Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming

作者：Martin Picard, Jiangwen Zhang, Saege Hancock, Olga Derbeneva, Ryan Golhar, Paweł Golik, Sean F. O’Hearn, Shawn Levy, Prasanth Potluri, Maria Lvova, Antonio Dávila, Chun Shi Lin, Juan C. Perín, Eric Rappaport, Håkon Håkonarson, Ian A. Trounce, Vincent Procaccio, Douglas C. Wallace · 发表于：Proceedings of the National Academy of Sciences · 年份：2014 · DOI：10.1073/pnas.1414028111 · 被引用次数：307 · 研究领域：Mitochondrial Function and Pathology、Metabolism and Genetic Disorders、RNA modifications and cancer

Variation in the intracellular percentage of normal and mutant mitochondrial DNAs (mtDNA) (heteroplasmy) can be associated with phenotypic heterogeneity in mtDNA diseases. Individuals that inherit the common disease-causing mtDNA tRNA(Leu(UUR)) 3243A>G mutation and harbor ∼10-30% 3243G mutant mtDNAs manifest diabetes and occasionally autism; individuals with ∼50-90% mutant mtDNAs manifest encephalomyopathies; and individuals with ∼90-100% mutant mtDNAs face perinatal lethality. To determine the basis of these abrupt phenotypic changes, we generated somatic cell cybrids harboring increasing levels of the 3243G mutant and analyzed the associated cellular phenotypes and nuclear DNA (nDNA) and mtDNA transcriptional profiles by RNA sequencing. Small increases in mutant mtDNAs caused relatively modest defects in oxidative capacity but resulted in sharp transitions in cellular phenotype and gene expression. Cybrids harboring 20-30% 3243G mtDNAs had reduced mtDNA mRNA levels, rounded mitochondria, and small cell size. Cybrids with 50-90% 3243G mtDNAs manifest induction of glycolytic genes, mitochondrial elongation, increased mtDNA mRNA levels, and alterations in expression of signal transduction, epigenomic regulatory, and neurodegenerative disease-associated genes. Finally, cybrids with 100% 3243G experienced reduced mtDNA transcripts, rounded mitochondria, and concomitant changes in nuclear gene expression. Thus, striking phase changes occurred in nDNA and mtDNA gene expression in ...