BACKGROUND: Pathogenic mitochondrial (mt)DNA mutations, which often cause life-threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second-generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins. METHODS: Based on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT. MAIN FINDINGS: MRT does not compromise pre-implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation. CONCLUSION: The maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT.
BACKGROUND: Pathogenic mitochondrial (mt)DNA mutations, which often cause life-threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second-generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins. METHODS: Based on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT. MAIN FINDINGS: MRT does not compromise pre-implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation. CONCLUSION: The maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT.
Authors: Daniel Paull; Valentina Emmanuele; Keren A Weiss; Nathan Treff; Latoya Stewart; Haiqing Hua; Matthew Zimmer; David J Kahler; Robin S Goland; Scott A Noggle; Robert Prosser; Michio Hirano; Mark V Sauer; Dieter Egli Journal: Nature Date: 2012-12-19 Impact factor: 49.962
Authors: Mark S Sharpley; Christine Marciniak; Kristin Eckel-Mahan; Meagan McManus; Marco Crimi; Katrina Waymire; Chun Shi Lin; Satoru Masubuchi; Nicole Friend; Maya Koike; Dimitra Chalkia; Grant MacGregor; Paolo Sassone-Corsi; Douglas C Wallace Journal: Cell Date: 2012-10-12 Impact factor: 41.582
Authors: Sophie Monnot; Nadine Gigarel; David C Samuels; Philippe Burlet; Laetitia Hesters; Nelly Frydman; René Frydman; Violaine Kerbrat; Benoit Funalot; Jelena Martinovic; Alexandra Benachi; Josué Feingold; Arnold Munnich; Jean-Paul Bonnefont; Julie Steffann Journal: Hum Mutat Date: 2011-01 Impact factor: 4.878