Molecular Genetics and Genomics

, Volume 287, Issue 11–12, pp 837–844

A possible role for mitochondrial dysfunction in migraine



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.


Energy metabolism Migraine Mitochondria Mitochondrial dysfunction Migraine pathogenesis Susceptibility 


  1. Akerman S, Holland PR, Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12(10):570–584. doi:10.1038/nrn3057 PubMedCrossRefGoogle Scholar
  2. 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):257–262PubMedCrossRefGoogle Scholar
  3. 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 PubMedCrossRefGoogle Scholar
  4. 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 PubMedCrossRefGoogle Scholar
  5. 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):263–272PubMedCrossRefGoogle Scholar
  6. 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):1209–1214PubMedCrossRefGoogle Scholar
  7. 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 PubMedCrossRefGoogle Scholar
  8. 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):113–119PubMedCrossRefGoogle Scholar
  9. 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):182–189PubMedCrossRefGoogle Scholar
  10. 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):71–74PubMedCrossRefGoogle Scholar
  11. 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):IV103–110Google Scholar
  12. 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 PubMedCrossRefGoogle Scholar
  13. 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 PubMedCrossRefGoogle Scholar
  14. 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):1120–1121PubMedCrossRefGoogle Scholar
  15. Cotter D, Guda P, Fahy E, Subramaniam S (2004) MitoProteome: mitochondrial protein sequence database and annotation system. Nucleic acids research 32(Database issue):D463–D467Google Scholar
  16. 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):375–376CrossRefGoogle Scholar
  17. 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):568–571PubMedCrossRefGoogle Scholar
  18. DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348(26):2656–2668. doi:10.1056/NEJMra022567 PubMedCrossRefGoogle Scholar
  19. DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC (1985) Mitochondrial myopathies. Ann Neurol 17(6):521–538. doi:10.1002/ana.410170602 PubMedCrossRefGoogle Scholar
  20. 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):400–405PubMedCrossRefGoogle Scholar
  21. 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 PubMedCrossRefGoogle Scholar
  22. Goadsby PJ (2003) Migraine: diagnosis and management. Intern Med J 33(9–10):436–442PubMedCrossRefGoogle Scholar
  23. 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 PubMedCrossRefGoogle Scholar
  24. Haan J, Terwindt GM, Maassen JA, Hart LM, Frants RR, Ferrari MD (1999) Search for mitochondrial DNA mutations in migraine subgroups. Cephalalgia 19(1):20–22PubMedCrossRefGoogle Scholar
  25. 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 PubMedCrossRefGoogle Scholar
  26. 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 PubMedCrossRefGoogle Scholar
  27. 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)PubMedCrossRefGoogle Scholar
  28. 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):490–495PubMedCrossRefGoogle Scholar
  29. Klopstock T, May A, Seibel P, Papagiannuli E, Diener HC, Reichmann H (1996) Mitochondrial DNA in migraine with aura. Neurology 46(6):1735–1738PubMedCrossRefGoogle Scholar
  30. 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 PubMedCrossRefGoogle Scholar
  31. 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 PubMedCrossRefGoogle Scholar
  32. 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 PubMedCrossRefGoogle Scholar
  33. 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 PubMedCrossRefGoogle Scholar
  34. 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):455–456PubMedCrossRefGoogle Scholar
  35. 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 PubMedCrossRefGoogle Scholar
  36. 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 PubMedCrossRefGoogle Scholar
  37. 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 PubMedCrossRefGoogle Scholar
  38. 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):477–480PubMedCrossRefGoogle Scholar
  39. Montagna P, Cortelli P, Barbiroli B (1994a) Magnetic-resonance spectroscopy studies in migraine. Cephalalgia 14(3):184–193PubMedCrossRefGoogle Scholar
  40. 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):666–669PubMedCrossRefGoogle Scholar
  41. 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):765–771PubMedCrossRefGoogle Scholar
  42. 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):39–42PubMedCrossRefGoogle Scholar
  43. Oldfors A, Tulinius M (2003) Mitochondrial encephalomyopathies. J Neuropathol Exp Neurol 62(3):217–227PubMedGoogle Scholar
  44. 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):1104–1110PubMedCrossRefGoogle Scholar
  45. 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):414–430PubMedCrossRefGoogle Scholar
  46. 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–S59PubMedGoogle Scholar
  47. 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):226–236PubMedCrossRefGoogle Scholar
  48. 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):376–380PubMedCrossRefGoogle Scholar
  49. 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):21–23PubMedCrossRefGoogle Scholar
  50. 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):382–383CrossRefGoogle Scholar
  51. 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):305–307PubMedCrossRefGoogle Scholar
  52. Sherratt HS (1991) Mitochondria: structure and function. Rev Neurol (France) 147(6–7):417–430Google Scholar
  53. 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):625PubMedCrossRefGoogle Scholar
  54. Sparaco M, Bonilla E, Dimauro S, Powers JM (1993) Neuropathology of mitochondrial encephalomyopathies due to mitochondrial-DNA defects. J Neuropathol Exp Neurol 52(1):1–10PubMedCrossRefGoogle Scholar
  55. Sparaco M, Feleppa M, Lipton RB, Rapoport AM, Bigal ME (2006) Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia 26(4):361–372PubMedCrossRefGoogle Scholar
  56. 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 PubMedCrossRefGoogle Scholar
  57. 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):e74PubMedCrossRefGoogle Scholar
  58. 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. Google Scholar
  59. 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 PubMedCrossRefGoogle Scholar
  60. 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):214–222PubMedCrossRefGoogle Scholar
  61. 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 PubMedCrossRefGoogle Scholar
  62. Wanic-Kossowska M (1997) Protective role of carnitine in acetate metabolism of patients with uremia treated by hemodialysis. Pol Arch Med Wewn 97(6):534–540PubMedGoogle Scholar
  63. Welch K (2003) Contemporary concepts of migraine pathogenesis. Neurology 61(Suppl):S2–S8PubMedCrossRefGoogle Scholar
  64. 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):538–541PubMedCrossRefGoogle Scholar
  65. 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):272–275PubMedCrossRefGoogle Scholar
  66. 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 PubMedCrossRefGoogle Scholar
  67. Wolff HG (1952) Headache mechanisms. Trans Pac Coast Otoophthalmol Soc Annu Meet 33:45–80PubMedGoogle Scholar
  68. 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 PubMedCrossRefGoogle Scholar
  69. 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 PubMedCrossRefGoogle Scholar
  70. 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 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Genomics Research Centre, Griffith Health InstituteGriffith UniversityGold CoastAustralia

Personalised recommendations