TY - JOUR
T1 - Mitochondrial gene replacement in primate offspring and embryonic stem cells
AU - Tachibana, Masahito
AU - Sparman, Michelle
AU - Sritanaudomchai, Hathaitip
AU - Ma, Hong
AU - Clepper, Lisa
AU - Woodward, Joy
AU - Li, Ying
AU - Ramsey, Cathy
AU - Kolotushkina, Olena
AU - Mitalipov, Shoukhrat
N1 - Funding Information:
Acknowledgements The authors acknowledge the Division of Animal Resources, Surgical Team, Endocrine Technology Core, Imaging & Morphology Core and Molecular & Cellular Biology Core at the Oregon National Primate Research Center for providing expertise and services that contributed to this project. We are grateful to W. Sanger and M. Nelson for karyotyping services, C. Penedo for microsatellite analysis and S. Wong for providing Sendai virus. We thank J. Hennebold, R. Stouffer and D. Wolf for consulting, helpful discussions and critical reading of the manuscript. This study was supported by start-up funds from Oregon National Primate Research Center, Oregon Stem Cell Center and grants from the National Institutes of Health.
PY - 2009/9/17
Y1 - 2009/9/17
N2 - 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.
AB - 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.
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U2 - 10.1038/nature08368
DO - 10.1038/nature08368
M3 - Article
C2 - 19710649
AN - SCOPUS:70349284435
SN - 0028-0836
VL - 461
SP - 367
EP - 372
JO - Nature
JF - Nature
IS - 7262
ER -