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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Neurodegenerative Diseases Associated with Mitochondrial DNA Mutations

Author(s): Olga A. Zhunina, Nikita G. Yabbarov, Andrey V. Grechko, Shaw-Fang Yet, Igor A. Sobenin and Alexander N. Orekhov*

Volume 26, Issue 1, 2020

Page: [103 - 109] Pages: 7

DOI: 10.2174/1381612825666191122091320

Price: $65


Mitochondrial dysfunction underlies several human chronic pathologies, including cardiovascular disorders, cancers and neurodegenerative diseases. Impaired mitochondrial function associated with oxidative stress can be a result of both nuclear and mitochondrial DNA (mtDNA) mutations. Neurological disorders associated with mtDNA mutations include mitochondrial encephalomyopathy, chronic progressive external ophthalmoplegia, neurogenic weakness, and Leigh syndrome. Moreover, mtDNA mutations were shown to play a role in the development of Parkinson and Alzheimer’s diseases. In this review, current knowledge on the distribution and possible roles of mtDNA mutations in the onset and development of various neurodegenerative diseases, with special focus on Parkinson’s and Alzheimer’s diseases has been discussed.

Keywords: Parkinson disease, alzheimer disease, neuropathy, oxidative stress, mitochondria, DNA damage, reactive oxygen species.

