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

Department of Pediatrics and Laboratory of Pediatrics and Neurology, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, Nijmegen, The Netherlands.
Annals of Neurology (Impact Factor: 9.98). 04/2008; 63(4):473-81. DOI: 10.1002/ana.21328
Source: PubMed


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.
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.
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.
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.

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    • "A reduced pyruvate oxidation rate that is normalized by addition of an uncoupler, such as FCCP, indicates a defect in complex V, the adenine nucleotide translocator, or the phosphate transporter (Jonckheere et al. 2008; Mayr et al. 2007). The MEGS assays described above not only provide in-depth information on the mitochondrial functional state, it has also been shown that these assays are more sensitive to detect mitochondrial defects, compared to measurements of individual OXPHOS enzyme activities (Janssen et al. 2008). In the case of a patient with a clinical phenotype with profound involvement of tissues other than muscle, a biopsy of the affected tissue should be considered. "
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