Oxidative phosphorylation defect in the brains of carriers of the tRNA(leu(UUR)) A3243G mutation in a MELAS pedigree

MELAS is a mitochondrial encephalomyopathy characterized clinically by recu rrent stroke-like episodes, seizures, sensorineural deafness, dementia, hyp ertrophic cardiomyopathy, and short stature. The majority of patients are h eteroplasmic for a mutation (A3243G) in the tRNA(leu(UUR)) gene in mitochon drial DNA (mtDNA). In cells cultured in vitro, the mutation produces a seve re mitochondrial translation defect only when the proportion of mutant mtDN As exceeds 95% of total mtDNAs, However, most patients are symptomatic well below this threshold, a paradox that remains unexplained. We studied the r elationship between the level of heteroplasmy for the mutant mtDNA and the clinical and biochemical abnormalities in a large pedigree that included 8 individuals carrying the A3243G mutation, 4 of whom were asymptomatic. Unex pectedly, we found that brain lactate, a sensitive indicator of oxidative p hosphorylation dysfunction, was linearly related to the proportion of mutan t mtDNAs in all individuals carrying the mutation, whether they were sympto matic or not. There was no evidence for threshold expression of the metabol ic defect. These results suggest that marked tissue-specific differences ma y exist in the pathogenic expression of the A3243G mutation and explain why a neurological phenotype can be observed at relatively low levels of heter oplasmy.