The
mitochondrial DNA (
mtDNA) codes for essential hydrophobic components of the system of oxidative phosphorylation. Diseases caused by
mtDNA defects are manifested as variable clinical phenotypes and the symptoms represent the involvement of tissues with high energy demand. Various approaches have been taken to treat
mitochondrial diseases by administration of redox compounds,
enzyme activators,
vitamins and
coenzymes or dietary measures. The
MELAS mutation at the base pair 3243 of
mitochondrial DNA demolishes a transcription termination sequence located within the
tRNA(Leu)[UUR] gene, resulting in synthesis of an abnormally large derivative of 16 S rRNA and defective translation. The activity of
NADH:Q
oxidoreductase (complex I) is often decreased and
lactic acidosis is a typical clinical finding. We hypothesized that defective translation of the seven mitochondrially coded subunits (of the total 41) of complex I may alter its affinity to the
NADH substrate in which case the activity decrease may be compensated for by increasing the
NADH concentration. A
MELAS patient was treated with oral
nicotinamide for 5 months. The blood
NAD content representing the
NAD +
NADH pool of erythrocytes rose 24 fold and the blood
lactate + pyrovate concentration fell by 50%. All these metabolic alterations suggested an improvement of the function of complex I or the whole mitochondrial respiratory chain. However, the kinetic properties of the patient's complex I were similar to the reference values. A tempting explanation is that the free
NADH concentration in mitochondria is normally at the level of K(m), so that the decreased activity of the respiratory chain can be compensated for by increased mitochondrial [
NADH]. Another possibility would be that the substrate shuttles for transport of reducing power of cytosolic
NADH into mitochondria (the
malate aspartate or
glycerol-3-
phosphate shuttles) may be enhanced by increased total
NAD +
NADH. Because the
malate-
aspartate shuttle is actually a pump for reducing equivalents driven by the mitochondrial membrane energization, it is proposed that the exacerbations of the
MELAS syndrome be partly due to a vicious circle initiated by a defect of complex I and affecting the active transport of the
hydrogen from cytosolic
NADH into the mitochondrion.