MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts.

• DOI: 10.1073/pnas.89.10.4221
• Publication Date: 2006-05-31T12:01:17Z
• Authors: A Chomyn; A Martinuzzi; M Yoneda; A Daga; O Hurko; D Johns; S T Lai; I Nonaka; C Angelini; G Attardi
• Keywords: MELAS syndrome; Lactic acidosis

The pathogenetic mechanism of the mitochondrial tRNA(LeuUUR) gene mutation responsible for MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome was investigated in transformants obtained by transfer mitochondria from three genetically unrelated patients into human DNA (mtDNA)-less (rho 0) cells. Marked defects protein synthesis respiratory activity were observed containing virtually pure mutant mtDNA, as compared to parent rho 0 cells (the 143B cell line) or exclusively wild-type derived one a maternally related asymptomatic individual. A striking protective effect against exerted levels residual mtDNA above 6%. occurs within binding site factor (mTERF) that promotes termination transcription at 16S rRNA/tRNA(LeuUUR) boundary. marked decrease affinity purified mTERF target sequence vitro assays. By contrast, RNA hybridization experiments failed show any significant change steady-state amounts two rRNA species, encoded upstream site, mRNAs downstream, carrying mutation.