Table 2.

Metabolic and pharmacological agents used to treat mitochondrial disease^a

Agent	Indication	Mechanism	Patient dose (per day)	Reference(s)
Cofactors that increase the production of ATP
CoQ	Mitochondrial disorders	Transfers electrons from complex I and II to complex III	Variable, 5 mg kg⁻¹	307, 308
Idebenone	Mitochondrial disorders	Transfers electrons from complex I and II to complex III	Variable; child, 5 mg kg⁻¹ day⁻¹; adult, 90 mg day⁻¹ (up to 225 mg day⁻¹)	237, 309
Succinate	Complex I deficiency	Bypasses complex I	6 g day⁻¹	244
Dimethylglycine	Mitochondrial disorders	Transfers electrons to CoQ	5 g kg⁻¹ if > 33kg, 50 mg kg⁻¹ if < 33 kg	310
Other cofactors and vitamin or metabolic supplements
Thiamine (vitamin B1)	PDH deficiency	Cofactor of PDH	Variable: child, 5 mg day⁻¹; adult, 90 mg day⁻¹ (up to 225 mg day⁻¹)	249, 250
Riboflavin (vitamin B2)	Complex I and II deficiency	Increases complex I and II activities	100 mg day⁻¹	289
Nicotinamide (vitamin B3)	MELAS	Increases nicotinamide adenine dinucleotide	50 mg kg⁻¹ day⁻¹	311
Dichloroacetate	Severe lactic acidosis	Reduces lactic acidosis, stimulates PDH	50 mg kg⁻¹	120, 256, 312, 313
Creatine monohydrate	Mitochondrial myopathy	Increases muscle phosphocreatine	10–20 g day⁻¹	314, 315
Carnitine	Carnitine deficiency	Increases carnitine level	3 g day⁻¹	258
L-arginine	MELAS	Increases nitric oxide production	0.15–0.3 g kg⁻¹ day⁻¹	258
Reactive oxygen species scavengers and mitochondrial antioxidants
CoQ/idebenone	Mitochondrial disorders	Act as antioxidant	Variable; child, 5 mg kg⁻¹ day⁻¹; adult, 90 mg day⁻¹ (up to 225 mg/day)	237, 307–309
Vitamin E	Mitochondrial disorders	Antioxidant	50 µg day⁻¹	–
Vitamin C (ascorbate)/vitamin K3 (menadione)	Mitochondrial disorders	Antioxidants, bypass complex III	4 g day⁻¹/40 mg day⁻¹	245–247
Lipoic acid	Pyruvate dehydrogenase deficiency	Acts as antioxidant, stimulates PDH	600 mg day⁻¹	261
Triacetyluridine	Mitochondrial disorders	De novo pyrimidine biosynthesis	Animal models	255
Modulation of the mtPTP
Cyclosporin A	–	Inhibits the mtPTP	In vitro studies	255
Nortriptyline	–	Inhibits the mtPTP	Animal models	269
Regulation of mitochondrial biogenesis
Sirtuin analogs	Mitochondrial disorders	Increase mitochondrial biogenesis	Animal models	273
Bezafibrate	Mitochondrial disorders	Increases mitochondrial biogenesis	In vitro studies, animal models	276
Exercise therapy and diet
High-fat diet	Mitochondrial disorders	Increases electron transfer	50%–60% calories	289
Ketonic diet	Intractable seizures, mitochondrial disorders	Bypasses glycolytic pathway	4:1 lipid:nonlipid ratio	100, 290
Endurance exercise	Mitochondrial myopathy	Aerobic training induces OXPHOS	–	280, 281
Resistance exercise	Mitochondrial myopathy	Activation and proliferation of satellite cells in muscle, shifting of heteroplasmy	–	282, 283

Abbreviations: CoQ, coenzyme CoQ₁₀; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; mtPTP, mitochondrial permeability transition pore; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase.