Fate and expression of the deleted mitochondrial DNA differ between human heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures.
We report on the variant phenotypic expression of mitochondrial genotypes in cultured skin fibroblasts and Epstein-Barr virus-transformed lymphocyte cultures from a patient with Pearson syndrome (McKusick no. 260560). Both cell types harbored a heteroplasmic population of normal and deleted mtDNA molecules. The deletion encompassed five tRNA genes and seven genes encoding subunits of cytochrome c oxidase, complex I, and ATPase. Patient skin fibroblasts and lymphocytes harbored 60 and 80% of deleted mtDNA molecules, respectively, and initially displayed defective respiratory chain activities. In both cases, there was a progressive recovery of respiratory chain activities during in vitro cell proliferation. In cultured skin fibroblasts, the loss of the deleted mtDNA molecules accounted for the recovery of normal respiratory chain activities. These features were prevented by allowing respiratory chain-deficient cells to grow in the presence of uridine (200 microM). In Epstein-Barr virus-transformed lymphocytes containing 60% of deleted mtDNA, the recovery of respiratory chain activities was attributable to an increase in the mtRNA translation efficiency rather than to an increased content in mtDNA or mtRNA. The present study suggests that the variant cellular responses to abnormal mitochondrial genotypes might contribute to the tissue-specific expression of mitochondrial disorders in vivo.
Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Institut National de la Santé et de la Recherche Médicale, Unité 12, Hôpital des Enfants-Malades, Paris, France.
T
T
Bourgeron
D
D
Chretien
A
A
Rötig
A
A
Munnich
P
P
Rustin
D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D004854:Herpesvirus 4, Human / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D010101:Oxygen Consumption; D010641:Phenotype; D017384:Sequence Deletion; D012867:Skin / Q000378:metabolism*; D013577:Syndrome; D014158:Transcription, Genetic
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV