Elsevier

Gene

Volume 543, Issue 1, 10 June 2014, Pages 1-7
Gene

Review
Epigenetics and migraine; complex mitochondrial interactions contributing to disease susceptibility

https://doi.org/10.1016/j.gene.2014.04.001Get rights and content

Abstract

Migraine is a common neurological disorder classified by the World Health Organisation (WHO) as one of the top twenty most debilitating diseases in the developed world. Current therapies are only effective for a proportion of sufferers and new therapeutic targets are desperately needed to alleviate this burden. Recently the role of epigenetics in the development of many complex diseases including migraine has become an emerging topic. By understanding the importance of acetylation, methylation and other epigenetic modifications, it then follows that this modification process is a potential target to manipulate epigenetic status with the goal of treating disease. Bisulphite sequencing and methylated DNA immunoprecipitation have been used to demonstrate the presence of methylated cytosines in the human D-loop of mitochondrial DNA (mtDNA), proving that the mitochondrial genome is methylated. For the first time, it has been shown that there is a difference in mtDNA epigenetic status between healthy controls and those with disease, especially for neurodegenerative and age related conditions. Given co-morbidities with migraine and the suggestive link between mitochondrial dysfunction and the lowered threshold for triggering a migraine attack, mitochondrial methylation may be a new avenue to pursue. Creative thinking and new approaches are needed to solve complex problems and a systems biology approach, where multiple layers of information are integrated is becoming more important in complex disease modelling.

Introduction

Migraine is a common neurological disorder characterised by severe head pain and an assortment of additional symptoms which can include nausea, photophobia, phonophobia and for some subtypes of migraine additional neurological symptoms. Migraine is classified according to the International Headache Society into two broad categories namely migraine without aura (MO) and migraine with aura (MA) (Eriksen et al., 2004, Olesen and Lipton, 1994). Most patients suffer from MO, with only 20% of sufferers experiencing an aura before the onset of a migraine attack. Approximately 12% of the Caucasian population suffers from this debilitating disease with almost 2/3 of sufferers being female. Migraine is classified by the World Health Organisation (WHO) as one of the top twenty most debilitating diseases in the developed world and poses a significant personal and economic burden (Leonardi et al., 2005).

In 2010 it was estimated that headache disorders in Europe cost an estimated €43.5 billion per year (Gustavsson et al., 2011). It has been shown that the cost incurred by continuous absenteeism from the work place as a result of employees being unable to work due to debilitating migraine attacks is actually higher than the direct cost of treatment. Also the total percentage of costs attributed to loss of work place productivity caused by chronic disease is by far dominated by migraine with 89% attributed to migraine and only 19% for other chronic conditions (Schultz et al., 2009). Current therapies are only effective for a proportion of sufferers and new therapeutic targets are desperately needed to alleviate this burden.

Various theories explaining the pathophysiology of migraine have been tested and modified for the last eight decades. The most supported current view is that migraine is a complex multifactorial disease with both predisposing genetic variance and environmental factors contributing to the final phenotype. The actual biological mechanism involved in a migraine attack is still debated, but is thought to be caused by activation of the trigeminal nerve causing pain sensation in the sensor cortex of the brain and/or a dysfunction of the neuronal nuclei located within the brain stem (Ho et al., 2010). The trigeminal vascular theory states that activation of the trigeminal nerve system by a neural, vascular or neurovascular trigger leads to a migraine. The trigeminal nerves carry pain signals from the meninges and blood vessels infusing the meninges to the trigeminal nucleus in the brain stem which in turn sends signals to the sensor cortex via the thalamus. The sensor cortex processes pain signals and other senses, thus leading to the sensation of pain experienced during migraine attacks (Oshinsky and Luo, 2006). This mechanism is illustrated in Fig. 1 below.

