Review Article | Published:

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

Nature volume 443, pages 787795 (19 October 2006) | Download Citation

Subjects

Abstract

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Cell death: critical control points. Cell 116, 205–219 (2004).

  2. 2.

    et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992).

  3. 3.

    et al. Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc. Natl Acad. Sci. USA 100, 1116–1121 (2003).

  4. 4.

    et al. Point mutations of the mtDNA control region in normal and neurodegenerative human brains. Am. J. Hum. Genet. 68, 529–532 (2001).

  5. 5.

    et al. Low mutational burden of individual acquired mitochondrial DNA mutations in brain. Genomics 73, 113–116 (2001).

  6. 6.

    , , , & High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum. Mol. Genet. 11, 133–145 (2002).

  7. 7.

    , , , & Human brain contains high levels of heteroplasmy in the noncoding regions of mitochondrial DNA. Proc. Natl Acad. Sci. USA 93, 12382–12387 (1996).

  8. 8.

    et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genet. 38, 515–517 (2006).

  9. 9.

    et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nature Genet. 38, 518–520 (2006).

  10. 10.

    Mitochondrial DNA and ageing. Biochim. Biophys. Acta 1757, 611–617 (2006).

  11. 11.

    , & Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc.) 70, 200–214 (2005).

  12. 12.

    , , & Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics 161, 661–672 (2002).

  13. 13.

    et al. High-quality life extension by the enzyme peptide methionine sulfoxide reductase. Proc. Natl Acad. Sci. USA 99, 2748–2753 (2002).

  14. 14.

    et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

  15. 15.

    et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004).

  16. 16.

    et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767 (2001).

  17. 17.

    , , , & Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183–4187 (2001).

  18. 18.

    et al. 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. Hum. Mol. Genet. 13, 1225–1240 (2004).

  19. 19.

    et al. Selective increase in cellular A β 42 is related to apoptosis but not necrosis. Neuroreport 11, 167–171 (2000).

  20. 20.

    et al. Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron 33, 677–688 (2002).

  21. 21.

    et al. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J. Neurochem. 89, 1308–1312 (2004).

  22. 22.

    , & Energy inhibition elevates β-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer's disease pathogenesis. J. Neurosci. 25, 10874–10883 (2005).

  23. 23.

    et al. β-Site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J. Neurochem. 92, 628–636 (2005).

  24. 24.

    , , , & Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. J. Alzheimers Dis. 6, 659–671 (2004).

  25. 25.

    et al. Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: a redox proteomics analysis. Neurobiol. Aging 27, 918–925 (2006).

  26. 26.

    et al. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production. Nature 440, 528–534 (2006).

  27. 27.

    et al. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424, 556–561 (2003).

  28. 28.

    et al. Cybrids in Alzheimer's disease: a cellular model of the disease? Neurology 49, 918–925 (1997).

  29. 29.

    et al. Does the mitochondrial genome play a role in the etiology of Alzheimer's disease? Hum. Genet. 119, 241–254 (2006).

  30. 30.

    , & Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc. Natl Acad. Sci. USA 101, 10726–10731 (2004).

  31. 31.

    , , & Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J. Cell Biol. 161, 41–54 (2003).

  32. 32.

    et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease. Science 304, 448–452 (2004).

  33. 33.

    et al. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1-42. J. Neurosci. 25, 672–679 (2005).

  34. 34.

    et al. Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15, 1437–1449 (2006).

  35. 35.

    , , , & β-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J. Neurochem. 80, 91–100 (2002).

  36. 36.

    et al. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease. Arch. Neurol. 45, 836–840 (1988).

  37. 37.

    , & Cytochrome oxidase deficiency in Alzheimer's disease. Neurology 40, 1302–1303 (1990).

  38. 38.

    , , , & Alzheimer's disease-associated amyloid β interacts with the human serine protease HtrA2/Omi. Neurosci. Lett. 357, 63–67 (2004).

  39. 39.

    et al. Nicastrin, presenilin, APH-1, and PEN-2 form active γ-secretase complexes in mitochondria. J. Biol. Chem. 279, 51654–51660 (2004).

  40. 40.

    et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci. 3, 1301–1306 (2000).

  41. 41.

    et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin–proteasome system and α-synuclein. Proc. Natl Acad. Sci. USA 102, 3413–3418 (2005).

  42. 42.

    et al. Mechanism of toxicity in rotenone models of Parkinson's disease. J. Neurosci. 23, 10756–10764 (2003).

  43. 43.

    et al. Mitochondrial complex I deficiency in Parkinson's disease. Lancet i, 1269 (1989).

  44. 44.

    et al. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology 53, 1787–1793 (1999).

  45. 45.

    et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364, 875–882 (2004).

  46. 46.

    et al. Sequence analysis of the entire mitochondrial genome in Parkinson's disease. Biochem. Biophys. Res. Commun. 290, 1593–1601 (2002).

  47. 47.

    et al. Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease. Neurobiol. Aging 25, 71–81 (2004).

  48. 48.

    et al. Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD. Ann. Neurol. 57, 564–567 (2005).

  49. 49.

    Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson's disease. J. Neurol. 249 (Suppl. 2), II11–II18 (2002).