Musicco C, Cormio G, Pesce V, et al. Mitochondrial dysfunctions in type I endometrial carcinoma: exploring their role in oncogenesis and tumor progression. Int J Mol Sci 2018; 19(7) E2076
[] [PMID: 30018222]
Kozin MS, Kulakova OG, Favorova OO. Involvement of mitochondria in neurodegeneration in multiple sclerosis. Biochemistry (Mosc) 2018; 83(7): 813-30.
[] [PMID: 30200866]
Sazonova MA, Ryzhkova AI, Sinyov VV, et al. New markers of atherosclerosis: a threshold level of heteroplasmy in mtDNA mutations. Vessel Plus 2017; 1: 182-91.
Martínez MS, García A, Luzardo E, et al. Energetic metabolism in cardiomyocytes: molecular basis of heart ischemia and arrhythmogenesis. Vessel Plus 2017; 1: 130-41.
Aliev G, Obrenovich ME, Tabrez S, et al. Link between cancer and Alzheimer disease via oxidative stress induced by nitric oxide-dependent mitochondrial DNA overproliferation and deletion. Oxid Med Cell Longev 2013; 2013 962984
[] [PMID: 23691268]
DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci 2008; 31: 91-123.
[] [PMID: 18333761]
Aliev G, Li Y, Palacios HH, Obrenovich ME. Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases. Recent Pat Cardiovasc Drug Discov 2011; 6(3): 222-41.
[] [PMID: 21906026]
Aliev G, Palacios HH, Gasimov E, et al. Oxidative stress induced mitochondrial failure and vascular hypoperfusion as a key initiator for the development of Alzheimer disease. Pharmaceuticals (Basel) 2010; 3(1): 158-87.
[] [PMID: 27713247]
Ehrenkrantz D, Silverman JM, Smith CJ, et al. Genetic epidemiological study of maternal and paternal transmission of Alzheimer’s disease. Am J Med Genet 1999; 88(4): 378-82.
[<378:AID-AJMG15>3.0.CO;2-8] [PMID: 10402505]
Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991; 41(4): 479-86.
[] [PMID: 2011243]
Aliev G, Smith MA, Seyidov D, et al. The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer’s disease. Brain Pathol 2002; 12(1): 21-35.
[] [PMID: 11770899]
Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60(8): 759-67.
[] [PMID: 11487050]
Swerdlow RH, Burns JM, Khan SM. The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta 2014; 1842(8): 1219-31.
[] [PMID: 24071439]
Hirai K, Aliev G, Nunomura A, et al. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 2001; 21(9): 3017-23.
[] [PMID: 11312286]
Moreira PI, Siedlak SL, Wang X, et al. Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy 2007; 3(6): 614-5.
[] [PMID: 17786024]
Maurer I, Zierz S, Möller HJ. A selective defect of cytochrome C oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging 2000; 21(3): 455-62.
[] [PMID: 10858595]
Wang X, Su B, Siedlak SL, et al. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 2008; 105(49): 19318-23.
[] [PMID: 19050078]
Lin FH, Lin R, Wisniewski HM, et al. Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer’s brains. Biochem Biophys Res Commun 1992; 182(1): 238-46.
[] [PMID: 1370613]
Petruzzella V, Chen X, Schon EA. Is a point mutation in the mitochondrial ND2 gene associated with Alzheimer’s disease. Biochem Biophys Res Commun 1992; 186(1): 491-7.
[] [PMID: 1352971]
Shoffner JM, Brown MD, Torroni A, et al. Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 1993; 17(1): 171-84.
[] [PMID: 8104867]
Hutchin T, Cortopassi G. A mitochondrial DNA clone is associated with increased risk for Alzheimer disease. Proc Natl Acad Sci USA 1995; 92(15): 6892-5.
[] [PMID: 7624338]
Davis RE, Miller S, Herrnstadt C, et al. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. Proc Natl Acad Sci USA 1997; 94(9): 4526-31.
[] [PMID: 9114023]
van der Walt JM, Dementieva YA, Martin ER, et al. Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 2004; 365(1): 28-32.
[] [PMID: 15234467]
King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 1989; 246(4929): 500-3.
[] [PMID: 2814477]
Khan SM, Cassarino DS, Abramova NN, et al. Alzheimer’s disease cybrids replicate beta-amyloid abnormalities through cell death pathways. Ann Neurol 2000; 48(2): 148-55.
[<148:AID-ANA3>3.0.CO;2-7] [PMID: 10939564]
Eckert GP, Renner K, Eckert SH, et al. Mitochondrial dysfunction--a pharmacological target in Alzheimer’s disease. Mol Neurobiol 2012; 46(1): 136-50.
[] [PMID: 22552779]
Aliev G, Smith MA, de la Torre JC, Perry G. Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer’s disease. Mitochondrion 2004; 4(5-6): 649-63.
[] [PMID: 16120422]
Reddy PH, Tripathi R, Troung Q, et al. Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer’s disease: implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta 2012; 1822(5): 639-49.
[] [PMID: 22037588]
Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004; 363(9423): 1783-93.
[] [PMID: 15172778]