Dysfunction of neuronal nuclei can be explained by migraine pain and trigeminovascular activation being caused by a central mechanism which may not require a primary sensory input (Goadsby and Akerman, 2012, Lambert et al., 2011). The most recent theory explaining migraine pathogenesis describes migraine as a dysfunction of the subcortical brain structures including the brainstem and diencephalic nuclei which are involved in modulating sensory inputs. The theory suggests that aura is triggered by dysfunction of these nuclei and that the same mechanism is responsible for the pain and other symptoms experienced during migraine attacks (Akerman et al., 2011). This theory challenges the importance of cortical spreading depression (CSD) in generating a migraine attack, a process which has previously been emphasized. CSD is a wave of neuronal and glial depolarization/neuronal hyperexcitability followed by a long lasting suppression of neural activity (de Almeida et al., 2009). This electrophysiological event has been linked to aura in the human visual cortex and is thought to be partly responsible for the sensory and motor disturbances experienced during MA attacks.

Section snippets

Heritability and migraine: a significant genetic contribution

Heritability is the proportion of a trait or disease phenotype which can be attributed to genetic variation. The official definition of heritability is the “proportion of phenotypic variation (VP) that is due to variation in genetic values (VG).” Genetic values (VG) include the combined effect of all loci as well as interactions within (dominance) and between (epistasis) loci. Two different basic heritability values can be calculated namely broad-sense and narrow-sense heritability. Broad-sense

Epigenetics

Epigenetics refers to partially heritable alterations which influence gene expression, not due to changes in DNA sequence but rather as a result of higher structural modifications. There are three main systems involved in epigenetic structuring namely; methylation, histone modification and RNA-associated silencing (Egger et al., 2004). It is well known that epigenetics plays a crucial role in gene regulation, growth and especially in development (Bird, 2007). Any alterations in epigenetic state

Epigenetic therapy

The initial thinking behind developing epigenetic therapies is that if it is possible to chemically manipulate factors such as methylation, acetylation etc., then it may be possible to alter regions where aberrant changes have taken place in order to try and restore the original state. Many agents capable of altering both methylation and acetylation have been discovered, and the applications of these are currently being tested (Egger et al., 2004). Agents include 5-azatine,

Rationale for investigation

Several lines of evidence exist to suggest that mitochondrial dysfunction may contribute to the pathogenesis of at least some subtypes of migraine. The brain and muscle are highly dependent on oxidative metabolism and are therefore the most severely affected tissues in the mitochondrial disorders. A variety of morphological, biochemical, imaging and genetic studies have provided evidence that mitochondrial dysfunction may play a role in migraine susceptibility (Sparaco et al., 2006). A

Mitochondrial methylation

Research interests in the relationship between nuclear DNA methylation, environmental exposures and disease outcome are well established. Epigenetic profiling has already become integrated into clinical practise for early diagnosis of cancer and as a molecular tool for determining cancer stages (Dehan et al., 2009, Laird, 2003). Bisulphite sequencing and methylated DNA immunoprecipitation in peripheral blood have been used to demonstrate the presence of methylated cytosines in the human D-loop

A multi-layered approach

For complex diseases where both a genetic and environmental component plays an integral role in pathogenesis, it is becoming more important to develop models which factor in both of these components. Epigenetic changes which are so heavily influenced by the environment have been intricately studied in the nuclear genome. Recent evidence directly suggests a link between nuclear epigenetic changes and migraine and indirectly suggests that the emerging field of mitochondrial methylation could

Conflict of interest

The authors declare that there is no conflict of interest.

Acknowledgements

Shani Stuart is the recipient of a QUT HDR Tuition Fee Sponsorship and QUT Postgraduate Research Award (QUTPRA) Scholarship for tuition fees and living allowance.

References (84)

  • V. Iacobazzi

    Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool

    Molecular Genetics and Metabolism

    (2013)
  • V. Infantino

    Impairment of methyl cycle affects mitochondrial methyl availability and glutathione level in Down's syndrome

    Molecular Genetics and Metabolism

    (2011)
  • H. Ino

    Mitochondrial leucine tRNA mutation in a mitochondrial encephalomyopathy

    Lancet

    (1991)
  • J.P. Issa

    Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies

    Blood

    (2004)
  • M. Ito

    Screening for mitochondrial, DNA heteroplasmy in children at risk for mitochondrial disease

    Mitochondrion

    (2001)
  • P.A. Jones et al.

