Marked Replicative Advantage of Human mtDNA Carrying a Point Mutation that Causes the MELAS Encephalomyopathy

• Published in: Proceedings of the National Academy of Sciences - PNAS 1992-12, Vol.89 (23), p.11164-11168
• Main Authors: Yoneda, Makoto, Chomyn, Anne, Martinuzzi, Andrea, Hurko, Orest, Attardi, Giuseppe
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Division; Cell growth; Cell lines; Cells, Cultured; Cloning, Molecular; Deoxyribonucleic acid; Diseases of striated muscles. Neuromuscular diseases; DNA; DNA Replication; DNA, Mitochondrial - metabolism; Doubling time; Exhibitions; Genetic mutation; Genetics; Genotypes; Humans; In Vitro Techniques; man; Medical disorders; Medical research; Medical sciences; MELAS syndrome; mitochondria; Mitochondrial DNA; Mitochondrial Encephalomyopathies - genetics; Molecules; Neurology; point mutation; Polymerase chain reaction; Transformed cell line
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.23.11164

The segregation of mutant and wild-type mtDNA was investigated in transformants constructed by transferring human mitochondria from individuals belonging to four pedigrees with the MELAS encephalomyopathy-associated mtDNA mutation (MELAS is mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) into human mtDNA-less (ρ⚬) cells. Five of 13 clonal cell lines containing mixtures of wild-type and mutant mtDNAs were found to undergo a rapid shift of their genotype toward the pure mutant type. The other 8 cell lines, which included 6 exhibiting nearly homoplasmic mutant mtDNA, on the contrary, maintained a stable genotype. Subcloning experiments and growth rate measurements clearly indicated that an intracellular replicative advantage of mutant mtDNA was mainly responsible for the dramatic shift toward the mutant genotype observed in the unstable cell lines.