Oxidative phosphorylation, i.e., ATP synthesis by the respiratory chain, is a ubiquitous metabolic pathway that supplies most organs and tissues with energy. Consequently, respiratory chain deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age, with any mode of inheritance, due to the twofold genetic origin of respiratory enzymes (nuclear DNA and mitochondrial DNA).
In the last few years, it has become increasingly clear that genetic defects of oxidative phosphorylation account for a large variety of clinical symptoms in childhood. Among 160 respiratory enzyme chain-deficient patients identified in our center, 40 percent were referred for a neuromuscular symptom and 60 percent presented with a nonneuromuscular disease.1 Overall, the diagnosis of respiratory chain deficiency is difficult to consider when the first symptom occurs. The diagnosis becomes easier when two seemingly unrelated symptoms are observed.
The mitochondrial respiratory chain catalyzes the oxidation of fuel molecules by oxygen and the concomitant energy transduction into ATP via five complexes, embedded in the inner mitochondrial membrane2 (Fig. 99-1). Complex I (NADH-coenzyme Q reductase) carries reducing equivalents from NADH to coenzyme Q (CoQ, ubiquinone) and consists of more than 40 different polypeptides, seven of which are encoded by mitochondrial DNA (mtDNA). Complex II (succinate-CoQ reductase) carries reducing equivalents from FADH2 to CoQ and contains four polypeptides, including the FAD-dependent succinate dehydrogenase and three iron-sulfur centers. This is the only complex that does not contain any mtDNA-encoded protein. Complex III (reduced CoQ-cytochrome c reductase) carries electrons from CoQ to cytochrome c. It contains 11 subunits, one of which (cytochrome b) is encoded by mtDNA. Complex IV (cytochrome c oxidase, COX), the terminal oxidase of the respiratory chain, catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen. It is composed of two cytochromes (a and a3 ), two copper atoms, and 13 different protein subunits, three of which are encoded by mtDNA.2
During the oxidation process, electrons are transferred to oxygen via the energy-transducing complexes of the respiratory chain: complexes I, III, and IV for NADH-producing substrates; complexes II, III, and IV for succinate; and complexes III and IV for FADH2, derived from the β-oxidation pathway via the electron transfer flavoprotein (ETF) and the ETF-CoQ oxidoreductase system (Fig. 99-1). CoQ, a highly hydrophobic quinone, and cytochrome c, a low-molecular-weight hemoprotein, act as “shuttles” between complexes. The free energy generated from the redox reactions is converted into a transmembrane proton gradient. Protons are pumped through complexes I, III, and IV of the respiratory chain, creating a charge differential. Complex V (ATP synthase) allows protons to flow back into the mitochondrial matrix and uses the released energy to synthesize ATP. Three ATP molecules are made for each NADH molecule oxidized.
Since the respiratory chain transfers NADH to oxygen, a disorder of oxidative phosphorylation should result in 1) an increase of reducing equivalents in both mitochondria and cytoplasm and 2) the functional impairment of the citric acid cycle, due to the excess of NADH and the lack of NAD. Therefore, an increase of ketone body (β-OH butyrate/acetoacetate) and lactate/pyruvate (L/P) molar ratios with secondary elevation of blood lactate might be found in the plasma of affected individuals.3 This is particularly true in the postabsorptive period, when more NAD is required to adequately oxidize glycolytic substrates. Similarly, as a consequence of the functional impairment of the citric acid cycle, ketone body synthesis increases after meals due to the channeling of acetyl-CoA toward ketogenesis. The elevation of total ketone bodies in a fed individual is paradoxical, as it should normally decrease after meals, due to insulin release (paradoxical hyperketonemia).4