Studies on molecular and biochemical aspects of mitochondrial encephalomyopathies

Abstract

Mitochondria are double membrane organelles present in the cytosol of eukaryotic cells. The main function of mitochondria is to produce energy in the form of ATP by utilizing oxygen and the byproducts of the oxidation of nutrients. The phenomenon of oxidative phosphorylation (OXPHOS) is carried out by five multi-subunit enzyme complexes located in the inner mitochondrial membrane. Mitochondrial encephalomyopathies are a heterogeneous group of clinical disorders caused by defects in mitochondrial respiratory chain. The incidence of such disorders is about 1:5000 and mostly occurring in early years after birth. Organs such as the brain, heart and skeletal muscle are highly energy dependent and thus vulnerable to defects in energy metabolism. Mitochondrial dysfunction is common cause of neuromuscular disorders in pediatric patients. In the present study, a total of 23 children diagnosed with possible encephalomyopathies were analyzed for mitochondrial dysfunction. Biochemical analysis of mitochondrial respiratory chain enzymes showed that= 64% of the patients had complex I deficiency, 7.1% had complex IV and 14.2% had combined complex I plus III deficiency. Among the complex I defective patients, 22.2% had defects in complex assembly. A significant loss of mitochondrial membrane potential by patient lymphoblasts and a declined ATP synthesis by complex I-dependent substrates was also evident. But, an increased ATP synthesis by complex II dependent substrates was observed in patient derived cell lines. Increase in ATP synthesis by complex II dependent substrates suggests a compensatory mechanism to use complex II as a secondary route for ATP production. Expression analysis of respiratory chain protein subunits by western blot showed a decline in complex I protein expression and increased expression of other respiratory chain complexes particularly complex IV and V, again suggesting a compensatory mechanism. The genetic cause of biochemical defect can be mutations in either mitochondrial DNA (mtDNA) or nuclear DNA.