nakano, I. (1984). Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. Journal of Neuropathology and Experimental Neurology, 43, 461–470. doi:10.1097/00005072-198409000-00001.

    PubMed  CAS  Google Scholar 

  75. Hodgson, J. G., Agopyan, N., Gutekunst, C. A., et al. (1999). A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron, 23, 181–192. doi:10.1016/S0896-6273(00)80764-3.

    PubMed  CAS  Google Scholar 

  76. Horton, T. M., Graham, B. H., Corral-Debranski, M., Shoffner, J. M., Kaufman, A. E., Beal, M. F., et al. (1995). Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington’s disease patients. Neurology, 45, 1879–1883.

    PubMed  CAS  Google Scholar 

  77. Howell, N., Elson, J. L., Chinnery, P. F., & Turnbull, D. M. (2005). mtDNA mutations and common neurodegenerative disorders. Trends in Genetics, 21, 583–586. doi:10.1016/j.tig.2005.08.012.

    PubMed  CAS  Google Scholar 

  78. Huang, C. C., Faber, P. W., Persichetti, F., Mittal, V., Vonsattel, J. P., MacDonald, M. E., et al. (1998). Amyloid formation by mutant huntingtin: Threshold, progressivity and recruitment of normal polyglutamine proteins. Somatic Cell and Molecular Genetics, 24, 217–233. doi:10.1023/B:SCAM.0000007124.19463.e5.

    PubMed  CAS  Google Scholar 

  79. Ikebe, S., Tanaka, M., Ohno, K., Sato, W., Hattori, K., Kondo, T., et al. (1990). Increase of deleted mitochondrial DNA in the striatum in Parkinson’s disease and senescence. Biochemical and Biophysical Research Communications, 170, 1044–1048. doi:10.1016/0006-291X(90)90497-B.

    PubMed  CAS  Google Scholar 

  80. Jauslin, M. L., Meier, T., Smith, R. A., & Murphy, M. P. (2003). Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB Journal, 17(13), 1972–1974.

    PubMed  CAS  Google Scholar 

  81. Jin, J., Meredeith, G. E., Chen, L., Zhou, Y., Xu, J., Shie, F. S., Lockhart, P., & Zhang, J. (2005). Quantitative proteomic analysis of mitochondrial proteins: Relevance to Lewy body formation and Parkinson's disease. Brain Research. Molecular Brain Research, 134, 119–138.

    PubMed  CAS  Google Scholar 

  82. Jonsson, P. A., Graffmo, K. S., Andersen, P. M., Brannstrom, T., Lindberg, M., Oliveberg, M., et al. (2006). Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models. Brain, 129, 451–464. doi:10.1093/brain/awh704.

    PubMed  Google Scholar 

  83. Kao, S., Chao, H. T., & Wei, Y. H. (1995). Mitochondrial deoxyribonucleic acid 4977-bp deletion is associated with diminished fertility and motility of human sperm. Biology of Reproduction, 52, 729–736. doi:10.1095/biolreprod52.4.729.

    PubMed  CAS  Google Scholar 

  84. Keller, J. N., Guo, Q., Holtsberg, F. W., Bruce-Keller, A. J., & Mattson, M. P. (1998). Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. Journal of Neuroscience, 18, 4439–4450.

    PubMed  CAS  Google Scholar 

  85. Khan, S. M., Cassarino, D. S., Abramova, N. N., Keeney, P. M., Borland, M. K., Timmer, P. A., et al. (2000). Alzheimer’s disease cybrids replicate beta-amyloid abnormalities through cell death pathways. Annals of Neurology, 48, 148–155. doi:10.1002/1531-8249(200008)48:2<148::AID-ANA3>3.0.CO;2-7.

    Google Scholar 

  86. Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., et al. (2007). SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO Journal, 26, 3169–3179. doi:10.1038/sj.emboj.7601758.

    PubMed  CAS  Google Scholar 

  87. Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., et al. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392, 605–608. doi:10.1038/33416.

    PubMed  CAS  Google Scholar 

  88. Kotake, Y. (1999). Pharmacologic properties of phenyl N-tert-butylnitrone. Antioxidants Redox Signaling, 1, 481–499.

    PubMed  CAS  Google Scholar 

  89. Kroemer, G. (2006). Mitochondria in cancer. Oncogene, 25, 4630–4632. doi:10.1038/sj.onc.1209589.

    PubMed  CAS  Google Scholar 

  90. Kujoth, G. C., Hiona, A., Pugh, T. D., et al. (2005). Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science, 309, 481–448. doi:10.1126/science.1112125.

    PubMed  CAS  Google Scholar 

  91. Kujoth, G. C., Leeuwenburgh, C., & Prolla, T. A. (2006). Mitochondrial DNA mutations and apoptosis in mammalian aging. Cancer Research, 66, 7386–7389. doi:10.1158/0008-5472.CAN-05-4670.

