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Muscle 3243A→G mutation load and capacity of the mitochondrial energy‐generating system
Author(s) -
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.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21328
Subject(s) - mitochondrial dna , mitochondrial myopathy , melas syndrome , mitochondrial disease , lactic acidosis , biology , mitochondrial respiratory chain , respiratory chain , mitochondrion , mutation , bioenergetics , mitochondrial encephalomyopathies , genetics , biochemistry , gene
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