Mitochondrial Modulators.
Treatment of mitochondrial disease is still in its infancy. Aside from symptom-based management, treatment of mitochon-drial disease focuses on maintaining optimal health, using preventive measures to mitigate symptom worsening during times of physiologic stress (such as infection, dehydration, or surgery), and avoiding mitochondrial toxins.
Scientific support for the use of vitamin-based and cofactor-based mitochondrial therapies is accumulating. Such pharmacologic supplements are intended to promote critical enzymatic reactions, reduce putative sequelae of excess free radicals, and scavenge toxic acyl coenzyme A (acyl CoA) molecules, which accumulate in mitochondrial disease. Some supplements also may act as alternative energy fuels or may bypass biochemical blocks within the respiratory chain, although these mechanisms are more widely debated. Exercise also has an important role in mitochondrial disease therapy, as it has been shown to reduce the burden of unhealthy mitochondria; increase the percentage of healthy, nonmutated mitochondrial DNA (mtDNA); and improve endurance and muscle function.
Current clinical goals for mitochondrial disease therapy are to increase energy production in the form of adenosine triphosphate (ATP) and reduce free radical production in an effort to improve, or at least stabilize, disease signs and symptoms. Among mitochondrial disease experts, there is anecdotal evidence of such improvement. A variety of scientific studies have also demonstrated some clinical improvement, although the vast majority of studies evaluating antioxidant efficacy in mitochondrial disease have been short-term, nonrandomized trials.
Ketogenic diet.
The ketogenic diet is a high-fat diet that effectively treats some forms of medically refractory epilepsy. Recent animal research has suggested that the ketogenic diet may be beneficial in optimizing mitochondrial function.
Coenzyme Q10.
The evidence supporting the use of coenzyme Q10 (CoQ10, also known as ubiquinone) in mitochondrial disease was reviewed in 2007. CoQ10 is endogenously synthesized in mammalian mitochondria and is an integral component of the mitochondrial electron transport chain, shuttling electrons from complexes I or II and a number of other electron donors, including electron transfer factor, which moves electrons from fatty acid beta oxidation.
CoQ10 is found in all cell and organelle membranes, where it can participate in redox shuttling. It has an important intracellular signaling role, as well as both antioxidant and pro-oxidant roles. CoQ10 modulates the mitochondrial permeability transition pore involved in apoptosis and activates uncoupling proteins.
Pharmacokinetics.
CoQ10 is insoluble in water. Powder formulations of CoQ10 have very poor intestinal absorption. No increase in CoQ10 plasma levels was achieved when 3000 mg/d was compared with administration of 2400 mg/d, suggesting a block to gastrointestinal absorption above 2400 mg in adults. Improved bioavailability has been seen with the use of nano-particles in suspension.
Recently, reduced CoQ has become commercially available in the form of ubiquinol. This formulation is three to five times better absorbed when compared with the oxidized form of CoQ, ubiquinone.
CoQ levels in blood and tissues fall with normal aging. CoQ levels in a 70-year-old are about 50% of those in a 20-year-old.
Riboflavin.
Riboflavin is a water-soluble B vitamin (B2) that serves as a flavoprotein precursor. It is a key building block in complex I and II and a cofactor in several other key enzymatic reactions involving fatty acid oxidation and the Krebs cycle.
Multiple acyl CoA dehydrogenase deficiency (MADD), typically caused by electron-transport flavoprotein dehydrogenase (ETFDH) gene mutations, is a known inborn error of metabolism involving several of these enzymatic reactions; riboflavin supplementation using moderate to high doses can lead to amelioration of symptoms and slowing of disease progression.
Several non-randomized studies have shown riboflavin to be efficacious in treating mitochondrial diseases, specifically complex I and/or complex II disease.
L-creatine.
Creatine, a compound present in cells, combines with phosphate in the mitochondria to form phosphocreatine. It serves as a source of high-energy phosphate, released during anaerobic metabolism. It also acts as an intracellular buffer for ATP and as an energy shuttle for the movement of high-energy phosphates from mitochondrial sites of production to cytoplasmic sites of utilization.
A randomized, controlled trial in adult patients with mitochondrial cytopathies showed benefits from creatine taken as an initial dose of 5 g twice a day for 2 weeks followed by 2 g twice a day for 1 week.
L-Carnitine.
L-Carnitine is a cellular compound that plays a critical role in the process of mitochondrial β-oxidation of fatty acids and the esterification of free fatty acids that may otherwise be sequestered by CoA. Carnitine transfers long-chain fatty acids across the mitochondrial inner membrane as acylcarnitine esters. These esters are oxidized to acetyl CoA, which enters the Krebs cycle and results in subsequent generation of ATP via oxidative phosphorylation.
Other redox agents.
Thiamine (B1), vitamins C and E, and alpha-lipoic acid also have been used in mitochondrial disease patients, individually or as part of an antioxidant cocktail. These therapies have less scientific data available regarding treatment of mitochondrial disease than the medications discussed here in more detail.