de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol 2006; 5(6): 525-35.
[] [PMID: 16713924]
Andalib S, Vafaee MS, Gjedde A. Parkinson’s disease and mitochondrial gene variations: a review. J Neurol Sci 2014; 346(1-2): 11-9.
[] [PMID: 25151610]
Bhat AH, Dar KB, Anees S, et al. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother 2015; 74: 101-10.
[] [PMID: 26349970]
Giasson BI, Jakes R, Goedert M, et al. A panel of epitope-specific antibodies detects protein domains distributed throughout human alpha-synuclein in Lewy bodies of Parkinson’s disease. J Neurosci Res 2000; 59(4): 528-33.
[<528:AID-JNR8>3.0.CO;2-0] [PMID: 10679792]
Palacino JJ, Sagi D, Goldberg MS, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 2004; 279(18): 18614-22.
[] [PMID: 14985362]
Gandhi S, Wood-Kaczmar A, Yao Z, et al. PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 2009; 33(5): 627-38.
[] [PMID: 19285945]
Irrcher I, Aleyasin H, Seifert EL, et al. Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet 2010; 19(19): 3734-46.
[] [PMID: 20639397]
Cookson MR. Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med 2012; 2(9) a009415
[] [PMID: 22951446]
Haskin J, Szargel R, Shani V, et al. AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson’s disease. Hum Mol Genet 2013; 22(10): 2083-96.
[] [PMID: 23393160]
de Vries RL, Przedborski S. Mitophagy and Parkinson’s disease: be eaten to stay healthy. Mol Cell Neurosci 2013; 55: 37-43.
[] [PMID: 22926193]
Wu W, Xu H, Wang Z, et al. PINK1-Parkin-mediated mitophagy protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury. PLoS One 2015; 10(7) e0132499
[] [PMID: 26161534]
Akbar M, Essa MM, Daradkeh G, et al. Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress. Brain Res 2016; 1637: 34-55.
[] [PMID: 26883165]
Keeney PM, Dunham LD, Quigley CK, Morton SL, Bergquist KE, Bennett JP Jr. Cybrid models of Parkinson’s disease show variable mitochondrial biogenesis and genotype-respiration relationships. Exp Neurol 2009; 220(2): 374-82.
[] [PMID: 19815014]
Keeney PM, Quigley CK, Dunham LD, et al. Mitochondrial gene therapy augments mitochondrial physiology in a Parkinson’s disease cell model. Hum Gene Ther 2009; 20(8): 897-907.
[] [PMID: 19374590]
Clark J, Dai Y, Simon DK. Do somatic mitochondrial DNA mutations contribute to Parkinson’s disease? Parkinsons Dis 2011; 2011659694
[] [PMID: 21603185]
Mancuso M, Filosto M, Orsucci D, Siciliano G. Mitochondrial DNA sequence variation and neurodegeneration. Hum Genomics 2008; 3(1): 71-8.
[] [PMID: 19129091]
Simon DK, Lin MT, Zheng L, et al. Somatic mitochondrial DNA mutations in cortex and Substantia nigra in aging and Parkinson’s disease. Neurobiol Aging 2004; 25(1): 71-81.
[] [PMID: 14675733]
Parker WD Jr, Parks JK. Mitochondrial ND5 mutations in idiopathic Parkinson’s disease. Biochem Biophys Res Commun 2005; 326(3): 667-9.
[] [PMID: 15596151]
Smigrodzki R, Parks J, Parker WD. High frequency of mitochondrial complex I mutations in Parkinson’s disease and aging. Neurobiol Aging 2004; 25(10): 1273-81.
[] [PMID: 15465623]
Siciliano G, Mancuso M, Ceravolo R, Lombardi V, Iudice A, Bonuccelli U. Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports. J Neurol Neurosurg Psychiatry 2001; 71(5): 685-7.
[] [PMID: 11606686]
Bender A, Schwarzkopf RM, McMillan A, et al. Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions. J Neurol 2008; 255(8): 1231-5.
[] [PMID: 18604467]
Simon DK, Pulst SM, Sutton JP, Browne SE, Beal MF, Johns DR. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology 1999; 53(8): 1787-93.
[] [PMID: 10563629]
Ekstrand MI, Terzioglu M, Galter D, et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA 2007; 104(4): 1325-30.
[] [PMID: 17227870]
Liang CL, Wang TT, Luby-Phelps K, German DC. Mitochondria mass is low in mouse Substantia nigra dopamine neurons: implications for Parkinson’s disease. Exp Neurol 2007; 203(2): 370-80.
[] [PMID: 17010972]
Chaturvedi RK, Flint Beal M. Mitochondrial diseases of the brain. Free Radic Biol Med 2013; 63: 1-29.
[] [PMID: 23567191]
Huerta C, Castro MG, Coto E, et al. Mitochondrial DNA polymorphisms and risk of Parkinson’s disease in Spanish population. J Neurol Sci 2005; 236(1-2): 49-54.
[] [PMID: 15975594]
Otaegui D, Paisán C, Sáenz A, et al. Mitochondrial polymporphisms in Parkinson’s disease. Neurosci Lett 2004; 370(2-3): 171-4.
[] [PMID: 15488317]
Hung K-M, Calkins MJ. Mitochondrial homeostatic disruptions are sensitive indicators of stress in neurons with defective mitochondrial DNA transactions. Mitochondrion 2016; 31: 9-19.
[] [PMID: 27581214]
