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


CONCLUSIONS
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.
Janssen
Antoon J M
AJ
Department of Pediatrics and Laboratory of Pediatrics and Neurology, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, Nijmegen, The Netherlands.
Schuelke
Markus
M
Smeitink
Jan A M
JA
Trijbels
Frans J M
FJ
Sengers
Rob C A
RC
Lucke
Barbara
B
Wintjes
Liesbeth T M
LT
Morava
Eva
E
van Engelen
Baziel G M
BG
Smits
Bart W
BW
Hol
Frans A
FA
Siers
Marloes H
MH
Ter Laak
Henk
H
van der Knaap
Marjo S
MS
Van Spronsen
Francjan J
FJ
Rodenburg
Richard J T
RJ
van den Heuvel
Lambert P
LP
D000241:Adenosine / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004579:Electron Transport / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D006147:Guanine / Q000502:physiology; D006801:Humans; D007223:Infant; D017241:MELAS Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D009154:Mutation / Q000235:genetics*
D004272:DNA, Mitochondrial; D006147:Guanine; D000241:Adenosine