Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome.
Decreased activity of complex I (NAD:ubiquinone oxidoreductase) is the most frequent biochemical finding associated with mutation at the base pair 3243 of the mitochondrial DNA. The mutation has been previously shown to lead to a defective translation. We hypothesized that due to an imperfect assembly of complex I subunits the substrate affinity of this enzyme may be lowered and this may be counteracted by increasing the mitochondrial NAD+NADH concentration. Therefore, we studied the effect and mechanism of action of nicotinamide treatment in a MELAS patient with the base pair 3243 mutation. Nicotinamide treatment was initiated after his first stroke-like episode. The blood NAD concentration (representing the intracellular concentration in erythrocytes) increased linearly being 24-fold at 6 weeks of treatment. Blood lactate and pyruvate concentration decreased by 50% within three days and 24 h urine lactate content within 2 weeks and we observed a clinical improvement together with a decrease in the lesion volume in magnetic resonance imaging within the first month. The cellular NAD increase upon nicotinamide administration was probably universal, because it occurred in a time and dose-dependent manner in cultured fibroblasts from both the patient and the controls. Alleviation of the lactate accumulation during the nicotinamide treatment suggests that an increase in the cellular NAD+NADH concentration leads to enhancement of the oxidation of reducing equivalents. However, the Km of complex I for NADH in skeletal muscle from the patient was similar to that of controls. This may indicate that physiologically mitochondrial complex I operates at non-saturating substrate concentration, and this may explain the effect of nicotinamide treatment.
Majamaa
K
K
Department of Neurology, University of Oulu, Finland.
Rusanen
H
H
Remes
A M
AM
Pyhtinen
J
J
Hassinen
I E
IE
D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D002220:Carbamazepine / Q000627:therapeutic use; D002478:Cells, Cultured; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D004827:Epilepsy / Q000188:drug therapy; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007773:Lactates / Q000097:blood* / Q000378:metabolism; D017241:MELAS Syndrome / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009243:NAD / Q000097:blood* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology / Q000627:therapeutic use*; D010101:Oxygen Consumption; D012867:Skin / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D007773:Lactates; D009243:NAD; D009536:Niacinamide; D002220:Carbamazepine; D016660:NAD(P)H Dehydrogenase (Quinone)