Muscle 3243A→G mutation load and capacity of the mitochondrial energy-generating system

• Published in: Annals of neurology Vol. 63; no. 4; pp. 473 - 481
• Main Authors: Janssen, Antoon J. M., Schuelke, Markus, Smeitink, Jan A. M., Trijbels, Frans J. M., Sengers, Rob C. A., Lucke, Barbara, Wintjes, Liesbeth T. M., Morava, Eva, van Engelen, Baziel G. M., Smits, Bart W., Hol, Frans A., Siers, Marloes H., Ter Laak, Henk, van der Knaap, Marjo S., Van Spronsen, Francjan J., Rodenburg, Richard J. T., van den Heuvel, Lambert P.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2008; Willey-Liss
• Subjects: Adenosine - genetics; Adolescent; Adult; Biological and medical sciences; Child; Child, Preschool; Diseases of striated muscles. Neuromuscular diseases; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Electron Transport - genetics; Energy Metabolism - genetics; Female; Guanine - physiology; Humans; Infant; Male; Medical sciences; MELAS Syndrome - diagnosis; MELAS Syndrome - genetics; MELAS Syndrome - metabolism; Middle Aged; Mitochondria, Muscle - genetics; Mitochondria, Muscle - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiology; Mutation - genetics; Neurology; Mitochondria; Nervous system diseases; Mutation
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21328

Objective The mitochondrial energy‐generating system (MEGS) encompasses the mitochondrial enzymatic reactions from oxidation of pyruvate to the export of adenosine triphosphate. It is investigated in intact muscle mitochondria by measuring the pyruvate oxidation and adenosine triphosphate production rates, which we refer to as the “MEGS capacity.” Currently, little is known about MEGS pathology in patients with mutations in the mitochondrial DNA. Because MEGS capacity is an indicator for the overall mitochondrial function related to energy production, we searched for a correlation between MEGS capacity and 3243A→G mutation load in muscle of patients with the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome. Methods In muscle tissue of 24 patients with the 3243A→G mutation, we investigated the MEGS capacity, the respiratory chain enzymatic activities, and the 3243A→G mutation load. To exclude coinciding mutations, we sequenced all 22 mitochondrial transfer RNA genes in the patients, if possible. Results We found highly significant differences between patients and control subjects with respect to the MEGS capacity and complex I, III, and IV activities. MEGS‐related measurements correlated considerably better with the mutation load than respiratory chain enzyme activities. We found no additional mutations in the mitochondrial transfer RNA genes of the patients. Interpretation The results show that MEGS capacity has a greater sensitivity than respiratory chain enzymatic activities for detection of subtle mitochondrial dysfunction. This is important in the workup of patients with rare or new mitochondrial DNA mutations, and with low mutation loads. In these cases we suggest to determine the MEGS capacity. Ann Neurol 2008