Abstract
Migraine is a common neurological disorder characterised by debilitating head pain and an assortment of additional symptoms which can include nausea, emesis, photophobia, phonophobia and occasionally visual sensory disturbances. Migraine is a complex disease caused by an interplay between predisposing genetic variants and environmental factors. It affects approximately 12 % of studied Caucasian populations with affected individuals being predominantly female. Genes involved in neurological, vascular or hormonal pathways have all been implicated in predisposition towards developing migraine. All of these are nuclear encoded genes, but given the role of mitochondria in a number of neurological disorders and in energy production it is possible that mitochondrial variants may play a role in the pathogenesis of this disease. Mitochondrial DNA has been a useful tool for studying population genetics and human genetic diseases due to the clear inheritance shown through successive generations. Given the clear gender bias found in migraine patients it may be important to investigate X-linked inheritance and mitochondrial-related variants in this disorder. This paper explores the possibility that mitochondrial DNA changes may play a role in migraine. Few variants in the mitochondrial genome have so far been investigated in migraine and new studies should be aimed towards investigating the role of mitochondrial DNA in this common disorder.
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Akerman S, Holland PR, Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12(10):570–584. doi:10.1038/nrn3057
Argov Z, Bank WJ, Maris J, Peterson P, Chance B (1987) Bioenergetic heterogeneity of human mitochondrial myopathies—phosphorus magnetic-resonance spectroscopy study. Neurology 37(2):257–262
Arnold DL, Taylor DJ, Radda GK (1985) Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy. Ann Neurol 18(2):189–196. doi:10.1002/ana.410180205
Asuni C, Manchia M, Deidda A, Stochino ME, Cherchi A, Del Zompo M (2010) Mixture analysis of age at onset in migraine without aura: evidence for three subgroups. Headache 50(8):1313–1319. doi:10.1111/j.1526-4610.2010.01671.x
Barbiroli B, Montagna P, Cortelli P, Martinelli P, Sacquegna T, Zaniol P, Lugaresi E (1990) Complicated migraine studied by phosphorus magnetic-resonance spectroscopy. Cephalalgia 10(5):263–272
Barbiroli B, Montagna P, Cortelli P, Funicello R, Iotti S, Monari L, Pierangeli G, Zaniol P, Lugaresi E (1992) Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura. Neurology 42(6):1209–1214
Barbiroli B, Montagna P, Martinelli P, Lodi R, Iotti S, Cortelli P, Funicello R, Zaniol P (1993) Defective brain energy metabolism shown by in vivo 31P MR spectroscopy in 28 patients with mitochondrial cytopathies. J Cereb Blood Flow Metab 13(3):469–474. doi:10.1038/jcbfm.1993.61
Bonilla E, Sciacco M, Tanji K, Sparaco M, Petruzzella V, Moraes CT (1992) New morphological approaches to the study of mitochondrial encephalomyopathies. Brain Pathol 2(2):113–119
Bresolin N, Martinelli P, Barbiroli B, Zaniol P, Ausenda C, Montagna P, Gallanti A, Comi GP, Scarlato G, Lugaresi E (1991) Muscle mitochondrial DNA deletion and 31P-NMR spectroscopy alterations in a migraine patient. J Neurol Sci 104(2):182–189
Casas F, Pineau T, Rochard P, Rodier A, Daury L, Dauca M, Cabello G, Wrutniak-Cabello C (2000) New molecular aspects of regulation of mitochondrial activity by fenofibrate and fasting. FEBS Lett 482(1–2):71–74