    PubMed  CAS  Google Scholar 

  92. Kwong, J. Q., Beal, M. F., & Manfredi, G. (2006). The role of mitochondria in inherited neurodegenerative diseases. Journal of Neurochemistry, 97, 1659–1675. doi:10.1111/j.1471-4159.2006.03990.x.

    PubMed  CAS  Google Scholar 

  93. LaFerla, F. M., Gree, K. N., & Oddo, S. (2007). Intracellular amyloid-beta in Alzheimer’s disease. Nature Reviews. Neuroscience, 8, 499–509. doi:10.1038/nrn2168.

    PubMed  CAS  Google Scholar 

  94. Lamming, D. W., Wood, J. G., & Sinclair, D. A. (2004). Small molecules that regulate lifespan: Evidence for xenohormesis. Molecular Microbiology, 53, 1003–1009. doi:10.1111/j.1365-2958.2004.04209.x.

    PubMed  CAS  Google Scholar 

  95. Langston, J. W., Ballard, P., Tetrud, J. W., & Irwin, I. (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219, 979–980. doi:10.1126/science.6823561.

    PubMed  CAS  Google Scholar 

  96. Leroy, E., Boyer, R., Auburger, G., et al. (1998). The ubiquitin pathway in Parkinson’s disease. Nature, 395, 451–452. doi:10.1038/26652.

    PubMed  CAS  Google Scholar 

  97. Li, F., Calingasan, N. Y., Yu, F., et al. (2004). Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. Journal of Neurochemistry, 89, 1308–1312. doi:10.1111/j.1471-4159.2004.02455.x.

    PubMed  CAS  Google Scholar 

  98. Li, S., & Li, X. J. (2006). Multiple pathways contribute to the pathogenesis of Huntington disease. Molecular Neurodegeneration, 1, 19. doi:10.1186/1750-1326-1-19.

    PubMed  Google Scholar 

  99. Liang, H., & Ward, W. F. (2006). PGC-1alpha: A key regulator of energy metabolism. Advances in Physiology Education, 30(4), 145–151. doi:10.1152/advan.00052.2006.

    PubMed  Google Scholar 

  100. Lin, M. T., & Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443, 787–795. doi:10.1038/nature05292.

    PubMed  CAS  Google Scholar 

  101. Liu, J., Lillo, C., Jonsson, P. A., et al. (2004). Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron, 43, 5–17. doi:10.1016/j.neuron.2004.06.016.

    PubMed  CAS  Google Scholar 

  102. Lustbader, J. W., Cirilli, M., Lin, C., et al. (2004). ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science, 304, 448–452. doi:10.1126/science.1091230.

    PubMed  CAS  Google Scholar 

  103. Manczak, M., Anekonda, T. S., Henson, E., Park, B. S., Quinn, J., & Reddy, P. H. (2006). Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: Implications for free radical generation and oxidative damage in disease progression. Human Molecular Genetics, 15, 1437–1449. doi:10.1093/hmg/ddl066.

    PubMed  CAS  Google Scholar 

  104. Manczak, M., Park, B. S., Jung, Y., & Reddy, P. H. (2004). Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: Implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Medicine, 5, 147–162. doi:10.1385/NMM:5:2:147.

    PubMed  CAS  Google Scholar 

  105. Mandelkow, E. M., Thies, E., Trinczek, B., Biernat, J., & Mandelkow, E. (2004). MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. Journal of Cell Biology, 167, 99–110. doi:10.1083/jcb.200401085.

    PubMed  CAS  Google Scholar 

  106. Martin, L. J. (2006). Mitochondriopathy in Parkinson disease and amyotrophic lateral sclerosis. Journal of Neuropathology and Experimental Neurology, 65, 1103–1110. doi:10.1097/01.jnen.0000248541.05552.c4.

    PubMed  CAS  Google Scholar 

  107. Mattson, M. P. (2004). Pathways towards and away from Alzheimer’s disease. Nature, 430, 631–639. doi:10.1038/nature02621.

    PubMed  CAS  Google Scholar 

  108. Mattson, M. P. (2007). Calcium and neurodegeneration. Aging Cell, 6, 337–350. doi:10.1111/j.1474-9726.2007.00275.x.

    PubMed  CAS  Google Scholar 

  109. Maurer, I., Zierz, S., & Moller, H. J. (2000). A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiology of Aging, 21, 455–462. doi:10.1016/S0197-4580(00)00112-3.

    PubMed  CAS  Google Scholar 

  110. Mohmmad Abdul, H., Sultana, R., Keller, J. N., St Clair, D. K., Markesbery, W. R., & Butterfield, D. A. (2006). Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1–42), HO and kainic acid: Implications for Alzheimer’s disease. Journal of Neurochemistry, 96, 1322–1335. doi:10.1111/j.1471-4159.2005.03647.x.

