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Neuropathological Aspects of Mitochondrial DNA Disease

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Abstract

Mitochondrial DNA disorders are an important cause of neurological disease, yet despite our awareness of the importance of these conditions, relatively little is known about the neuropathology of these disorders and even less about the mechanisms involved in neuronal dysfunction and death. In this review we detail important features from neuropathological studies available and highlight deficiencies that are currently limiting our understanding of mitochondrial DNA disease. We also discuss possible future approaches that might resolve some of these outstanding issues. Further study of these disorders is critical because mitochondria play a central role in neuronal survival and it is likely that an understanding of the mechanisms involved in neuronal dysfunction and cell death in mitochondrial DNA disease may have implications for other neurodegenerative diseases.

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References

  1. McFarland, R., Taylor, R. W., and Turnbull, D. M. 2002. The neurology of mitochondrial DNA disease. Lancet Neurol. 1:345–351.

    Google Scholar 

  2. Johnson, M. A., Bindoff, L. A., and Turnbull, D. M. 1993. Cytochrome c oxidase activity in single muscle fibers: Assay techniques and diagnostic applications. Ann. Neurol. 33:28–35.

    PubMed  Google Scholar 

  3. Sciacco, M. and Bonilla, E. 1996. Cytochemistry and immunocytochemistry of mitochondria in tissue sections. Methods Enzymol. 264:509–521.

    PubMed  Google Scholar 

  4. DiMauro, S. and Schon, E. A. 2001. Mitochondrial DNA mutations in human disease Am. J. Med. Genet. 106:18–26.

    PubMed  Google Scholar 

  5. Tanji, K., Kunimatsu, T., Vu, T. H., and Bonilla, E. 2001. Neuropathological features of mitochondrial disorders. Semin. Cell Dev. Biol. 12:429–439.

    PubMed  Google Scholar 

  6. Shapira, Y., Cederbaum, S. D., Cancilla, P. A., Nielsen, D., and Lippe, B. M. 1975. Familial poliodystrophy, mitochondrial myopathy, and lactate acidemia. Neurology 25:614–621.

    PubMed  Google Scholar 

  7. Kuriyama, M., Umezaki, H., Fukuda, Y., Osame, M., Koike, K., Tateishi, J., and Igata, A. 1984. Mitochondrial encephalomyopathy with lactate-pyruvate elevation and brain infarctions. Neurology 34:72–77.

    PubMed  Google Scholar 

  8. Ohama, E., Ohara, S., Ikuta, F., Tanaka, K., Nishizawa, M., and Miyatake, T. 1987. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy Acta Neuropathol. (Berl.) 74:226–233.

    Google Scholar 

  9. Ihara, Y., Namba, R., Kuroda, S., Sato, T., and Shirabe, T. 1989. Mitochondrial encephalomyopathy (MELAS): Pathological study and successful therapy with coenzyme Q10 and idebenone J. Neurol. Sci. 90:263–271.

    PubMed  Google Scholar 

  10. Mizukami, K., Sasaki, M., Suzuki, T., Shiraishi, H., Koizumi, J., Ohkoshi, N., Ogata, T., Mori, N., Ban, S., and Kosaka, K. 1992. Central nervous system changes in mitochondrial encephalomyopathy: Light and electron microscopic study. Acta Neuropathol. (Berl.) 83:449–452.

    Google Scholar 

  11. Tsuchiya, K., Miyazaki, H., Akabane, H., Yamamoto, M., Kondo, H., Mizusawa, H., and Ikeda, K. 1999. MELAS with prominent white matter gliosis and atrophy of the cerebellar granular layer: A clinical, genetic, and pathological study. Acta Neuropathol. (Berl.) 97:520–524.

    Google Scholar 

  12. Mori, O., Yamazaki, M., Ohaki, Y., Arai, Y., Oguro, T., Shimizu, H., and Asano, G. 2000. Mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) with prominent degeneration of the intestinal wall and cactus-like cerebellar pathology. Acta Neuropathol. (Berl.) 100:712–717.

    Google Scholar 

  13. Kishi, M. and Takamori, K. 1988. The presence of cytochromes in oral anaerobic bacteria, especially in Bacteroides oralis. Showa Shigakkai Zasshi 8:203–209.

    PubMed  Google Scholar 

  14. Sparaco, M., Bonilla, E., DiMauro, S., and Powers, J. M. 1993. Neuropathology of mitochondrial encephalomyopathies due to mitochondrial DNA defects. J. Neuropathol. Exp. Neurol. 52:1–10.

