ALTERATION OF MITOCHONDRIAL-DNA AND RNA LEVEL IN HUMAN FIBROBLASTS WITH IMPAIRED VITAMIN-B12 COENZYME SYNTHESIS

Alterations of mitochondrial (mt) nucleic acid metabolism in methylmal onic aciduria (MMA) were studied in two cell lines from skin fibroblas ts of patients with mitochondrial (GM00595) or cytosolic (GM10011) def ects in the biosynthesis pathways of cobalamin coenzymes, The mtDNA le vel increased two-fold in GM00595 cells, which carry a mt defect in th e adenosylcobalamin synthesis, whereas no appreciable change was found in GM10011 cells. The content of the two rRNAs 16S and 12S mtRNAs, no rmalized for the mtDNA copy number, decreased by 70% and 50% in GM0059 5 and GM10011, respectively. The normalized content of ND1, ND2 and CO I mRNAs decreased in GM00595, but was unchanged in GM10011, Respirato ry chain complex activities measured in these two cell lines were not different from control activities. These data suggest that the mainten ance of the mt function is due to doubling of mtDNA and that this comp ensatory response takes place only in those cells in which the greater reduction of the level of rRNA might have brought the content of thes e transcripts below the threshold value for optimal expression of the mt genome. (C) 1998 Federation of European Biochemical Societies.