    PubMed  Google Scholar 

  111. Moreira, P. I., Santos, M. S., Seica, R., & Oliveira, C. R. (2007). Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes. Journal of the Neurological Sciences, 257, 206–214. doi:10.1016/j.jns.2007.01.017.

    Google Scholar 

  112. Murphy, M. P., Echtay, K. S., Blaikie, F. H., et al. (2003). Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation: Studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tert-butylnitrone. Journal of Biological Chemistry, 278, 48534–48545. doi:10.1074/jbc.M308529200.

    PubMed  CAS  Google Scholar 

  113. Murphy, M. P., & Smith, R. A. (2007). Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annual Review of Pharmacology and Toxicology, 47, 629–656. doi:10.1146/annurev.pharmtox.47.120505.105110.

    PubMed  CAS  Google Scholar 

  114. Nichols, W. C., Pankratz, N., Hernandez, D., Paisan-Ruiz, C., et al. (2005). Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet, 365, 410–412.

    PubMed  CAS  Google Scholar 

  115. Nunomura, A., Castellani, R. J., Zhu, X., Moreira, P. I., Perry, G., & Smith, M. A. (2006). Involvement of oxidative stress in Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 65, 631–641. doi:10.1097/01.jnen.0000228136.58062.bf.

    PubMed  CAS  Google Scholar 

  116. Orr, A. L., Li, S., Wang, C. E., Wang, J., Rong, J., Xu, X., et al. (2008). N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. Journal of Neuroscience, 28, 2783–2792. doi:10.1523/JNEUROSCI.0106-08.2008.

    PubMed  CAS  Google Scholar 

  117. Ozawa, T., Tanaka, M., Ikebe, S., Ohno, K., Kondo, T., & Mizuno, Y. (1990). Quantitative determination of deleted mitochondrial DNA relative to normal DNA in parkinsonian striatum by a kinetic PCR analysis. Biochemical and Biophysical Research Communications, 172, 483–489. doi:10.1016/0006-291X(90)90698-M.

    PubMed  CAS  Google Scholar 

  118. Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron, 44, 595–600. doi:10.1016/j.neuron.2004.10.023.

    PubMed  CAS  Google Scholar 

  119. Panov, A. V., Gutekunst, C. A., Leavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., et al. (2002). Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nature Neuroscience, 5, 731–736.

    PubMed  CAS  Google Scholar 

  120. Panov, A. V., Lund, S., & Greenamyre, J. T. (2005). Ca2 + -induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington’s disease individuals. Molecular and Cellular Biochemistry, 269, 143–152. doi:10.1007/s11010-005-3454-9.

    PubMed  CAS  Google Scholar 

  121. Parker, J. A., Arango, M., Abderrahmane, S., Lambert, E., Tourette, C., Catoire, H., et al. (2005). Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nature Genetics, 37, 349–350. doi:10.1038/ng1534.

    PubMed  CAS  Google Scholar 

  122. Parker, W. D., Jr., Boyson, S. J., & Parks, J. K. (1989). Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Annals of Neurology, 26, 719–723. doi:10.1002/ana.410260606.

    PubMed  Google Scholar 

  123. Parker, W. D., Jr., Filley, C. M., & Parks, J. K. (1990). Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology, 40, 1302–1303.

    PubMed  Google Scholar 

  124. Patel, N. V., Gordon, M. N., Connor, K. E., Good, R. A., Engelmann, R. W., Mason, J., Morgan, D. G., Morgan, T. E., & Finch, C. E. (2005). Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiology of Aging, 26, 995–1000.

    PubMed  CAS  Google Scholar 

  125. Perez, M. K., Paulson, H. L., Pendse, S. J., Saionz, S. J., Bonini, N. M., & Pittman, R. N. (1998). Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. Journal of Cell Biology, 143, 1457–1470. doi:10.1083/jcb.143.6.1457.

    PubMed  CAS  Google Scholar 

  126. Perry, G., Roder, H., Nunomura, A., et al. (1999). Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. NeuroReport, 10, 2411–4215.

    PubMed  CAS  Google Scholar 

  127. Petri, S., Kiaei, M., Damiano, M., Hiller, A., Wille, E., Manfredi, G., Calingasan, N. Y., Szeto, H. H., & Beal, M. F. (2006). Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis. Journal of Neurochemistry, 98, 1141–1148.

    Google Scholar 

  128. Pocernich, C. B., Cardin, A. L., Racine, C. L., Lauderback, C. M., & Butterfield, D. A. (2001). Glutathione elevation and its protective role in acrolein-induced protein damage in synaptosomal membranes: Relevance to brain lipid peroxidation in neurodegenerative disease. Neurochemistry International, 39, 141–149. doi:10.1016/S0197-0186(01)00012-2.

