title: Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.
abstract: Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors.forename: M P
authors.initials: MP
authors.lastname: King
authors.forename: Y
authors.initials: Y
authors.lastname: Koga
authors.forename: M
authors.initials: M
authors.lastname: Davidson
authors.forename: E A
authors.initials: EA
authors.lastname: Schon
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D015152:Blotting, Northern; D001928:Brain Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000378:metabolism; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D006822:Hybrid Cells; D007150:Immunohistochemistry; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010101:Oxygen Consumption; D014176:Protein Biosynthesis; D012356:RNA, Transfer, Leu / Q000235:genetics*; D013577:Syndrome
chemical_list: D004272:DNA, Mitochondrial; D012356:RNA, Transfer, Leu