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: 11.91). 04/2008; 63(4):473-81. DOI: 10.1002/ana.21328
Source: PubMed

ABSTRACT 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.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Establishing a diagnosis in patients with a suspected mitochondrial disorder is often a challenge. Both knowledge of the clinical spectrum of mitochondrial disorders and the number of identified disease-causing molecular genetic defects are continuously expanding. The diagnostic examination of patients requires a multi-disciplinary clinical and laboratory evaluation in which the biochemical examination of the mitochondrial functional state often plays a central role. In most cases, a muscle biopsy provides the best opportunity to examine mitochondrial function. In addition to activity measurements of individual oxidative phosphorylation enzymes, analysis of mitochondrial respiration, substrate oxidation, and ATP production rates is performed to obtain a detailed picture of the mitochondrial energy-generating system. On the basis of the compilation of clinical, biochemical, and other laboratory test results, candidate genes are selected for molecular genetic testing. In patients in whom an unknown genetic variant is identified, a compatible biochemical phenotype is often required to firmly establish the diagnosis. In addition to the current role of the biochemical analysis in the diagnostic examination of patients with a suspected mitochondria disorder, this report gives a future perspective on the biochemical diagnosis in view of both the expanding genotypes of mitochondrial disorders and the possibilities for high throughput molecular genetic diagnosis.
    Journal of Inherited Metabolic Disease 05/2010; 34(2):283-92. DOI:10.1007/s10545-010-9081-y · 4.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Myostatin (Mstn) participates in the regulation of skeletal muscle size and emerges as a reg-ulator of muscle metabolism. We here hypothesized that lack of myostatin profoundly de-presses oxidative phosphorylation dependent muscle function. For this extent, we explored Mstn-/- mice as a model for the constitutive absence of myostatin and AAV-mediated over-expression of myostatin propeptide as a model of myostatin blockade in adult wildtype mice. We show that muscles from Mstn-/- mice, although larger and stronger, fatigue ex-tremely rapidly. Myostatin deficiency shifts muscle from aerobic towards anaerobic energy metabolism as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise induced lactic acido-sis. In consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn-/- mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the con-genital fiber-type switch towards a glycolytic phenotype of constitutive Mstn-/- mice. Hence we over-expressed myostatin propeptide in adult mice, which did not affect fiber-type dis-tribution, while nonetheless causing increased muscle fatigability, diminished exercise ca-pacity and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus reg-ulating the delicate balance between muscle mass, muscle force, energy metabolism and endurance capacity.
    AJP Regulatory Integrative and Comparative Physiology 06/2014; 307(4). DOI:10.1152/ajpregu.00377.2013 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clinical disorders known to affect inherited gamma-amino butyric acid (GABA) metabolism are autosomal reces-sively inherited succinic semialdehyde dehydrogenase and GABA-transaminase deficiency. The clinical presentation of succinic semialdehyde dehydrogenase deficiency includes intellectual disability, ataxia, obsessive-compulsive disorder and epilepsy with a nonprogressive course in typical cases, although a progressive form in early childhood as well as deterioration in adulthood with worsening epilepsy are reported. GABA-transaminase deficiency is associated with a severe neonatal-infantile epileptic encephalopathy.