    PubMed  CAS  Google Scholar 

  129. Polymeropoulos, M. H., Lavedan, C., Leroy, E., et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276, 2045–2047. doi:10.1126/science.276.5321.2045.

    PubMed  CAS  Google Scholar 

  130. Qin, W., Chachich, M., Lane, M., et al. (2006a). Calorie restriction attenuates Alzheimer’s disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). Journal of Alzheimer’s Disease, 10, 417–422.

    PubMed  CAS  Google Scholar 

  131. Qin, W., Yang, T., Ho, L., et al. (2006b). Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. Journal of Biological Chemistry, 281, 21745–21754. doi:10.1074/jbc.M602909200.

    PubMed  CAS  Google Scholar 

  132. Rabol, R., Boushel, R., & Dela, F. (2006). Mitochondrial oxidative function and type 2 diabetes. Applied Physiology, Nutrition, and Metabolism, 31, 675–683. doi:10.1139/H06-071.

    PubMed  Google Scholar 

  133. Ran, Q., Liang, H., Gu, M., Qi, W., Walter, C. A., Roberts, L. J., et al. (2004). Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis. Journal of Biological Chemistry, 279, 55137–55146. doi:10.1074/jbc.M410387200.

    PubMed  CAS  Google Scholar 

  134. Reddy, P. H. (2006a). Amyloid precursor protein-mediated free radicals and oxidative damage: Implications for the development and progression of Alzheimer’s disease. Journal of Neurochemistry, 96, 1–13. doi:10.1111/j.1471-4159.2005.03530.x.

    PubMed  CAS  Google Scholar 

  135. Reddy, P. H. (2006b). Mitochondrial oxidative damage in aging and Alzheimer’s disease: Implications for mitochondrially targeted antioxidant therapeutics. Journal of Biomedicine & Biotechnology, 31372, 13.

    Google Scholar 

  136. Reddy, P. H. (2007). Mitochondrial dysfunction in aging and Alzheimer’s disease: Strategies to protect neurons. Antioxidants Redox Signaling, 9, 1647–1658. doi:10.1089/ars.2007.1754.

    PubMed  CAS  Google Scholar 

  137. Reddy, P. H., & Beal, M. F. (2005). Are mitochondria critical in the pathogenesis of Alzheimer’s disease? Brain Research. Brain Research Reviews, 49, 618–632. doi:10.1016/j.brainresrev.2005.03.004.

    PubMed  CAS  Google Scholar 

  138. Reddy, P. H., & Beal, M. F. (2008). Amyloid beta, mitochondrial dysfunction, and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease. Trends in Molecular Medicine, 14, 45–53. doi:10.1016/j.molmed.2007.12.002.

    PubMed  CAS  Google Scholar 

  139. Reddy, P. H., & McWeeney, S. (2006). Mapping cellular transcriptosomes in autopsied Alzheimer’s disease subjects and relevant animal models. Neurobiology of Aging, 27, 1060–1077. doi:10.1016/j.neurobiolaging.2005.04.014.

    PubMed  CAS  Google Scholar 

  140. Reddy, P. H., McWeeney, S., Park, B. S., Manczak, M., Gutala, R. V., Partovi, D., et al. (2004). Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: Up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer’s disease. Human Molecular Genetics, 13, 1225–1240. doi:10.1093/hmg/ddh140.

    PubMed  CAS  Google Scholar 

  141. Reddy, P. H., & Tagle, D. A. (1999). Biology of trinucleotide repeat disorders. In P. M. Mattson (Ed.) (Vol. 3). Genetic aberrancies and neurodegenerative disorders. Advances in cell aging and gerontology. Stanford, Connecticut: Jai press Inc.

  142. Reddy, P. H., Williams, M., Charles, V., Garrett, L., Pike-Bucanan, L., Whetsell, W. O. Jr., Miller, G., & Tagle, D. A. (1998). Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nature Genetics, 20, 198–202.

    Google Scholar 

  143. Reddy, P. H., Williams, M., & Tagle, D. A. (1999). Recent advances in understanding the pathogenesis of Huntington’s disease. Trends in Neurosciences, 22, 248–255. doi:10.1016/S0166-2236(99)01415-0.

    PubMed  CAS  Google Scholar 

  144. Richter, C., Park, J. W., & Ames, B. N. (1988). Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proceedings of the National Academy of Sciences of the United States of America, 85, 6465–6467. doi:10.1073/pnas.85.17.6465.

    PubMed  CAS  Google Scholar 

  145. Rogaeva, E., Meng, Y., Lee, J. H., et al. (2007). The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genetics, 39, 168–177. doi:10.1038/ng1943.