Chance B, Clark BJ, Nioka S, Subramanian H, Maris JM, Argov Z, Bode H (1985) Phosphorus nuclear magnetic resonance spectroscopy in vivo. Circulation 72(5 Pt 2):IV103–110
Chinnery PF, Howel D, Turnbull DM, Johnson MA (2003) Clinical progression of mitochondrial myopathy is associated with the random accumulation of cytochrome c oxidase negative skeletal muscle fibres. J Neurol Sci 211(1–2):63–66. doi:10.1016/S0022-510x(03)00039-X
Chuquet J, Hollender L, Nimchinsky EA (2007) High-resolution in vivo imaging of the neurovascular unit during spreading depression. J Neurosci 27(15):4036–4044. doi:10.1523/JNEUROSCI.0721-07.2007
Cortelli P, Zacchini A, Barboni P, Malpassi P, Carelli V, Montagna P (1995) Lack of association between mitochondrial T(Rnaleu(Uur)) point mutation and cluster headache. Lancet 345(8957):1120–1121
Cotter D, Guda P, Fahy E, Subramaniam S (2004) MitoProteome: mitochondrial protein sequence database and annotation system. Nucleic acids research 32(Database issue):D463–D467
de Almeida RF, Leao IA, Gomes JB, Da Silva AA Jr, Teixeira AL (2009) Migraine with persistent visual aura: response to furosemide. Clinics (Sao Paulo) 64(4):375–376
Di Gennaro G, Buzzi MG, Ciccarelli O, Santorelli FM, Pierelli F, Fortini D, D’Onofrio M, Costa A, Nappi G, Casali C (2000) Assessing the relative incidence of mitochondrial DNA A3243G in migraine without aura with maternal inheritance. Headache 40(7):568–571
DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348(26):2656–2668. doi:10.1056/NEJMra022567
DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC (1985) Mitochondrial myopathies. Ann Neurol 17(6):521–538. doi:10.1002/ana.410170602
Finnila S, Autere J, Lehtovirta M, Hartikainen P, Mannermaa A, Soininen H, Majamaa K (2001) Increased risk of sensorineural hearing loss and migraine in patients with a rare mitochondrial DNA variant 4336A>G in tRNAGln. J Med Genet 38(6):400–405
Finsterer J (2008) Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). J Neurol Sci 272(1–2):20–33. doi:10.1016/j.jns.2008.05.011
Goadsby PJ (2003) Migraine: diagnosis and management. Intern Med J 33(9–10):436–442
Goadsby PJ, Akerman S (2012) The trigeminovascular system does not require a peripheral sensory input to be activated—migraine is a central disorder focus on ‘effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system’. Cephalalgia 32(1):3–5. doi:10.1177/0333102411430267
Haan J, Terwindt GM, Maassen JA, Hart LM, Frants RR, Ferrari MD (1999) Search for mitochondrial DNA mutations in migraine subgroups. Cephalalgia 19(1):20–22
Ho TW, Goadsby PJ (2010) CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 6(10):573–582. doi:10.1038/nrneurol.2010.127
Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM (2008) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70(16):1304–1312. doi:10.1212/01.WNL.0000286940.29755.61
Humphrey PP, Feniuk W, Perren MJ, Beresford IJ, Skingle M, Whalley ET (1990) Serotonin and migraine. Ann N Y Acad Sci 600:587–598 (discussion 598–600)
Kabbouche MA, Powers SW, Vockell AL, LeCates SL, Hershey AD (2003) Carnitine palmitoyltransferase II (CPT2) deficiency and migraine headache: two case reports. Headache 43(5):490–495
Klopstock T, May A, Seibel P, Papagiannuli E, Diener HC, Reichmann H (1996) Mitochondrial DNA in migraine with aura. Neurology 46(6):1735–1738
Lambert GA, Truong L, Zagami AS (2011) Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system. Cephalalgia 31(14):1439–1451. doi:10.1177/0333102411422383
Lea R, Colson N, Quinlan S, Macmillan J, Griffiths L (2009) The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability. Pharmacogenet Genomics 19(6):422–428. doi:10.1097/FPC.0b013e32832af5a3
