Molecular pathology of Luft disease and structure and function of mitochondria

Luft disease, studied in detail by Luft et al. (1962) is characterized clinically by hypermetabolism and consequent abnormal transpiration. In their study, Luft and coworkers revealed that the hypermetabolism is caused by extensive uncoupling of mitochondrial respiration in skeletal muscle tissue. They also discovered that the muscle mitochondria had been structurally modified with the cristae assuming a zig-zag conformation. The mitochondrial enzymes functioned normally, the abnormality being confined to the extensive uncoupling of respiration. In an earlier study (Sjöstrand et al., 1988) it was revealed that the zig-zag conformation is caused by removal of some tricarboxylic acid cycle enzymes from the cristae, exposing the interior of the cristae to the matrix fluid. Applying a coupling theory proposed by Sjöstrand (1990, 1991), leakage of protons from the cristae should impair coupling of respiration and ATP synthesis. The structural damage is conceived of to be caused by a genetic defect preventing proper aggregation of the enzyme molecules in the cristae. Luft disease may therefore be the first known disease caused primarily by a structural disorder at the molecular level. The symptoms of the disease reveal the importance of the compact and ordered aggregation of the enzyme molecules in the cristae for coupling of respiration.