Mitochondrial dysfunction implicated in migraines

In the 1930s, it was suggested that migraine was associated with a decrease in blood sugar (Gray et al. 1935). Despite this hypothesis of the existence of a relationship between migraine and mitochondrial energetic metabolic dysfunction, the majority of research has focused on the vascular, neurovascular and neurological aspects of the disease. It was not until the publications of Willem Amery in 1982 that this hypothesis reappeared, in which a metabolic disorder is involved in the pathogenesis of migraines (Amery 1982). Since then, several scientific elements have been added, reinforcing the hypothesis that migraines could, at least partially, be due to an energy deficit syndrome.

Mitochondrial dysfunction

In migraine patients, it has been shown that markers of energy metabolism, such as adenosine triphosphate (ATP), lactate, which plays a fundamental role in anaerobic glycolysis, or magnesium, an essential cofactor for the production of ATP were modified. Indeed, a decrease in brain ATP has been observed between attacks in migraine sufferers with aura, compared to healthy patients (Lodi et al. 2001). A reduction in free cytosolic magnesium was observed in the occipital lobes during and between attacks (Ramadan et al. 1989). As for lactate, the data seem to vary between studies, with a higher rate in migraine patients with aura, but these results have not been reproduced in patients without aura (Reyngoudt et al. 2011; Watanabe et al. 1996 ). The level of phosphocreatine (a molecule of phosphorylated creatine rich in energy, used in the muscles during the synthesis of ATP) is reduced in migraine patients while the level of adenosine diphosphate is increased (Montagna et al. 1994); this indicates a low intracellular energy level, as well as a probable mitochondrial dysfunction. These conditions can lead to the inability of neurons to cope with an increased energy requirement, making the brains of migraine patients more sensitive to certain stimuli, which trigger the attack.

A lack of ATP disrupts the functioning of neuronal ion pumps, the membranes depolarize and an intracellular influx of Ca ²⁺ causes the massive release of glutamate (De Baaij et al. 2015). The latter leads to a massive depolarization of neurons in cascade and ultimately, severe neuronal dysfunction. This massive depolarization of neurons is reminiscent of the DCE that we described previously.

One of the elements that has directed a number of research on migraines towards the metabolic aspect is the study of MELAS syndrome, a genetic disease caused by mutations in mitochondrial DNA, and which, as its acronym indicates, associates a myopathy (M), encephalopathy (E), lactic acidosis (LA) and pseudo-strokes (S). In addition to these symptoms, one can find unilateral headaches of sudden onset, vision disorders such as diplopia or scotoma, speech difficulties, nausea or vomiting and exacerbated pain during physical activity. These are all signs that are also found in migraine patients (Kugler et al. 2007) and which suggest that migraine could also be associated with a metabolic alteration, involving the mitochondria.

During glycolysis, the mitochondria transform pyruvate into acetyl-CoA then during a respiratory chain into ATP and lactate (Dimauro et al. 2004). In migraine patients, a dysfunction of this respiratory chain could explain the variations in the patient's energy metabolism (Gross et al. 2019).