Martikainen MH, Kytövuori L, Majamaa K. Juvenile parkinsonism, hypogonadism and Leigh-like MRI changes in a patient with m.4296G>A mutation in mitochondrial DNA. Mitochondrion 2013; 13(2): 83-6.
[] [PMID: 23395828]
Cassereau J, Codron P, Funalot B. Inherited peripheral neuropathies due to mitochondrial disorders. Rev Neurol (Paris) 2014; 170(5): 366-74.
[] [PMID: 24768438]
Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984; 16(4): 481-8.
[] [PMID: 6093682]
Finsterer J. Mitochondrial disorders, cognitive impairment and dementia. J Neurol Sci 2009; 283(1-2): 143-8.
[] [PMID: 19268975]
Turnbull HE, Lax NZ, Diodato D, Ansorge O, Turnbull DM. The mitochondrial brain: from mitochondrial genome to neurodegeneration. Biochim Biophys Acta 2010; 1802(1): 111-21.
[] [PMID: 19647794]
Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 1997; 120(Pt 10): 1713-21.
[] [PMID: 9365365]
Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol 1987; 74(3): 226-33.
[] [PMID: 3673514]
Gilchrist JM, Sikirica M, Stopa E, Shanske S. Adult-onset MELAS. Evidence for involvement of neurons as well as cerebral vasculature in strokelike episodes. Stroke 1996; 27(8): 1420-3.
[] [PMID: 8711813]
Molnár MJ, Valikovics A, Molnár S, et al. Cerebral blood flow and glucose metabolism in mitochondrial disorders. Neurology 2000; 55(4): 544-8.
[] [PMID: 10953189]
Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. 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 1980; 47(1): 117-33.
[] [PMID: 6774061]
Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 1990; 61(6): 931-7.
[] [PMID: 2112427]
Nagashima T, Kato H, Maguchi S, et al. A mitochondrial encephalo-myo-neuropathy with a nucleotide position 3271 (T-C) point mutation in the mitochondrial DNA. Neuromuscul Disord 2001; 11(5): 470-6.
[] [PMID: 11404119]
Boulet L, Karpati G, Shoubridge EA. Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 1992; 51(6): 1187-200.
[PMID: 1334369]
Sciacco M, Bonilla E. Cytochemistry and immunocytochemistry of mitochondria in tissue sections. Methods Enzymol 1996; 264: 509-21.
[] [PMID: 8965723]
Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242(4884): 1427-30.
[] [PMID: 3201231]
Yu-Wai-Man P, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 2003; 72(2): 333-9.
[] [PMID: 12518276]
Harding AE, Riordan-Eva P, Govan GG. Mitochondrial DNA diseases: genotype and phenotype in Leber’s hereditary optic neuropathy. Muscle Nerve Suppl 1995; 3: S82-4.
[] [PMID: 7603533]
Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 2004; 23(1): 53-89.
[] [PMID: 14766317]
Hudson G, Keers S, Yu-Wai-Man P, et al. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet 2005; 77(6): 1086-91.
[] [PMID: 16380918]
Agostino A, Valletta L, Chinnery PF, et al. Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 2003; 60(8): 1354-6.
[] [PMID: 12707443]
Auré K, Ogier de Baulny H, Laforêt P, Jardel C, Eymard B, Lombès A. Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression? Brain 2007; 130(Pt 6): 1516-24.
[] [PMID: 17439982]
Debrosse S, Parikh S. Neurologic disorders due to mitochondrial DNA mutations. Semin Pediatr Neurol 2012; 19(4): 194-202.
[] [PMID: 23245552]
Duno M, Wibrand F, Baggesen K, Rosenberg T, Kjaer N, Frederiksen AL. A novel mitochondrial mutation m.8989G>C associated with neuropathy, ataxia, retinitis pigmentosa - the NARP syndrome. Gene 2013; 515(2): 372-5.
[] [PMID: 23266623]
Sinyov VV, Sazonova MA, Ryzhkova AI, et al. Potential use of buccal epithelium for genetic diagnosis of atherosclerosis using mtDNA mutations. Vessel Plus 2017; 1: 145-50.
Aliev G, Palacios HH, Walrafen B, Lipsitt AE, Obrenovich ME, Morales L. Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease. Int J Biochem Cell Biol 2009; 41(10): 1989-2004.
[] [PMID: 19703659]
Aliev G, Seyidova D, Lamb BT, et al. Mitochondria and vascular lesions as a central target for the development of Alzheimer’s disease and Alzheimer disease-like pathology in transgenic mice. Neurol Res 2003; 25(6): 665-74.
[] [PMID: 14503022]
Aliev G, Gasimov E, Obrenovich ME, et al. Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer’s disease. Vasc Health Risk Manag 2008; 4(3): 721-30.
[] [PMID: 18827923]
Oyewole AO, Birch-Machin MA. Mitochondria-targeted antioxidants. FASEB J 2015; 29(12): 4766-71.
[] [PMID: 26253366]
Takahashi M, Takahashi K. Water-soluble CoQ10 as a prosiming anti-aging agent for neurological dysfunction in brain mitochondria. Antioxidants 2019; 8(3) E61
[] [PMID: 30862106]
Young ML, Franklin JL. The mitochondria-targeted antioxidant MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg-AD mice. Mol Cell Neurosci 2019; 101 103409 Epub ahead of print
[] [PMID: 31521745]

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