    PubMed  Google Scholar 

  15. Tanahashi, C., Nakayama, A., Yoshida, M., Ito, M., Mori, N., and Hashizume, Y. 2000. MELAS with the mitochondrial DNA 3243 point mutation: A neuropathological study. Acta Neuropathol. (Berl.) 99:31–38.

    Google Scholar 

  16. Sue, C. M., Crimmins, D. S., Soo, Y. S., Pamphlett, R., Presgrave, C. M., Kotsimbos, N., Jean-Francois, M. J., Byrne, E., and Morris, J. G. 1998. Neuroradiological features of six kindreds with MELAS tRNA (Leu) A2343G point mutation: Implications for pathogenesis. J. Neurol. Neurosurg. Psychiatry 65:233–240.

    PubMed  Google Scholar 

  17. Hirano, M. and Pavlakis, S. G. 1994. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): Current concepts. J. Child Neurol. 9:4–13.

    PubMed  Google Scholar 

  18. Sparaco, M., Bonilla, E., DiMauro, S., and Powers, J. M. 1993. Neuropathology of mitochondrial encephalomyopathies due to mitochondrial DNA defects. J. Neuropathol. Exp. Neurol. 52:1–10.

    PubMed  Google Scholar 

  19. Silvestri, G., Ciafaloni, E., Santorelli, F. M., Shanske, S., Servidei, S., Graf, W. D., Sumi, M., and DiMauro, S. 1993. Clinical features associated with the A → G transition at nucleotide 8344 of mtDNA (“MERRF mutation”). Neurology 43:1200–1206.

    PubMed  Google Scholar 

  20. Sasaki, H., Kuzuhara, S., Kanazawa, I., Nakanishi, T., and Ogata, T. 1983. Myoclonus, cerebellar disorder, neuropathy, mitochondrial myopathy, and ACTH deficiency. Neurology 33:1288–1293.

    PubMed  Google Scholar 

  21. Takeda, S., Wakabayashi, K., Ohama, E., and Ikuta, F. 1988. Neuropathology of myoclonus epilepsy associated with ragged-red fibers (Fukuhara's disease). Acta Neuropathol. (Berl.) 75:433–440.

    Google Scholar 

  22. Berkovic, S. F., Carpenter, S., Evans, A., Karpati, G., Shoubridge, E. A., Andermann, F., Meyer, E., Tyler, J. L., Diksic, M., Arnold, D., Wolfe, L. S., Andermann, E., and Hakim, A. M. 1989. Myoclonus epilepsy and ragged-red fibres (MERRF): I. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain 112:1231–1260.

    PubMed  Google Scholar 

  23. Fukuhara, N., Tokiguchi, S., Shirakawa, K., and Tsubaki, T. 1980. Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): Disease entity or a syndrome? Light-and electron-microscopic studies of two cases and review of literature. J. Neurol. Sci. 47:117–133.

    PubMed  Google Scholar 

  24. McKelvie, P. A., Morley, J. B., Byrne, E., and Marzuki, S. 1991. Mitochondrial encephalomyopathies: A correlation between neuropathological findings and defects in mitochondrial DNA. J. Neurol. Sci. 102:51–60.

    PubMed  Google Scholar 

  25. Fukuhara, N. 1991. MERRF: A clinicopathological study—Relationships between myoclonus epilepsies and mitochondrial myopathies. Rev. Neurol. (Paris) 147:476–479.

    Google Scholar 

  26. Zeviani, M., Moraes, C. T., DiMauro, S., Nakase, H., Bonilla, E., Schon, E. A., and Rowland, L. P. 1988. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339–1346.

    PubMed  Google Scholar 

  27. Adornato, B. and Lampert, P. 1971. Status spongiosus of nervous tissue: Electron microscopic studies. Acta Neuropathol. (Berl.) 19:271–289.

    Google Scholar 

  28. Oldfors, A., Fyhr, I. M., Holme, E., Larsson, N. G., and Tulinius, M. 1990. Neuropathology in Kearns-Sayre syndrome. Acta Neuropathol. (Berl.) 80:541–546.

    Google Scholar 

  29. Tanji, K., DiMauro, S., and Bonilla, E. 1999. Disconnection of cerebellar Purkinje cells in Kearns-Sayre syndrome. J. Neurol. Sci. 166:64–70.

    PubMed  Google Scholar 

  30. Tanji, K., Vu, T. H., Schon, E. A., DiMauro, S., and Bonilla, E. 1999. Kearns-Sayre syndrome: Unusual pattern of expression of subunits of the respiratory chain in the cerebellar system. Ann. Neurol. 45:377–383.