    PubMed  CAS  Google Scholar 

  146. Rolo, A. P., & Palmeira, C. M. (2006). Diabetes and mitochondrial function: Role of hyperglycemia and oxidative stress. Toxicology and Applied Pharmacology, 212, 167–178. doi:10.1016/j.taap.2006.01.003.

    PubMed  CAS  Google Scholar 

  147. Saunders, A. M., Strittmatter, W. J., Schmechel, D., George-Hyslop, H. P., Perricak-Vance, M. A., Joo, S. H., et al. (1993). Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology, 43, 1467–1472.

    PubMed  CAS  Google Scholar 

  148. Sasaki, S., Warita, H., Murakami, T., Abe, K., & Iwata, M. (2004). Ultrastructural study of mitochondria in the spinal cord of transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathologica, 107, 461–474.

    Google Scholar 

  149. Sayer, J. A., Manczak, M., Akileswaran, L., Reddy, P. H., & Coghlan, V. M. (2005). Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin: Implications for nuclear toxicity in Huntington’s disease pathogenesis. Neuromolecular Medicine, 7, 297–310. doi:10.1385/NMM:7:4:297.

    PubMed  CAS  Google Scholar 

  150. Schapira, A. H. (2006). Mitochondrial disease. Lancet, 368, 70–82. doi:10.1016/S0140-6736(06)68970-8.

    PubMed  CAS  Google Scholar 

  151. Schapira, A. H., Cooper, J. M., Dexter, D., Clark, J. B., Jenner, P., & Marsden, C. D. (1990). Mitochondrial complex I deficiency in Parkinson’s disease. Journal of Neurochemistry, 54, 823–827. doi:10.1111/j.1471-4159.1990.tb02325.x.

    PubMed  CAS  Google Scholar 

  152. Schilling, G., Becher, M. W., Sharp, A. H., et al. (1999). Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Human Molecular Genetics, 8, 397–407. doi:10.1093/hmg/8.3.397.

    PubMed  CAS  Google Scholar 

  153. Schmidt, C., Lepsverdize, E., Chi, S. L., Das, A. M., Pizzo, S. V., Dityatev, A., & Schachner, M. (2007). Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Molecular Psychiatry [Epub ahead of print].

  154. Schriner, S. E., Linford, N. J., Martin, G. M., et al. (2005). Extension of murine lifespan by overexpression of catalase targeted to mitochondria. Science, 308, 1909–1911. doi:10.1126/science.1106653.

    PubMed  CAS  Google Scholar 

  155. Schultz, D., & Harrison, D. G. (2000). Quest for fire: Seeking the source of pathogenic oxygen radicals in atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 1412–1423.

    PubMed  CAS  Google Scholar 

  156. Selkoe, D. J. (2001). Alzheimer’s disease: Genes, proteins, and therapy. Physiological Reviews, 81, 741–766.

    PubMed  CAS  Google Scholar 

  157. Seong, I. S., Ivanova, E., Lee, J. M., et al. (2005). HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Human Molecular Genetics, 14, 2871–2880.

    Google Scholar 

  158. Sheu, S. S., Nauduri, D., & Anders, M. W. (2006). Targeting antioxidants to mitochondria: A new therapeutic direction. Biochimica et Biophysica Acta, 1762, 256–265.

    PubMed  CAS  Google Scholar 

  159. Shimohata, T., Nakajima, T., Yamada, M., et al. (2000). Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nature Genetics, 26, 29–36. doi:10.1038/79139.

    PubMed  CAS  Google Scholar 

  160. Shirane, M., & Nakayama, K. I. (2003). Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nature Cell Biology, 5, 28–37. doi:10.1038/ncb894.

    PubMed  CAS  Google Scholar 

  161. Sian, J., Dexter, D. T., Lees, A. J., Daniel, S., Agid, Y., Javoy-Agid, F., et al. (1994). Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Annals of Neurology, 36, 348–355. doi:10.1002/ana.410360305.

    PubMed  CAS  Google Scholar 

  162. Siler-Marsiglio, K. I., Pan, Q., Paiva, M., Madorsky, I., Kurana, N. C., & Heato, M. B. (2005). Mitochondrially targeted vitamin E and vitamin E mitigate ethanol-mediated effects on cerebellar granule cell antioxidant defense systems. Brain Research, 1052, 202–211.

    PubMed  CAS  Google Scholar 

  163. Simon, D. K., Pulst, S. M., Sutton, J. P., Browne, S. E., Beal, M. F., & John, D. R. (1999). Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology, 53, 1787–1793.

    PubMed  CAS  Google Scholar 

  164. Simmons, R. A. (2006). Developmental origins of diabetes: The role of oxidative stress. Free Radical Biology and Medicine, 40, 917–922. doi:10.1016/j.freeradbiomed.2005.12.018.

    PubMed  CAS  Google Scholar 

  165. Smith, M. A., Hirai, K., Hsiao, K., Pappolla, M. A., Harris, P. L., Siedlak, S. L., et al. (1998). Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. Journal of Neurochemistry, 70, 2212–2215.

