Metabolic interventions against complex I deficiency in MELAS syndrome

Abstract

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.