Assisted reproductive technologies to prevent human mitochondrial disease transmission

Andy Greenfield, Peter Braude, Frances Flinter, Robin Lovell-Badge, Caroline Ogilvie & Anthony C F Perry

Nature Biotechnology, 09 November 2017

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.

(a) Schematic of PNT. (b) Schematic of MST. (c) PB1T and MST. A combination of both techniques can be used to create two reconstituted donated oocytes from one oocyte carrying mutated mitochondria. (d) PB2T and PNT. As in c, the genetic material from one patient oocyte could be used in two donated oocytes to create two reconstituted embryos with normal mitochondria.

Figure 4: Protocols for mitochondrial replacement therapy.