Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine

Abstract

The mechanisms of migraine pathogenesis are not completely clear, but ³¹P-nuclear magnetic resonance studies revealed brain energy deficit in migraineurs. As glycolysis is the main process of energy production in the brain, mitochondria may play an important role in migraine pathogenesis. Nutrition is an important aspect of migraine pathogenesis, as many migraineurs report food-related products as migraine triggers. Apart from approved anti-migraine drugs, many vitamins and supplements are considered in migraine prevention and therapy, but without strong supportive evidence. In this review, we summarize and update information about nutrients that may be important for mitochondrial functions, energy production, oxidative stress, and that are related to migraine. Additionally, we present a brief overview of caffeine and alcohol, as they are often reported to have ambiguous effects in migraineurs. The nutrients that can be considered to supplement the diet to prevent and/or ameliorate migraine are riboflavin, thiamine, magnesium ions, niacin, carnitine, coenzyme Q10, melatonin, lipoic acid, pyridoxine, folate, and cobalamin. They can supplement a normal, healthy diet, which should be adjusted to individual needs determined mainly by the physiological constitution of an organism. The intake of caffeine and alcohol should be fine-tuned to the history of their use, as withdrawal of these agents in regular users may become a migraine trigger.

Keywords: dietary intervention in migraine; energy production; glycolysis; migraine; mitochondria; oxidative stress.

Figure 1

Synthesis of ATP from glucose, the main process of energy production in the brain, consists of three essential stages: glycolysis; the citric acid cycle (TCA); and oxidative phosphorylation. Glycolysis occurs in the cytoplasm, and uses ATP to split glucose into two pyruvate molecules. This process gives a net gain of two ATP molecules. In an aerobic environment, each pyruvate becomes acetyl CoA (acetyl coenzyme A), and goes to the mitochondria matrix to perform the TCA cycle, resulting in the production of CO₂, NADH (nicotinamide adenine dinucleotide), FADH₂ (dihydroflavine adenine dinucleotide), and ATP. The generation of coenzymes NADH and FADH₂ is critical, as they donate electrons and hydrogen to ETC in the inner mitochondrial membrane within the cristate to produce more ATP—one molecule of glucose gives 36 ATP molecules.

Figure 2

Migraine associates with mitochondrial dysfunction and energy production. Impairment of the electron transport chain (ETC) in mitochondria may result in decreased ATP production. There are several reasons and consequences of this impairment, including mutations and epimutations in both mitochondrial DNA (mtDNA) and nuclear DNA (ncDNA), decrease in the activity of mitochondrial superoxide dismutase (SOD2), which, along with impaired ETC, may contribute to increased production of reactive oxygen and nitrogen species (ROS and RNS, respectively), activation of cytochrome-c oxidase and nitric oxide, high levels of lactate and pyruvate, as well as other effects, which together may be involved in migraine headache (red star) induction.

Figure 3

Potential beneficial effects of riboflavin in migraine. Riboflavin may exert protective effects in migraine, symbolized here by a red star, by the modulation of the mitochondria-energy production-oxidative stress pathway, but its details are poorly known. Riboflavin may reduce oxidative stress associated with migraine. Riboflavin targets complex I of the electron transport chain (ETC, simplified here to complexes I–IV), whose activity may decrease in migraineurs, especially those with non-H mitochondrial haplotype (non-H). Riboflavin may ameliorate energy deficit resulted from malfunction of the complex I, and, in this way, decreases migraine-related symptoms. These activities result from the involvement of riboflavin in mitochondrial homeostasis. Riboflavin may also reduce neuroinflammation, important in migraine pathogenesis.

Figure 4

Some nutrients may prevent or cure migraine. Certain nutrients may improve energy production, and reduce energy deficit in the brain through improvement of mitochondrial functions, resulting in increased ATP production, and reduction of oxidative stress through decreasing reactive oxygen and nitrogen species (ROS and RNS, respectively). Such an action may prevent or ameliorate migraine (red star). Some candidates for such compounds are: riboflavin; thiamine; magnesium ions (Mg2+); niacin; carnitine; coenzyme Q10 CoQ10); melatonin; lipoic acid (LA); pyridoxine; folate; and cobalamin.