Chapter 99

## Abstract

The Metabolic Dysfunction  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 Fig. 99-1

The mitochondrial respiratory chain. ETF = electron transfer flavoprotein; UQ = quinone.

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