Three-parent babies: Mitochondrial replacement therapies

Abstract

The mitochondria are intracellular organelles, and just like the cell nucleus they have their own genome. They are extremely important for normal body functioning and are responsible for ATP production - the main energy source for the cell. Mitochondrial diseases are associated with mutations in mitochondrial DNA and are inherited exclusively from the mother. They can affect organs that depend on energy metabolism, such as skeletal muscles, the cardiac system, the central nervous system, the endocrine system, the retina and liver, causing various incurable diseases. Mitochondrial replacement techniques provide women with mitochondrial defects a chance to have normal biological children. The goal of such treatment is to reconstruct functional oocytes and zygotes, in order to avoid the inheritance of mutated genes; for this the nuclear genome is withdrawn from an oocyte or zygotes, which carries mitochondrial mutations, and is implanted in a normal anucleated cell donor. Currently, the options of a couple to prevent the transmission of mitochondrial diseases are limited, and mitochondrial donation techniques provide women with mitochondrial defects a chance to have normal children. The nuclear genome can be transferred from oocytes or zygotes using techniques such as pronuclear transfer, spindle transfer, polar body transfer and germinal vesicle transfer. This study presents a review of developed mitochondrial substitution techniques, and its ability to prevent hereditary diseases.

Keywords: mitochondrial; mitochondrial donation; mitochondrial mutations; mitochondrial replacement; mtDNA; reproductive technology.

Figure 1

Flow chart representing the study’s methodology (Created by the author).

Figure 2

Bottle neck representation. The first bottle neck occurs in oocyte maturation, starting in primordial cells with 10 to 200 copies of mtDNA that replicate at random, to the mature oocyte with 100,000 to 600,000 copies. The second bottle neck occurs after oocyte fertilization by the spermatozoid, the zygote formed has 100,000 to 600,000 copies of mtDNA which are randomly reduced to the formation of primordial cells with 10 to 200 copies (Adapted from Craven et al., 2017).

Figure 3

A - Representation of pronucleus transfer, where two PNs are withdrawn from the zygote with mutated mitochondria and transferred to an abnormal zygote that had its PNs previously removed. B - Representation of the maternal spindle transfer, where the spindle is removed and transferred to an oocyte in MII that had the spindle previously removed, followed by fertilization of the reconstructed oocyte (Adapted from Craven et al., 2017).

Figure 4

A - PBI transfer Representation, where it is withdrawn from the oocyte in MII and transferred to an oocyte in MII with the spindle previously removed, followed by fertilization of the reconstructed oocyte. B - Representation a PBII transfer, where it is removed from an azygote in the pronucleus stage and transferred to azygote with the maternal nucleus and PBII previously removed (Adapted from Craven et al., 2017).

Figure 5

A - Terminal vesicle transfer representation, where the germinal vesicle I is removed and transferred to an oocyte that had its germinal vesicle previously removed, then the constructed oocyte undergoes in vitro maturation followed by fertilization. B - Plasma transfer representation, which consists of transferring from 5 to 15% of the cytoplasm content of a healthy donor to the oocyte of the patient with mutated mitochondria, followed by oocyte fertilization (Adapted from Craven et al. 2017).