    PubMed  CAS  Google Scholar 

  166. Smith, M. A., Perry, G., Richey, P. L., Sayre, L. M., Anderson, V. E., Beal, M. F., et al. (1996). Oxidative damage in Alzheimer’s. Nature, 382, 120–121. doi:10.1038/382120b0.

    PubMed  CAS  Google Scholar 

  167. Smith, R. A., Porteous, C. M., Coulter, C. V., & Murphy, M. P. (1999). Selective targeting of an antioxidant to mitochondria. European Journal of Biochemistry, 263, 709–716.

    PubMed  CAS  Google Scholar 

  168. Stamer, K., Vogel, R., Thies, E., Mandelkow, E., & Mandelkow, E. M. (2002). Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons & enhances oxidative stress. Journal of Cell Biology, 156, 1051–1063. doi:10.1083/jcb.200108057.

    PubMed  CAS  Google Scholar 

  169. St-Pierre, J., Drori, S., Uldry, M., et al. (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127, 397–408. doi:10.1016/j.cell.2006.09.024.

    PubMed  CAS  Google Scholar 

  170. Strauss, K. M., Martins, L. M., Plun-Favreau, H., et al. (2005). Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Human Molecular Genetics, 14, 2099–2111. doi:10.1093/hmg/ddi215.

    PubMed  CAS  Google Scholar 

  171. Sultana, R., Perluigi, M., & Butterfield, D. A. (2006). Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer’s disease: Insights into mechanism of neurodegeneration from redox proteomics. Antioxidants Redox Signaling, 8, 2021–2037. doi:10.1089/ars.2006.8.2021.

    PubMed  CAS  Google Scholar 

  172. Swerdlow, R. H. (2007a). Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies. Journal of Neuroscience Research, 85, 3416–3428. doi:10.1002/jnr.21167.

    PubMed  CAS  Google Scholar 

  173. Swerdlow, R. H. (2007b). Treating neurodegeneration by modifying mitochondria: Potential solutions to a complex problem. Antioxidants Redox Signaling, 9, 1591–1603. doi:10.1089/ars.2007.1676.

    PubMed  CAS  Google Scholar 

  174. Swerdlow, R. H., & Khan, S. M. (2004). A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Medical Hypotheses, 63, 8–20. doi:10.1016/j.mehy.2003.12.045.

    PubMed  CAS  Google Scholar 

  175. Swerdlow, R. H., Parks, J. K., Cassarino, D. S., Maguire, D. J., Maguire, R. S., Bennett, J. P., Jr., et al. (1997). Cybrids in Alzheimer’s disease: A cellular model of the disease? Neurology, 49, 918–925.

  176. Szeto, H. H. (2006a). Mitochondria-targeted peptide antioxidants: Novel neuroprotective agents. AAPS Journal, 8, E521–E531. doi:10.1208/aapsj080362.

    PubMed  CAS  Google Scholar 

  177. Szeto, H. H. (2006b). Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS Journal, 8, E277–E283.

    PubMed  CAS  Google Scholar 

  178. Szeto, H. H. (2008). Mitochondria-Targeted Cytoprotective Peptides for Ischemia-Reperfusion Injury. Antioxidants Redox Signaling, 10, 601–620. doi: 10.1089/ars.2007.1892.

    PubMed  CAS  Google Scholar 

  179. Szeto, H. H., Lovelace, J. L., Fridland, G., Soong, Y., Fasolo, J., Wu, D., et al. (2001). In vivo pharmacokinetics of selective mu-opioid peptide agonists. Journal of Pharmacology and Experimental Therapeutics, 298, 57–61.

    PubMed  CAS  Google Scholar 

  180. Szeto, H. H., Schiller, P. W., Zhao, K., & Luo, G. (2005). Fluorescent dyes alter intracellular targeting and function of cell-penetrating tetrapeptides. FASEB Journal, 19, 118–120.

    PubMed  CAS  Google Scholar 

  181. Tabrizin, S. J., Cleeter, M. W., Xuereb, J., Taanman, J. W., Cooper, J. M., & Schapira, A. H. (1999). Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Annals of Neurology, 45, 25–32. doi:10.1002/1531–8249(199901)45:1<25::AID-ART6>3.0.CO;2-E

    Google Scholar 

  182. Taira, T., Saito, Y., Niki, T., Iguchi-Ariga, S. M., Takahashi, K., & Ariga, H. (2004). DJ–1 has a role in antioxidative stress to prevent cell death. EMBO Reports, 5, 213–218. doi:10.1038/sj.embor.7400074.

    PubMed  CAS  Google Scholar 

  183. Takuma, K., Yao, J., Huang, J., Xu, H., Chen, X., Luddy, J., et al. (2005). ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB Journal, 19, 597–598.

