Complex disorder or mitochondrial disease comprises a steadily growing group of genetically and clinically heterogenous enzyme-complex defects characterized by altered energy metabolism (mitochondrial oxidative phosphorylation) and a wide range of neurological, cardiac, muscular, and endocrine disorders. The system of oxidative phosphorylation is composed of the respiratory chain multi-protein enzyme complexes I-V and the two electron-carriers coenzyme Q (CoQ or ubiquinone) and cytochrome c. The symptoms associated with mitochondrial disease are primarily due to a lack of energy in tissues and thus organs with the highest energy requirements suffer first and foremost.
“Mitochondrial medicine” was defined by Luft and Moyan-Hughes in the late 1980s and became the subject of numerous investigations of the metabolic disorders affecting the muscles and the brain. Mitochondria were first recognized in 1898 by Bend. The term comes from the Greek mitos (thread) and chondros (grain). The concept of cellular respiration was defined and studied in the 1920s.
In the 1970s and mid-1980s, the standard classification of respiratory chain disorders rested on the biochemical phenotype, however, this approach for mitochondrial DNA (mtDNA) mutations leading to respiratory inefficiencies is now less clear. It is accepted that most mtDNA mutations affect the subunit synthesis either through a mutation in a key transfer RNA (tRNA) gene or through deletion of a series of tRNA genes. The presence of tRNA mutations may, among other mechanisms, lead to amino acid dysfunction most probably within larger subunits.
TABLE C-1Mitochondrial Respiratory Chain Composition by Complex ||Download (.pdf) TABLE C-1 Mitochondrial Respiratory Chain Composition by Complex
|Complex ||I ||II ||III ||IV ||V |
|Enzyme ||NADH-CoQ reductase ||Succinate-CoQ reductase ||CoQ-cytochrome C reductase ||Cytochrome C oxidase ||ATP synthase |
|Inhibitor ||Rotenone, Amytal ||TTFA malonate ||Antimycin A ||Cyanide carbon, monoxide azide ||Oligomycin |
|Nuclear DNA subunits ||39 ||4 ||10 ||10 ||≈14 |
|Mitochondrial DNA ||7 ||0 ||1 ||3 ||2 |
|subunits ||ND1—6, ND4L || ||Cytochrome b ||Cytochrome oxidase I, II, III ||ATPase 6, ATPase 8 |
|Flavoprotein ||Flavin mononucleotide ||FAD (SDAH) || || || |
|Iron protein ||Iron sulfur (FeS) protein ||FeS protein, SDHB ||Rieke FeS, cytochrome (heme) b, c1 ||Cytochrome (heme) a, a3 || |
|Other features || ||Membrane proteins, Cytochrome b560, SDHC, SDHD || ||Copper protein || |
|Associated disorders ||Alzheimer, parkinsonism, cardiomyopathy, Barth Syndrome, lethal infantile encephalopathy, Infantile Crigler-Najjar Syndrome, LHON, Leigh, MELAS, MERRF, Myopathy ± Crigler-Najjar Syndrome, PEO ||KSS, Leigh, Myopathy during infancy ± Crigler-Najjar Syndrome, paraganglioma, pheochromocytoma ||Cardiomyopathy, fatal infantile myopathy, Leber myopathy ± Crigler-Najjar Syndrome, PEO 6 Fragile Syndrome ||Alpers ataxia; deafness; Leber atrophy; Leigh; myopathy, infantile; myopathy, benign; myopathy, fatal; adult rhabdomyolysis, PEO; KSS; MNGIE; MERRF; MELAS ||Leber atrophy, Leigh, NARP |