DEFICIENCY OF THE HUMAN MITOCHONDRIAL TRANSCRIPTION FACTOR H-MTTFA ININFANTILE MITOCHONDRIAL MYOPATHY IS ASSOCIATED WITH MTDNA DEPLETION

Recent studies show that patients presenting with cytochrome oxidase ( COX) deficiency in infancy may have reduced mitochondrial DNA (mtDNA) in muscle. The human mitochondrial transcription factor A (h-mtTFA) ma y be an important regulator of both transcription and replication of m tDNA. h-mtTFA levels were investigated in cell lines which were either free of mtDNA (rho(o)) or temporarily depleted by treatment with dide oxycytidine (ddC), and in tissue from three patients with mtDNA deplet ion and cytochrome oxidase deficiency. h-mtTFA was compared with other mitochondrial proteins such as pyruvate dehydrogenase and porin by We stern blotting. The ratio of mtDNA and h-mtTFA mRNA to reference nucle ar probes was measured by dual labelling of dot blots. The ratio of mt DNA to nuclear DNA in skeletal muscle was low in muscle in the three p atients and in other tissues in one. h-mtTFA was low in cells depleted either permanently or transiently of mtDNA, and this reduction in h-m tTFA roughly paralleled mtDNA levels. Similarly, treatment of rho(o) c ell lines with ddC induced a reduction in mtDNA as well as h-mtTFA pro tein. The relationship between h-mtTFA and mtDNA levels suggests that they may be causally linked. MtDNA depletion was accompanied by an inc rease in the level of h-mtTFA RNA in the cell lines but low levels in the patient. This suggests that either h-mtTFA regulates mtDNA levels, or that h-mtTFA expression may be regulated by a feedback mechanism i nitiated by MtDNA Depletion.