    PubMed  CAS  Google Scholar 

  184. Tamagno, E., Gugglielmotto, M., Argno, M., Borghi, R., Autelli, R., Giliberto, L., et al. (2008). Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. Journal of Neurochemistry, 104, 683–695.

    PubMed  CAS  Google Scholar 

  185. Thies, E., & Mandelkow, E. M. (2007). Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. Journal of Neuroscience, 27, 2896–2907. doi:10.1523/JNEUROSCI.4674-06.2007.

    PubMed  CAS  Google Scholar 

  186. Thomas, B & Beal, M. F. (2007). Parkinson’s disease. Human molecular genetics, 16(Spec No. 2), R183–R194.

  187. Thomas, D. A., Stauffer, C., Zhao, K., Yang, H., Sharma, V. K., Szeto, H. H., et al. (2007). Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function. Journal of the American Society of Nephrology, 18, 213–222. doi:10.1681/ASN.2006080825.

    PubMed  CAS  Google Scholar 

  188. Tissenbaum, H. A., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410, 227–230. doi:10.1038/35065638.

    PubMed  CAS  Google Scholar 

  189. Trifunovic, A., Wredenberg, A., Falkenberg, M., et al. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 429, 417–423. doi:10.1038/nature02517.

    PubMed  CAS  Google Scholar 

  190. Trimmer, P. A., Swerdlow, R. H., Park, J. K., Keeney, P., Bennet, J. P., Miller, S. W., et al. (2004). Abnormal mitochondrial morphology in sporadic Parkinson’s and Alzheimer’s disease cybrid cell lines. Experimental Neurology, 162, 37–50. doi:10.1006/exnr.2000.7333.

    Google Scholar 

  191. Trushina, E., Dyer, R. B., Badger, J. D., & 2nd., (2004). Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Molecular and Cellular Biology, 24, 8195–8209. doi:10.1128/MCB.24.18.8195-8209.2004.

  192. Trushina, E., & McMurray, C. T. (2007). Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience, 145, 1233–1248. doi:10.1016/j.neuroscience.2006.10.056.

    PubMed  CAS  Google Scholar 

  193. Valente, E. M., Abou-Sleiman, P. M., Caputo, V., et al. (2004). Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science, 304, 1158–1160. doi:10.1126/science.1096284.

    PubMed  CAS  Google Scholar 

  194. Van Blerkom, J. (2008). Mitochondria as regulatory forces in oocytes, preimplantation embryos and stem cells. Reproductive Biomedicine Online, 16, 553–569.

    PubMed  Article  Google Scholar 

  195. Van Raamsdonk, J. M., Warby, S. C., & Hayden, M. R. (2007). Selective degeneration in YAC mouse models of Huntington disease. Brain Research Bulletin, 72, 124–31. doi:10.1016/j.brainresbull.2006.10.018.

    PubMed  Google Scholar 

  196. Van Remmen, H., Qi, W., Sabia, M., Freeman, G., Estlack, L., Yang, H., et al. (2004). Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radical Biology and Medicine, 36, 1625–1634. doi:10.1016/j.freeradbiomed.2004.03.016.

    PubMed  Google Scholar 

  197. Vijayvergiya, C., Beal, M. F., Buck, J., & Manfredi, G. (2005). Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. Journal of Neuroscience, 25, 2463–2470. doi:10.1523/JNEUROSCI.4385-04.2005.

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  199. Vonsattel, J. P., Myers, R. H., Stevens, T. J., Ferrante, R. J., Bird, E. D., & Richardson, E. P., Jr. (1985). Neuropathological classification of Huntington’s disease. Journal of Neuropathology and Experimental Neurology, 44, 559–577. doi:10.1097/00005072-198511000-00003.

    PubMed  CAS  Google Scholar 

  200. Wallace, D. C. (1999). Mitochondrial diseases in man and mouse. Science, 283, 1482–1448. doi:10.1126/science.283.5407.1482.

    PubMed  CAS  Google Scholar 

  201. Wallace, D. C. (2005a). A mitochondrial paradigm of metabolic & degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annual Review of Genetics, 39, 359–407. doi:10.1146/annurev.genet.39.110304.095751.

    PubMed  CAS  Google Scholar 

  202. Wallace, D. C. (2005b). The mitochondrial genome in human adaptive radiation and disease: On the road to therapeutics and performance enhancement. Gene, 354, 169–180. doi:10.1016/j.gene.2005.05.001.

    PubMed  CAS  Google Scholar 

  203. Wang, J., Ho, L., Qin, W., et al. (2005a). Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB Journal, 19, 659–661. doi:10.1096/fj.04-2370com.

    PubMed  Google Scholar 

  204. Wang, H. Q., Nakaya, Y., Du, Z., et al. (2005b). Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2. Human Molecular Genetics, 14, 1889–1902. doi:10.1093/hmg/ddi195.

