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Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children.
Biochem Soc Trans. 2016 08 15; 44(4):1091-100.BS

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+Show Affiliations

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.Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.Institute of Reproductive Sciences, University of Oxford, Oxford OX3 9DU, U.K.Institute of Reproductive Sciences, University of Oxford, Oxford OX3 9DU, U.K.School of Biosciences, University of Birmingham, Birmingham, U.K.Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.Nuffield Department of Obstetrics and Gynaecology University of Oxford, The Women's Centre, Oxford OX3 9DU, U.K.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27528757

Citation

Diot, Alan, et al. "Modulating Mitochondrial Quality in Disease Transmission: Towards Enabling Mitochondrial DNA Disease Carriers to Have Healthy Children." Biochemical Society Transactions, vol. 44, no. 4, 2016, pp. 1091-100.
Diot A, Dombi E, Lodge T, et al. Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children. Biochem Soc Trans. 2016;44(4):1091-100.
Diot, A., Dombi, E., Lodge, T., Liao, C., Morten, K., Carver, J., Wells, D., Child, T., Johnston, I. G., Williams, S., & Poulton, J. (2016). Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children. Biochemical Society Transactions, 44(4), 1091-100. https://doi.org/10.1042/BST20160095
Diot A, et al. Modulating Mitochondrial Quality in Disease Transmission: Towards Enabling Mitochondrial DNA Disease Carriers to Have Healthy Children. Biochem Soc Trans. 2016 08 15;44(4):1091-100. PubMed PMID: 27528757.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children. AU - Diot,Alan, AU - Dombi,Eszter, AU - Lodge,Tiffany, AU - Liao,Chunyan, AU - Morten,Karl, AU - Carver,Janet, AU - Wells,Dagan, AU - Child,Tim, AU - Johnston,Iain G, AU - Williams,Suzannah, AU - Poulton,Joanna, PY - 2016/04/05/received PY - 2016/8/17/entrez PY - 2016/8/17/pubmed PY - 2017/7/15/medline KW - mitochondrial replacement therapy KW - mitophagy KW - mtDNA bottleneck SP - 1091 EP - 100 JF - Biochemical Society transactions JO - Biochem. Soc. Trans. VL - 44 IS - 4 N2 - 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. SN - 1470-8752 UR - https://www.unboundmedicine.com/medline/citation/27528757/Modulating_mitochondrial_quality_in_disease_transmission:_towards_enabling_mitochondrial_DNA_disease_carriers_to_have_healthy_children_ L2 - https://portlandpress.com/biochemsoctrans/article-lookup/doi/10.1042/BST20160095 DB - PRIME DP - Unbound Medicine ER -