title: Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children.
abstract: One in 400 people has a maternally inherited mutation in mtDNA potentially causing incurable disease. In so-called heteroplasmic disease, mutant and normal mtDNA co-exist in the cells of carrier women. Disease severity depends on the proportion of inherited abnormal mtDNA molecules. Families who have had a child die of severe, maternally inherited mtDNA disease need reliable information on the risk of recurrence in future pregnancies. However, prenatal diagnosis and even estimates of risk are fraught with uncertainty because of the complex and stochastic dynamics of heteroplasmy. These complications include an mtDNA bottleneck, whereby hard-to-predict fluctuations in the proportions of mutant and normal mtDNA may arise between generations. In 'mitochondrial replacement therapy' (MRT), damaged mitochondria are replaced with healthy ones in early human development, using nuclear transfer. We are developing non-invasive alternatives, notably activating autophagy, a cellular quality control mechanism, in which damaged cellular components are engulfed by autophagosomes. This approach could be used in combination with MRT or with the regular management, pre-implantation genetic diagnosis (PGD). Mathematical theory, supported by recent experiments, suggests that this strategy may be fruitful in controlling heteroplasmy. Using mice that are transgenic for fluorescent LC3 (the hallmark of autophagy) we quantified autophagosomes in cleavage stage embryos. We confirmed that the autophagosome count peaks in four-cell embryos and this correlates with a drop in the mtDNA content of the whole embryo. This suggests removal by mitophagy (mitochondria-specific autophagy). We suggest that modulating heteroplasmy by activating mitophagy may be a useful complement to mitochondrial replacement therapy.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K. joanna.poulton@obs-gyn.ox.ac.uk.
authors.forename: Alan
authors.initials: A
authors.lastname: Diot
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.
authors.forename: Eszter
authors.initials: E
authors.lastname: Dombi
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Lodge
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liao
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.
authors.forename: Karl
authors.initials: K
authors.lastname: Morten
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.
authors.forename: Janet
authors.initials: J
authors.lastname: Carver
authors.affiliation: Institute of Reproductive Sciences, University of Oxford, Oxford OX3 9DU, U.K.
authors.forename: Dagan
authors.initials: D
authors.lastname: Wells
authors.affiliation: Institute of Reproductive Sciences, University of Oxford, Oxford OX3 9DU, U.K.
authors.forename: Tim
authors.initials: T
authors.lastname: Child
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, U.K.
authors.forename: Iain G
authors.initials: IG
authors.lastname: Johnston
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.
authors.forename: Suzannah
authors.initials: S
authors.lastname: Williams
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.
authors.forename: Joanna
authors.initials: J
authors.lastname: Poulton
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D000072741:Maternal Inheritance / Q000235:genetics; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy; D000069321:Mitochondrial Replacement Therapy / Q000379:methods; D063306:Mitophagy / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation
chemical_list: D004272:DNA, Mitochondrial
keywords: mitochondrial replacement therapy; mitophagy; mtDNA bottleneck