    PubMed  CAS  Google Scholar 

  205. Watanabe, M., Dykes-Hoberg, M., Culotta, V. C., Price, D. L., Wong, P. C., & Rothstein, J. D. (2001). Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiology of Disease, 8, 933–941. doi:10.1006/nbdi.2001.0443.

    PubMed  CAS  Google Scholar 

  206. West, A. B., Morre, D. J., Biskup, S., Bugayenko, A., Smith, W·W., Ross, C. A., Dawson, V. L., Dawson, T. M. (2005). Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proceedings of the National Academy of Sciences of the United States of America, 102, 16842–1687.

  207. Weydt, P., Pineda, V. V., Torrence, A. E., et al. (2006). Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metabolism, 4, 349–362. doi:10.1016/j.cmet.2006.10.004.

    PubMed  CAS  Google Scholar 

  208. Wilson, R. B. (2006). Iron dysregulation in Friedreich ataxia. Seminars in Pediatric Neurology, 3, 166–175. doi:10.1016/j.spen.2006.08.005.

    Google Scholar 

  209. Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., et al. (1995). An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron, 14, 1105–1116. doi:10.1016/0896-6273(95)90259-7.

    PubMed  CAS  Google Scholar 

  210. Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., et al. (2004). Sirtuin Ctivators mimic caloric restriction and delay ageing in metazoans. Nature, 430, 686–689. doi:10.1038/nature02789.

    PubMed  CAS  Google Scholar 

  211. Yoon, Y. S., Yoon, D. S., Lim, I. K., et al. (2006). Formation of elongated giant mitochondria in DFO-induced cellular senescence: Involvement of enhanced fusion process through modulation of Fis1. Journal of Cellular Physiology, 209, 468–480. doi:10.1002/jcp. 20753.

    PubMed  CAS  Google Scholar 

  212. Zhang, L., Shimoji, M., Thomas, B., Moore, D. J., Yu, S. W., Marupudi, N. I., Torp, R., Torgner, I. A., Ottersen, O. P., Dawso, T. M., & Dawson, V. L. (2005). Mitochondrial localization of the Parkinson's disease related protein DJ-1: Implications for pathogenesis. Human Molecular Genetics, 14, 2063–2073.

  213. Zhao, K., Luo, G., Zhao, G. M., Schiller, P. W., & Szeto, H. H. (2003). Transcellular transport of a highly polar 3 + net charge opioid tetrapeptide. Journal of Pharmacology and Experimental Therapeutics, 304, 425–432. doi:10.1124/jpet.102.040147.

    PubMed  CAS  Google Scholar 

  214. Zhao, G. M., Wu, D., Soong, Y., Shimoyama, M., Berezowska, I., Schiller, P. W., et al. (2002). Profound spinal tolerance after repeated exposure to a highly selective mu-opioid peptide agonist: Role of delta-opioid receptors. Journal of Pharmacology and Experimental Therapeutics, 302, 188–196. doi:10.1124/jpet.302.1.188.

    PubMed  CAS  Google Scholar 

  215. Zhao, K., Zhao, G. M., Wu, D., Soong, Y., Birk, A. V., Schiller, P. W., et al. (2004). Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. Journal of Biological Chemistry, 279, 34682–34690. doi:10.1074/jbc.M402999200.

    PubMed  CAS  Google Scholar 

  216. Zimprich, A., Biskup, S., Leitner, P., et al. (2004). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron, 44, 601–607. doi:10.1016/j.neuron.2004.11.005.

    PubMed  CAS  Google Scholar 

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Acknowledgments

I sincerely thank Drs. Maria Manczak and Wei Zhao (postdoctoral scientists in the lab) for their technical assistance of MitoQ and SS-31 treatments of N2a cells. The research presented in this article was supported by grants from the American Federation for Aging Research, National Institutes of Health (AG028072 and AG026051), and KaloBios Pharmaceuticals, Inc.

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Correspondence to P. Hemachandra Reddy.

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Reddy, P.H. Mitochondrial Medicine for Aging and Neurodegenerative Diseases. Neuromol Med 10, 291–315 (2008). https://doi.org/10.1007/s12017-008-8044-z

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Keywords

  • Amyloid beta
  • Alzheimer's disease
  • Amyotrophic lateral sclerosis
  • Amyloid precursor protein
  • Adenosine triphosphate
  • Caloric restricted
  • Electron transport chain
  • FRDA
  • Freidriech ataxia
  • Hydrogen peroxide
  • Huntington's disease
  • Mitochondrial DNA
  • Peroxisome proliferator activated receptor–coactivator
  • Superoxide radical
  • Oxidative phosphorylation
  • Parkinson's disease
  • Reactive oxygen species
  • SS peptide