    PubMed  Google Scholar 

  31. Cottrell, D. A., Ince, P. G., Blakely, E. L., Johnson, M. A., Chinnery, P. F., Hanna, M., and Turnbull, D. M. 2000. Neuropathological and histochemical changes in a multiple mitochondrial DNA deletion disorder. J. Neuropathol. Exp. Neurol. 59:621–627.

    PubMed  Google Scholar 

  32. Leigh, D. 1951. Subacute necrotizing encephalomyelopathy in an infant. J. Neurol. Neurosurg. Psychiatry 14:216–221.

    Google Scholar 

  33. Rahman, S., Blok, R. B., Dahl, H. H., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., and Thorburn, D. R. 1996. Leigh syndrome: Clinical features and biochemical and DNA abnormalities. Ann. Neurol. 39:343–351.

    PubMed  Google Scholar 

  34. Hasegawa, H., Matsuoka, T., Goto, Y., and Nonaka, I. 1991. Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Ann. Neurol. 29:601–605.

    PubMed  Google Scholar 

  35. Goto, Y., Horai, S., Matsuoka, T., Koga, Y., Nihei, K., Kobayashi, M., and Nonaka, I. 1992. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): A correlative study of the clinical features and mitochondrial DNA mutation. Neurology 42:545–550.

    PubMed  Google Scholar 

  36. Goto, Y. 1995. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve 3:S107–S112.

    PubMed  Google Scholar 

  37. Clark, J. M., Marks, M. P., Adalsteinsson, E., Spielman, D. M., Shuster, D., Horoupian, D., and Albers, G. W. 1996. MELAS: Clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy. Neurology 46:223–227.

    PubMed  Google Scholar 

  38. Sakuta, R. and Nonaka, I. 1989. Vascular involvement in mitochondrial myopathy. Ann. Neurol. 25:594–601.

    PubMed  Google Scholar 

  39. Gilchrist, J. M., Sikirica, M., Stopa, E., and Shanske, S. 1996. Adult-onset MELAS: Evidence for involvement of neurons as well as cerebral vasculature in strokelike episodes. Stroke 27:1420–1423.

    PubMed  Google Scholar 

  40. Tokunaga, M., Mita, S., Sakuta, R., Nonaka, I., and Araki, S. 1993. Increased mitochondrial DNA in blood vessels and ragged-red fibers in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Ann. Neurol. 33:275–280.

    PubMed  Google Scholar 

  41. Love, S. and Hilton, D. A. 1996. Assessment of the distribution of mitochondrial ribosomal RNA in melas and in thrombotic cerebral infarcts by in situ hybridization. J. Pathol. 178:182–189.

    PubMed  Google Scholar 

  42. Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roc, B. A., Sanger, F., Schreier, P. H., Smith, A. J., Staden, R., and Young, I. G. 1981. Sequence and organization of the human mitochondrial genome. Nature 290:457–465.

    PubMed  Google Scholar 

  43. Lightowlers, R. N., Chinnery, P. F., Turnbull, D. M., and Howell, N. 1997. Mammalian mitochondrial genetics: Heredity, heteroplasmy and disease. Trends Genetics 13:450–455.

    Google Scholar 

  44. Chinnery, P., Howell, N., Lightowlers, R., and Turnbull, D. 1997. Molecular pathology of MELAS and MERRF: The relationship between mutation load and clinical phenotype. Brain 120:1713–1721.

    PubMed  Google Scholar 

  45. Weber, K., Wilson, J. N., Taylor, L., Brierley, E., Johnson, M. A., Turnbull, D. M., and Bindoff, L. A. 1997. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am. J. Hum. Genet. 60:373–380.

    PubMed  Google Scholar 

  46. Chinnery, P. F., Samuels, D. C., Elson, J., and Turnbull, D. M. 2002. Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: Is there a common mechanism? Lancet 360:1323–1325.

    PubMed  Google Scholar 

  47. Chinnery, P. F. and Samuels, D. C. 1999. Relaxed replication of mtDNA: A model with implications for the expression of disease. Am. J. Hum. Genet. 64:1158–1165.

    PubMed  Google Scholar 

  48. Zhou, L., Chomyn, A., Attardi, G., and Miller, C. A. 1997. Myoclonic epilepsy and ragged red fibers (MERRF) syndrome: Selective vulnerability of CNS neurons does not correlate with the level of mitochondrial tRNAlys mutation in individual neuronal isolates. J. Neurosci. 17:7746–7753.

