Mitochondria are essential cytoplasmic organelles that generate energy (ATP) by oxidative phosphorylation and mediate key cellular processes such as apoptosis. They are maternally inherited and in humans contain a 16,569-base-pair circular genome (mtDNA) encoding 37 genes required for oxidative phosphorylation. Mutations in mtDNA cause a range of pathologies, commonly affecting energy-demanding tissues such as muscle and brain. Because mitochondrial diseases are incurable, attention has focused on limiting the inheritance of pathogenic mtDNA by mitochondrial replacement therapy (MRT). MRT aims to avoid pathogenic mtDNA transmission between generations by maternal spindle transfer, pronuclear transfer or polar body transfer: all involve the transfer of nuclear DNA from an egg or zygote containing defective mitochondria to a corresponding egg or zygote with normal mitochondria. Here we review recent developments in animal and human models of MRT and the underlying biology. These have led to potential clinical applications; we identify challenges to their technical refinement.
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A.C.F.P. is grateful for support from the Medical Research Council, UK (grants MR/N000080/1 and MR/N020294/1). The authors thank Rob Taylor, Charlotte Alston, Emma Watson, Sam Byerley, Jane Stewart and Robert McFarland (Wellcome Centre for Mitochondrial Research Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust) for unpublished data included in Table 2.
The authors declare no competing financial interests.
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Greenfield, A., Braude, P., Flinter, F. et al. Assisted reproductive technologies to prevent human mitochondrial disease transmission. Nat Biotechnol 35, 1059–1068 (2017) doi:10.1038/nbt.3997
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