Li M, Schonberg A, Schaefer M, Schroeder R, Nasidze I, Stoneking M (2010) Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am J Hum Genet 87(2):237–249. doi:10.1016/j.ajhg.2010.07.014
Littlewood J, Glover V, Sandler M, Peatfield R, Petty R, Clifford Rose F (1984) Low platelet monoamine oxidase activity in headache: no correlation with phenolsulphotransferase, succinate dehydrogenase, platelet preparation method or smoking. J Neurol Neurosurg Psychiatry 47(4):338–343. doi:10.1136/jnnp.47.4.338
Majamaa K, Finnila S, Turkka J, Hassinen IE (1998) Mitochondrial DNA haplogroup U as a risk factor for occipital stroke in migraine. Lancet 352(9126):455–456
Maruszak A, Zekanowski C (2011) Mitochondrial dysfunction and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 35(2):320–330. doi:10.1016/j.pnpbp.2010.07.004
Mauskop A, Varughese J (2012) Why all migraine patients should be treated with magnesium. J Neural Transm 119(5):575–579. doi:10.1007/s00702-012-0790-2
Metea MR, Newman EA (2006) Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling. J Neurosci 26(11):2862–2870. doi:10.1523/JNEUROSCI.4048-05.2006
Montagna P, Sacquegna T, Martinelli P, Cortelli P, Bresolin N, Moggio M, Baldrati A, Riva R, Lugaresi E (1988) Mitochondrial abnormalities in migraine. Preliminary findings. Headache 28(7):477–480
Montagna P, Cortelli P, Barbiroli B (1994a) Magnetic-resonance spectroscopy studies in migraine. Cephalalgia 14(3):184–193
Montagna P, Cortelli P, Monari L, Pierangeli G, Parchi P, Lodi R, Iotti S, Frassineti C, Zaniol P, Lugaresi E, Barbiroli B (1994b) P-31-magnetic resonance spectroscopy in migraine without aura. Neurology 44(4):666–669
Moraes CT, Schon EA, Dimauro S, Miranda AF (1989) Heteroplasmy of mitochondrial genomes in clonal cultures from patients with Kearns-Sayre syndrome. Biochem Biophys Res Commun 160(2):765–771
Okada H, Araga S, Takeshima T, Nakashima K (1998) Plasma lactic acid and pyruvic acid levels in migraine and tension-type headache. Headache 38(1):39–42
Oldfors A, Tulinius M (2003) Mitochondrial encephalomyopathies. J Neuropathol Exp Neurol 62(3):217–227
Olesen J, Diener H, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM, Con BBCPo (2004) Calcitonin gene-related peptide receptor antagonist BIBN4096BS for the acute treatment of migraine. N Engl J Med 350(11):1104–1110
Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM (2009) A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol 11(6):414–430
Pringsheim T, Davenport W, Mackie G, Worthington I, Aube M, Christie SN, Gladstone J, Becker WJ (2012) Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci 39(2 Suppl 2):S1–S59
Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M (2008) Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 28(3):226–236
Sacquegna T, Lodi R, Decarolis P, Tinuper P, Cortelli P, Zaniol P, Funicello R, Montagna P, Barbiroli B (1992) Brain energy-metabolism studied by P-31-Mr spectroscopy in a case of migraine with prolonged aura. Acta Neurol Scand 86(4):376–380
Sangiorgi S, Mochi M, Riva R, Cortelli P, Monari L, Pierangeli G, Montagna P (1994) Abnormal platelet mitochondrial function in patients affected by migraine with and without aura. Cephalalgia 14(1):21–23
Saxena R, de Bakker PIW, Groop LC, Daly MJ, Altshuler D (2007) Associating mitochondrial DNA variation with complex traits—reply to Elson et al. Am J Hum Genet 80(2):382–383
Seibel P, Grunewald T, Gundolla A, Diener HC, Reichmann H (1996) Investigation on the mitochondrial transfer RNA(Leu)(UUR) in blood cells from patients with cluster headache. J Neurol 243(4):305–307
