METABOLIC INTERVENTIONS AGAINST COMPLEX-I DEFICIENCY IN MELAS SYNDROME

The mitochondrial DNA (mtDNA) codes for essential hydrophobic componen ts of the system of oxidative phosphorylation. Diseases caused by mtDN A defects are manifested as variable clinical phenotypes and the sympt oms represent the involvement of tissues with high energy demand. Vari ous approaches have been taken to treat mitochondrial diseases by admi nistration of redox compounds, enzyme activators, vitamins and coenzym es or dietary measures. The MELAS mutation at the base pair 3243 of mi tochondrial DNA demolishes a transcription termination sequence locate d within the tRNA(Leu[UUR]) gene, resulting in synthesis of an abnorma lly large derivative of 16 S rRNA and defective translation. The activ ity of NADH:Q oxidoreductase (complex I) is often decreased and lactic acidosis is a typical clinical finding. We hypothesized that defectiv e translation of the seven mitochondrially coded subunits (of the tota l 41) of complex I may alter its affinity to the NADH substrate in whi ch case the activity decrease may be compensated for by increasing the NADH concentration. A MELAS patient was treated with oral nicotinamid e for 5 months. The blood NAD content representing the NAD + NADH pool of erythrocytes rose 24 fold and the blood lactate + pyrovate concent ration fell by 50%. All these metabolic alterations suggested an impro vement of the function of complex I or the whole mitochondrial respira tory 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 o f 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. B ecause the malate-aspartate shuttle is actually a pump for reducing eq uivalents driven by the mitochondrial membrane energization, it is pro posed that the exacerbations of the MELAS syndrome be partly due to a vicious circle initiated by a defect of complex I and affecting the ac tive transport of the hydrogen from cytosolic NADH into the mitochondr ion.