  50. 50.

    A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005).

  51. 51.

    , , , & Enhanced substantia nigra mitochondrial pathology in human α-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. 186, 158–172 (2004).

  52. 52.

    et al. Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 26, 41–50 (2006).

  53. 53.

    et al. Mice lacking α-synuclein are resistant to mitochondrial toxins. Neurobiol. Dis. 21, 541–548 (2006).

  54. 54.

    et al. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131, 2183–2194 (2004).

  55. 55.

    et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. 279, 18614–18622 (2004).

  56. 56.

    et al. Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov. Disord. 19, 544–548 (2004).

  57. 57.

    et al. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum. Mol. Genet. 12, 517–526 (2003).

  58. 58.

    et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum. Mol. Genet. 15, 883–895 (2006).

  59. 59.

    et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304, 1328–1331 (2004).

  60. 60.

    et al. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc. Natl Acad. Sci. USA 102, 8024–8029 (2005).

  61. 61.

    et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259 (2003).

  62. 62.

    et al. DJ-1 is present in a large molecular complex in human brain tissue and interacts with α-synuclein. J. Neurochem. 93, 1524–1532 (2005).

  63. 63.

    et al. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum. Mol. Genet. 14, 71–84 (2005).

  64. 64.

    et al. Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum. Mol. Genet. 15, 1816–1825 (2006).

  65. 65.

    et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl Acad. Sci. USA 101, 9103–9108 (2004).

  66. 66.

    et al. Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc. Natl Acad. Sci. USA 102, 13670–13675 (2005).

  67. 67.

    et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263–273 (2005).

  68. 68.

    et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl Acad. Sci. USA 102, 5215–5220 (2005).

  69. 69.

    , , , & Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc. Natl Acad. Sci. USA 103, 12517–12522 (2006).

  70. 70.

    et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

  71. 71.

    et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum. Mol. Genet. 14, 3477–3492 (2005).

  72. 72.

    et al. Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J. Biol. Chem. 280, 34025–34032 (2005).

  73. 73.

    et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc. Natl Acad. Sci. USA 103, 10793–10798 (2006).

  74. 74.

    et al. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl Acad. Sci. USA 102, 16842–16847 (2005).

  75. 75.

    et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum. Mol. Genet. 14, 2099–2111 (2005).

  76. 76.

    et al. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol. Cell. Biol. 24, 9848–9862 (2004).

  77. 77.

    et al. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem. 277, 29626–29633 (2002).

  78. 78.

    et al. Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J. Neurochem. 96, 1349–1361 (2006).

  79. 79.

    & Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J. Neurosci. 18, 3241–3250 (1998).

  80. 80.

    et al. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. (Berl.) 102, 293–305 (2001).

  81. 81.

    , & ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 4, 16 (2003).

  82. 82.

    , , & Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. J. Neurosci. 25, 2463–2470 (2005).

  83. 83.

    et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43, 5–17 (2004).

  84. 84.

    , , , & Mitochondrial localization of mutant superoxide dismutase 1 triggers caspase-dependent cell death in a cellular model of familial amyotrophic lateral sclerosis. J. Biol. Chem. 277, 50966–50972 (2002).

  85. 85.

    & Amyotrophic lateral sclerosis: a proposed mechanism. Proc. Natl Acad. Sci. USA 99, 9010–9014 (2002).

  86. 86.

    et al. Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43, 19–30 (2004).

  87. 87.

    , , & Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology 43, 2689–2695 (1993).

  88. 88.

    et al. Mitochondrial defect in Huntington's disease caudate nucleus. Ann. Neurol. 39, 385–389 (1996).

  89. 89.

    & Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J. Biol. Chem. 280, 30773–30782 (2005).

  90. 90.

    et al. Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc. Natl Acad. Sci. USA 92, 7105–7109 (1995).

  91. 91.

    et al. Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol. Biol. Cell 17, 1652–1663 (2006).

  92. 92.

    et al. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nature Neurosci. 5, 731–736 (2002).

  93. 93.

    , , , & Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum. Mol. Genet. 13, 1407–1420 (2004).

  94. 94.

    & Mechanisms of transcription dysregulation in Huntington's disease. Clin. Neurosci. Res. 3, 165–177 (2003).

  95. 95.

    & Transcriptional abnormalities in Huntington disease. Trends Genet. 19, 233–238 (2003).

  96. 96.

    , , , & PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell 7, 673–682 (2001).

  97. 97.

    et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010–1014 (2004).

  98. 98.

    et al. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron 47, 29–41 (2005).

  99. 99.

    et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice. Cell 119, 121–135 (2004).

  100. 100.

    et al. Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. Exp. Neurol. 175, 87–97 (2002).

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health and the American Federation for Aging Research/Beeson Program. We apologize to our many colleagues whose work we were unable to cite due to space limitations.

Author information

Affiliations

  1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Room F-610, 525 East 68th Street, New York 10021, USA.

    • Michael T. Lin
    •  & M. Flint Beal

Authors

  1. Search for Michael T. Lin in:

  2. Search for M. Flint Beal in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to M. Flint Beal.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nature05292

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing