Mitochondrial DNA Mutations in Disease, Aging, and Neurodegeneration
Amy K. Reeve
Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorKim J. Krishnan
Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorDoug Turnbull
Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorAmy K. Reeve
Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorKim J. Krishnan
Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorDoug Turnbull
Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorAbstract
Patients with disorders from mutations in the mitochondrial genome have variable phenotypes, but common to many of these disorders are underlying changes in postmitotic cells, particularly neurons and muscle fibers. The mitochondrial dysfunction caused by these mutations has been shown to be associated with signs of apoptosis and to cause cell loss. Mutations of the mitochondrial genome have also been shown to accumulate with age and in common neurodegenerative diseases, such as Parkinson's disease. This review presents recent data to show that the information gained from studying patients with mitochondrial disorders can help our understanding of the role of mitochondrial DNA mutations in brain aging and neurodegeneration.
References
- 1 Chen, H. & D.C. Chan. 2005. Emerging functions of mammalian mitochondrial fusion and fission. Hum. Mol. Genet. 14: R283–R289.
- 2 Hengartner, M.O. 2000. The biochemistry of apoptosis. Nature 407: 770–776.
- 3 Rizzuto, R., P. Bernardi & T. Pozzan. 2000. Mitochondria as all-round players of the calcium game. J. Physiol. 529(Pt 1): 37–47.
- 4 Harman, D. 1972. The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20: 145–147.
- 5 Linnane, A.W., S. Marzuki, T. Ozawa & M. Tanaka. 1989. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1: 642–645.
- 6 Margulis, L. 1971. Symbiosis and evolution. Sci. Am. 225: 48–57.
- 7 Malka, F., A. Lombes & M. Rojo. 2006. Organization, dynamics and transmission of mitochondrial DNA: focus on vertebrate nucleoids. Biochimica Et Biophysica Acta 1763: 463–472.
- 8 McFarland, R., R.W. Taylor & D.M. Turnbull. 2007. Mitochondrial disease–its impact, etiology, and pathology. Curr. Top. Dev. Biol. 77: 113–155.
- 9 Caron, F., C. Jacq & J. Rouviere-Yaniv. 1979. Characterization of a histone-like protein extracted from yeast mitochondria. Proc. Natl. Acad. Sci. USA 76: 4265–4269.
- 10 Nakabeppu, Y. 2001. Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage. Prog. Nucleic Acid Res. Mol. Biol. 68: 75–94.
- 11 Chinnery, P.F., D.C. Samuels, J. Elson & D.M. Turnbull. 2002. Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360: 1323–1325.
- 12 Wallace, D.C. 1992. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science (New York, N.Y.) 256: 628–632.
- 13 Yoneda, M., A. Chomyn, A. Martinuzzi, et al . 1992. Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proc. Natl. Acad. Sci. USA 89: 11164–11168.
- 14 Elson, J.L., D.C. Samuels, D.M. Turnbull & P.F. Chinnery. 2001. Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am. J. Hum. Genet. 68: 802–806.
- 15 Diaz, F., M.P. Bayona-Bafaluy, M. Rana, et al . 2002. Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucl. Acids Res. 30: 4626–4633.
- 16 Schaefer, A.M., C. Phoenix, J.L. Elson, et al . 2006. Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology 66: 1932–1934.
- 17 McFarland, R., R.W. Taylor & D.M. Turnbull. 2002. The neurology of mitochondrial DNA disease. Lancet Neurol. 1: 343–351.
- 18 Filosto, M., G. Tomelleri, P. Tonin, et al . 2007. Neuropathology of mitochondrial diseases. Biosci. Rep. 27: 23–30.
- 19 Betts, J., E. Jaros, R.H. Perry, et al . 2006. Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. Neuropathol. Appl. Neurobiol. 32: 359–373.
- 20 Betts, J., R.N. Lightowlers & D.M. Turnbull. 2004. Neuropathological aspects of mitochondrial DNA disease. Neurochem. Res. 29: 505–511.
- 21 Man, P.Y., D.M. Turnbull & P.F. Chinnery. 2002. Leber hereditary optic neuropathy. J. Med. Genet. 39: 162–169.
- 22 Sciacco, M., E. Bonilla, E.A. Schon, et al . 1994. Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum. Mol. Genet. 3: 13–19.
- 23 Itoh, K., S. Weis, P. Mehraein & J. Muller-Hocker. 1996. Cytochrome c oxidase defects of the human substantia nigra in normal aging. Neurobiol. Aging 17: 843–848.
- 24 Aure, K., G. Fayet, J.P. Leroy, et al . 2006. Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation. Brain 129: 1249–1259.
- 25 Michikawa, Y., F. Mazzucchelli, N. Bresolin, et al . 1999. Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science (New York, N.Y.) 286: 774–779.
- 26 Wang, Y., Y. Michikawa, C. Mallidis, et al . 2001. Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc. Natl. Acad. Sci. USA 98: 4022–4027.
- 27 Cantuti-Castelvetri, I., M.T. Lin, K. Zheng, et al . 2005. Somatic mitochondrial DNA mutations in single neurons and glia. Neurobiol. Aging 26: 1343–1355.
- 28 Bua, E., J. Johnson, A. Herbst, et al . 2006. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am. J. Hum. Genet. 79: 469–480.