    Cellular differentiation, cytidine analogs and DNA methylation

    Cell

    (1980)
  • P. Lestienne et al.

    Kearns–Sayre syndrome with muscle mitochondrial DNA deletion

    Lancet

    (1988)
  • P.A. Marks et al.

    Histone deacetylases

    Current Opinion in Pharmacology

    (2003)
  • Y. Nishigaki

    Extensive screening system using suspension array technology to detect mitochondrial DNA point mutations

    Mitochondrion

    (2010)
  • D. Passaro

    Epigenetic chromatin modifications in the cortical spreading depression

    Brain Research

    (2010)
  • I.A. Qureshi et al.

    Epigenetic mechanisms underlying human epileptic disorders and the process of epileptogenesis

    Neurobiology of Disease

    (2010)
  • A. Schaller

    Impairment of mitochondrial tRNA(Ile) processing by a novel mutation associated with chronic progressive external ophthalmoplegia

    Mitochondrion

    (2011)
  • K. Tanji

    Neuropathological features of mitochondrial disorders

    Seminars in Cell & Developmental Biology

    (2001)
  • R.W. Taylor

    A novel mitochondrial DNA point mutation in the tRNA(Ile) gene: studies in a patient presenting with chronic progressive external ophthalmoplegia and multiple sclerosis

    Biochemical and Biophysical Research Communications

    (1998)
  • G. Uziel

    Neuromuscular syndrome associated with the 3291T  C mutation of mitochondrial DNA: a second case

    Neuromuscular Disorders

    (2000)
  • M. Wessman

    Migraine: a complex genetic disorder

    Lancet Neurology

    (2007)
  • A.T. Willingham et al.

    TUF love for “junk” DNA

    Cell

    (2006)
  • L.J. Wong et al.

    Mitochondrial DNA analysis in clinical laboratory diagnostics

    Clinica Chimica Acta; International Journal of Clinical Chemistry

    (2005)
  • H. Zhao

    Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family

    American Journal of Human Genetics

    (2004)
  • S. Akerman et al.

    Diencephalic and brainstem mechanisms in migraine

    Nature Reviews. Neuroscience

    (2011)
  • K. Anamika

    Lessons from genome-wide studies: an integrated definition of the coactivator function of histone acetyl transferases

    Epigenetics & Chromatin

    (2010)
  • S. Bandiera

    Nuclear outsourcing of RNA interference components to human mitochondria

    PLoS One

    (2011)
  • A. Bird

    Perceptions of epigenetics

    Nature

    (2007)
  • M.D. Brown

    Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations

    Human Mutation

    (1995)
  • B.A. Chestnut

    Epigenetic regulation of motor neuron cell death through DNA methylation

    Journal of Neuroscience

    (2011)
  • D. Cotter

    MitoProteome: mitochondrial protein sequence database and annotation system

    Nucleic Acids Research

    (2004)
  • P. Dehan

    DNA methylation and cancer diagnosis: new methods and applications

    Expert Review of Molecular Diagnostics

    (2009)
  • S. DiMauro

    Mitochondrial myopathies

    Annals of Neurology

    (1985)
  • R. Egensperger

    Association of the mitochondrial tRNA(A4336G) mutation with Alzheimer's and Parkinson's diseases

    Neuropathology and Applied Neurobiology

    (1997)
  • G. Egger

    Epigenetics in human disease and prospects for epigenetic therapy

    Nature

    (2004)
  • E. Eising

    Epigenetic mechanisms in migraine: a promising avenue?

    BMC Medicine

    (2013)
  • M.K. Eriksen et al.

    New international classification of migraine with aura (ICHD-2) applied to 362 migraine patients

    European Journal of Neurology

    (2004)
  • Cited by (0)

    1

    Joint first authors.

    View full text