NUCLEARLY ENCODED MITOCHONDRIAL PROTEIN SYNTHESIS FACTORS CAN ‘CURE THE RESPIRATORY DEFECTS DUE TO PATHOGENETIC HUMAN EQUIVALENT BASE SUBSTITUTIONS IN YEAST MT tRNA GENES

Mitochondria are cell organelles specialized for respiration and oxidative phosphorylation and constitute therefore the most important energy producers in the cell. They contain their own genome (mt DNA) and their own protein synthesizing machinery, which is partly coded by mt DNA (tRNA, rRNA) and partly by nuclear DNA. A defective functionality of mitochondria can produce very severe, mainly neurodegenerative diseases, which therefore can be due either to nuclear or to mitochondrial mutations. Many mt mutations are located in tRNA genes. However mt DNA often also harbours base substitutions devoid of pathological significance which are not easily distinguished from mutations causing severe diseases. This distinction is very important to predict the effects of some base substitutions. In the course of a previous program we have shown that the pathogenic human equivalent mutations can be introduced into the mitochondrial genome of yeast, in which the study of respiratory defects and of their molecular mechanisms is specially easy. We then observed that the mitochondrial defects caused by the pathogenic human equivalent mutations in tRNA genes can be relieved or rescued by the high level (overexpression) of nuclearly encoded protein synthesis factors, which interact with the mutated tRNA and probably can correct its defective structure. In the present program we wish to develop the research in this direction aiming to clarify the mechanisms by which the defects are suppressed and those which regulate the overexpression of protein synthesis factors. These studies can open therapeutical perspectives for mitochondrial diseases, for which up to now no effective treatment exists.