- 29 Corral-Debrinski, M., T. Horton, M.T. Lott, et al . 1992. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat. Genet. 2: 324–329.
- 30 Krishnan, K.J., L.C. Greaves, A.K. Reeve & D.M. Turnbull. 2007. Mitochondrial DNA mutations and aging. Ann. N Y Acad. Sci. 1100: 227–240.
- 31 Taylor, R.W., M.J. Barron, G.M. Borthwick, et al . 2003. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112: 1351–1360.
- 32 Simon, D.K., M.T. Lin, C.H. Ahn, et al . 2001. Low mutational burden of individual acquired mitochondrial DNA mutations in brain. Genomics 73: 113–116.
- 33 Murdock, D.G., N.C. Christacos & D.C. Wallace. 2000. The age-related accumulation of a mitochondrial DNA control region mutation in muscle, but not brain, detected by a sensitive PNA-directed PCR clamping based method. Nucleic Acids Res. 28: 4350–4355.
- 34 Pak, J.W., F. Vang, C. Johnson, et al . 2005. MtDNA point mutations are associated with deletion mutations in aged rat. Exp. Gerontol. 40: 209–218. Epub 2005 Jan 18.
- 35 Kraytsberg, Y., E. Kudryavtseva, A.C. McKee, et al . 2006. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38: 518–520.
- 36 Bender, A., K.J. Krishnan, C.M. Morris, et al . 2006. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38: 515–517.
- 37 Vives-Bauza, C., A.L. Andreu, G. Manfredi, et al . 2002. Sequence analysis of the entire mitochondrial genome in Parkinson's disease. Biochem. Biophys. Res. Commun. 290: 1593–1601.
- 38 Fearnley, J.M. & A.J. Lees. 1991. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114(Pt 5): 2283–2301.
- 39 Beal, M.F. 2005. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 58: 495–505.
- 40 Wallace, D.C., J.M. Shoffner, I. Trounce, et al . 1995. Mitochondrial DNA mutations in human degenerative diseases and aging. Biochim. Biophys. Acta 1271: 141–151.
- 41 Horton, T.M., B.H. Graham, M. Corral-Debrinski, et al . 1995. Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients. Neurology 45: 1879–1883.
- 42 Lin, M.T., D.K. Simon, C.H. Ahn, et al . 2002. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum. Mol. Genet. 11: 133–145.
- 43 Simon, D.K., M.T. Lin, L. Zheng, et al . 2004. Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease. Neurobiol. Aging 25: 71–81.
- 44 Smigrodzki, R., J. Parks & W.D. Parker. 2004. High frequency of mitochondrial complex I mutations in Parkinson's disease and aging. Neurobiol. Aging 25: 1273–1281.
- 45 Chinnery, P.F., G.A. Taylor, N. Howell, et al . 2001. Point mutations of the mtDNA control region in normal and neurodegenerative human brains. Am. J. Hum. Genet. 68: 529–532.
- 46 Pyle, A., T. Foltynie, W. Tiangyou, et al . 2005. Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD. Ann. Neurol. 57: 564–567.
- 47 Vermulst, M., J.H. Bielas, G.C. Kujoth, et al . 2007. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat. Genet. 39: 540–543.
- 48 Kraytsberg, Y. & K. Khrapko. 2005. Single-molecule PCR: an artifact-free PCR approach for the analysis of somatic mutations. Expert. Rev. Mol. Diagn. 5: 809–815.
- 49 Swerdlow, R.H., J.K. Parks, S.W. Miller, et al . 1996. Origin and functional consequences of the complex I defect in Parkinson's disease. Ann. Neurol. 40: 663–671.
- 50 Schapira, A.H., J.M. Cooper, D. Dexter, et al . 1990. Mitochondrial complex I deficiency in Parkinson's disease. J. Neurochem. 54: 823–827.
- 51 Aomi, Y., C.S. Chen, K. Nakada, et al . 2001. Cytoplasmic transfer of platelet mtDNA from elderly patients with Parkinson's disease to mtDNA-less HeLa cells restores complete mitochondrial respiratory function. Biochem. Biophys. Res. Commun. 280: 265–273.
- 52 Cottrell, D.A., E.L. Blakely, M.A. Johnson, et al . 2001. Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology 57: 260–264.
- 53 Reeve A.K., K.J. Krishnan, J.L. Elson, et al . 2008. Nature of mitochondrial DNA deletions in Substantia Nigra neurons. Am. J. Hum. Genet. 82(1): 228–238.
- 54 Ekstrand, M.I., M. Terzioglu, D. Galter, et al . 2007. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl. Acad. Sci. USA 104: 1325–1330.
- 55 Sorensen, L., M. Ekstrand, J.P. Silva, et al . 2001. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J. Neurosci. 21: 8082–8090.
- 56 Trifunovic, A., A. Wredenberg, M. Falkenberg, et al . 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.
- 57 Kujoth, G.C., A. Hiona, T.D. Pugh, et al . 2005. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science (New York, N.Y.) 309: 481–484.
- 58 Someya, S., T. Yamasoba, G.C. Kujoth, et al . 2007. The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase gamma. Neurobiol. Aging 29(7): 1080–1092.