Mitochondrial gene replacement in primate offspring and embryonic stem cells.
Mitochondria are found in all eukaryotic cells and contain their own genome (mitochondrial DNA or mtDNA). Unlike the nuclear genome, which is derived from both the egg and sperm at fertilization, the mtDNA in the embryo is derived almost exclusively from the egg; that is, it is of maternal origin. Mutations in mtDNA contribute to a diverse range of currently incurable human diseases and disorders. To establish preclinical models for new therapeutic approaches, we demonstrate here that the mitochondrial genome can be efficiently replaced in mature non-human primate oocytes (Macaca mulatta) by spindle-chromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg. The reconstructed oocytes with the mitochondrial replacement were capable of supporting normal fertilization, embryo development and produced healthy offspring. Genetic analysis confirmed that nuclear DNA in the three infants born so far originated from the spindle donors whereas mtDNA came from the cytoplast donors. No contribution of spindle donor mtDNA was detected in offspring. Spindle replacement is shown here as an efficient protocol replacing the full complement of mitochondria in newly generated embryonic stem cell lines. This approach may offer a reproductive option to prevent mtDNA disease transmission in affected families.
Tachibana
Masahito
M
Oregon National Primate Research Center, USA.
Sparman
Michelle
M
Sritanaudomchai
Hathaitip
H
Ma
Hong
H
Clepper
Lisa
L
Woodward
Joy
J
Li
Ying
Y
Ramsey
Cathy
C
Kolotushkina
Olena
O
Mitalipov
Shoukhrat
S
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics*; D004624:Embryo Transfer; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D005260:Female; D005307:Fertilization in Vitro; D050259:Genes, Mitochondrial / Q000235:genetics*; D054629:Genome, Mitochondrial / Q000235:genetics*; D008253:Macaca mulatta / Q000196:embryology / Q000235:genetics*; D008297:Male; D008540:Meiosis; D028361:Mitochondrial Diseases / Q000235:genetics / Q000517:prevention & control; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D027724:Reproductive Techniques, Assisted
D004272:DNA, Mitochondrial