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 the mutation at the base pair 3243 of the mitochondrial DNA. The mutation has been previo usly shown to lead to a defective translation. We hypothesized that du e to an imperfect assembly of complex I subunits the substrate affinit y of this enzyme may be lowered and this may be counteracted by increa sing the mitochondrial NAD+NADH concentration. Therefore, we studied t he effect and mechanism of action of nicotinamide treatment in a MELAS patient with the base pair 3243 mutation. Nicotinamide treatment was initialed after his first stroke-like episode. The blood NAD concentra tion (representing the intracellular concentration in erythrocytes) in creased 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 impr ovement together with a decrease in the lesion volume in magnetic reso nance imaging within the first month. The cellular NAD increase upon n icotinamide 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 ce llular NAD+NADH concentration leads to enhancement of the oxidation of reducing equivalents. However, the Km of complex I for NADH in skelet al muscle from the patient was similar to that of controls. This may i ndicate that physiologically mitochondrial complex I operates at non-s aturating substrate concentration, and this may explain the effect of nicotinamide treatment.