Sherratt HS (1991) Mitochondria: structure and function. Rev Neurol (France) 147(6–7):417–430
Shimomura T, Kitano A, Marukawa H, Mishima K, Isoe K, Adachi Y, Takahashi K (1994) Point mutation in platelet mitochondrial tRNA(Leu(UUR)) in patient with cluster headache. Lancet 344(8922):625
Sparaco M, Bonilla E, Dimauro S, Powers JM (1993) Neuropathology of mitochondrial encephalomyopathies due to mitochondrial-DNA defects. J Neuropathol Exp Neurol 52(1):1–10
Sparaco M, Feleppa M, Lipton RB, Rapoport AM, Bigal ME (2006) Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia 26(4):361–372
Tanji K, Kunimatsu T, Vu TH, Bonilla E (2001) Neuropathological features of mitochondrial disorders. Semin Cell Dev Biol 12(6):429–439. doi:10.1006/scdb.2001.0280
Taylor RW, Taylor GA, Durham SE, Turnbull DM (2001) The determination of complete human mitochondrial DNA sequences in single cells: implications for the study of somatic mitochondrial DNA point mutations. Nucleic Acids Res 29(15):e74
Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS (2003) Characterization of the human heart mitochondrial proteome. Nat Biotech 21(3):281–286. http://www.nature.com/nbt/journal/v21/n3/suppinfo/nbt793_S1.html
Tyni T, Paetau A, Strauss AW, Middleton B, Kivela T (2004) Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Res 56(5):744–750. doi:10.1203/01.PDR.0000141967.52759.83
Uncini A, Lodi R, Di Muzio A, Silvestri G, Servidei S, Lugaresi A, Iotti S, Zaniol P, Barbiroli B (1995) Abnormal brain and muscle energy metabolism shown by 31P-MRS in familial hemiplegic migraine. J Neurol Sci 129(2):214–222
Wang Q, Ito M, Adams K, Li BU, Klopstock T, Maslim A, Higashimoto T, Herzog J, Boles RG (2004) Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome. Am J Med Genet A 131(1):50–58. doi:10.1002/ajmg.a.30323
Wanic-Kossowska M (1997) Protective role of carnitine in acetate metabolism of patients with uremia treated by hemodialysis. Pol Arch Med Wewn 97(6):534–540
Welch K (2003) Contemporary concepts of migraine pathogenesis. Neurology 61(Suppl):S2–S8
Welch KM, Levine SR, D’Andrea G, Schultz LR, Helpern JA (1989) Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy. Neurology 39(4):538–541
Wieser T, Mueller C, Evers S, Zierz S, Deufel T (2003) Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing. Clin Chem Lab Med 41(3):272–275
Winklhofer KF, Haass C (2010) Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta 1802(1):29–44. doi:10.1016/j.bbadis.2009.08.013
Wolff HG (1952) Headache mechanisms. Trans Pac Coast Otoophthalmol Soc Annu Meet 33:45–80
Wong LJC, Boles RG (2005) Mitochondrial DNA analysis in clinical laboratory diagnostics. Clin Chim Acta 354(1–2):1–20. doi:10.1016/j.cccn.2004.11.003
Yang JL, Weissman L, Bohr VA, Mattson MP (2008) Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair 7(7):1110–1120. doi:10.1016/j.dnarep.2008.03.012
Zaki EA, Freilinger T, Klopstock T, Baldwin EE, Heisner KR, Adams K, Dichgans M, Wagler S, Boles RG (2009) Two common mitochondrial DNA polymorphisms are highly associated with migraine headache and cyclic vomiting syndrome. Cephalalgia 29(7):719–728. doi:10.1111/j.1468-2982.2008.01793.x
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Stuart, S., Griffiths, L.R. A possible role for mitochondrial dysfunction in migraine. Mol Genet Genomics 287, 837–844 (2012). https://doi.org/10.1007/s00438-012-0723-7
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DOI: https://doi.org/10.1007/s00438-012-0723-7