Table 1.
Treatments evaluated in patients with mitochondrial diseases
Agent | Specific mechanism(s) of action | Highest level of clinical study in humans |
---|---|---|
Increase of substrate supply to respiratory chain | ||
Carnitine | Fatty acid transfer for citric acid cycle intermediates | Case report71 |
Niacin | Precursor for NADH, which transfers electrons from intermediates to the respiratory chain | Case report72 |
Thiamine | Enhancement of pyruvate dehydrogenase to decarboxylate pyruvate for oxidation | Case report73 |
Dichloroacetate | Inhibition of pyruvate dehydrogenase kinase to increase availability of pyruvate for oxidation | Randomized, placebo-controlled crossover trial in MELAS due to m.3243A>G mutation (negative outcome)34 |
Augmentation of respiratory chain components | ||
Riboflavin | Precursor for flavin adenine dinucleotide, an electron carrier bound to complexes I and II | Open-label study in complex I deficiency (positive outcome)8 |
Coenzyme Q10 | Electron carrier from complexes I and II to complex III | Randomized, placebo-controlled crossover trial (negative outcome)32 |
Idebenone | Analogue of coenzyme Q10 | Randomized, placebo-controlled trial in Leber hereditary optic neuropathy (negative outcome)36 |
EPI-743 | Analogue of vitamin E | Open-label study in Leigh syndrome and Leber hereditary optic neuropathy (positive outcome)39,47 |
Bypass of respiratory chain components | ||
Succinate | Citric acid cycle intermediate which donates electrons directly to complexes I and II, thus partially bypassing complex I | Case report12 |
Vitamins C and K | Bypass of complex III | Case report13 |
Energy buffering | ||
Creatine | ATP storage in muscles via the creatine phosphokinase system | Randomized, placebo-controlled crossover trials in mitochondrial myopathies (negative outcomes in two trials, positive surrogate end points in one trial)35,52,73 |
Antioxidant activity | ||
Cysteine | Increases muscle availability of glutathione peroxidase | Randomized, placebo-controlled crossover trial in progressive external ophthalmoplegia (negative outcome)14 |
Lipoic acid | β-ketoacid dehydrogenase cofactor with antioxidant properties | Case report66; randomized, placebo-controlled crossover trial (with creatine and coenzyme Q10; negative outcomes in various mitochondrial myopathies)46 |
Dimethylglycine | Antioxidant activity | Randomized, placebo-controlled crossover trial in Saguenay Lac-St-Jean cytochrome c oxidase deficiency (negative outcome)15 |
Oxidative capacity adaptations | ||
Aerobic exercise training | Reversal of deconditioning and/or mitochondrial adaptation to improve oxidative capacity | Randomized, non-blinded controlled trial in mitochondrial myopathies (positive outcome)17,51,65,75 |
Resistance exercise training | Myofibre regeneration and presumed gene shifting | Open-label study (positive outcome)76,77 |
Nitric oxide metabolism | ||
Arginine | Substrate for nitric oxide synthase | Open-label placebo-controlled trial in MELAS due to m.3243A>G mutation (positive outcome)18 |
Abbreviation: MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.