    PubMed  Google Scholar 

  49. Tanji, K., Schon, E. A., DiMauro, S., and Bonilla, E. 2000. Kearns-sayre syndrome: Oncocytic transformation of choroid plexus epithelium. J. Neurol. Sci. 178:29–36.

    PubMed  Google Scholar 

  50. Ohama, E. and Ikuta, F. 1987. Involvement of choroid plexus in mitochondrial encephalomyopathy (MELAS). Acta Neuropathol. (Berl.) 75:1–7.

    Google Scholar 

  51. Kepes, J. J. 1983. Oncocytic transformation of choroid plexus epithelium. Acta Neuropathol. (Berl.) 62:145–148.

    Google Scholar 

  52. Ohama, E., Ikuta, F., and Nakamura, N. 1988. Mitochondrial abnormalities in choroid plexus of Leigh disease. Brain Dev. 10:30–35.

    PubMed  Google Scholar 

  53. Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J. D., and Nikoskelainen, E. K. 1988. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427–1430.

    PubMed  Google Scholar 

  54. Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Oztas, S., Qui, W.-Q., Arnos, K. S., Cortopassi, G. A., Jabier, L., Rotter, J. I., Shohat, M., and Fischel-Ghodsian, N. 1993. Mitochondrial ribosomal RNA mutations associated with both antibiotic-induced and non-sydromic deafness. Nat. Genet. 4:289–294.

    PubMed  Google Scholar 

  55. Taylor, R. W., Giordano, C., Davidson, M. M., d'Amati, G., Bain, H., Hayes, C. M., Leonard, H., Barron, M. J., Casali, C., Santorelli, F. M., Hirano, M., Lightowlers, R. N., DiMauro, S., and Turnbull, D. M. 2003. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 41:1786–1796.

    PubMed  Google Scholar 

  56. Lynn, S., Borthwick, G. M., Charnley, R. M., Walker, M., and Turnbull, D. M. 2003. Heteroplasmic ratio of the A3243G mitochondrial DNA mutation in single pancreatic beta cells. Diabetologia 46:296–299.

    PubMed  Google Scholar 

  57. Sorensen, L., Ekstrand, M., Silva, J. P., Lindqvist, E., Xu, B., Rustin, P., Olson, L., and Larsson, N. G. 2001. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J. Neurosci. 21:8082–8090.

    PubMed  Google Scholar 

  58. Nakada, K., Inoue, K., and Hayashi, J. I. 2001. Mito-mice: Animal models for mitochondrial DNA-based diseases. Semin. Cell Dev. Biol. 12:459–465.

    PubMed  Google Scholar 

  59. Inoue, K., Nakada, K., Ogura, A., Isobe, K., Gota, Y.-I., Nonaka, I., and Hayashi, J.-I. 2000. Generation of mice with mitochondrial dysfunction by intriducing mouse mtDNA carrying a deletion into zygotes. Nat. Genet. 26:176–181.

    PubMed  Google Scholar 

  60. Larsson, N. G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., and Clayton, D. A. 1998. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18:231–236.

    PubMed  Google Scholar 

  61. Sciacco, M., Gasparo-Rippa, P., Vu, T. H., Tanji, K., Shanske, S., Mendell, J. R., Schon, E. A., DiMauro, S., and Bonilla, E. 1998. Study of mitochondrial DNA depletion in muscle by single-fiber polymerase chain reaction. Muscle Nerve 21:1374–1381.

    PubMed  Google Scholar 

  62. Sorensen, L., Ekstrand, M., Silva, J. P., Lindqvist, E., Xu, B., Rustin, P., Olson, L., and Larsson, N. G. 2001. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J. Neurosci. 21:8082–8090.

    PubMed  Google Scholar 

  63. Nicholls, D. G. and Budd, S. L. 2000. Mitochondria and neuronal survival. Physiol. Rev. 80:315–360.

    PubMed  Google Scholar 

  64. Schon, E. A. and Manfredi, G. 2003. Neuronal degeneration and mitochondrial dysfunction. J. Clin. Invest. 111:303–312.

    PubMed  Google Scholar 

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  1. Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, United Kingdom

    Joanne Betts, Robert N. Lightowlers & Douglass M. Turnbull

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Betts, J., Lightowlers, R.N. & Turnbull, D.M. Neuropathological Aspects of Mitochondrial DNA Disease. Neurochem Res 29, 505–511 (2004). https://doi.org/10.1023/B:NERE.0000014821.07269.8d

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