Mitochondrial Genetic Drift after Nuclear Transfer in Oocytes

Abstract

Mitochondria are energy-producing intracellular organelles containing their own genetic material in the form of mitochondrial DNA (mtDNA), which codes for proteins and RNAs essential for mitochondrial function. Some mtDNA mutations can cause mitochondria-related diseases. Mitochondrial diseases are a heterogeneous group of inherited disorders with no cure, in which mutated mtDNA is passed from mothers to offspring via maternal egg cytoplasm. Mitochondrial replacement (MR) is a genome transfer technology in which mtDNA carrying disease-related mutations is replaced by presumably disease-free mtDNA. This therapy aims at preventing the transmission of known disease-causing mitochondria to the next generation. Here, a proof of concept for the specific removal or editing of mtDNA disease-related mutations by genome editing is introduced. Although the amount of mtDNA carryover introduced into human oocytes during nuclear transfer is low, the safety of mtDNA heteroplasmy remains a concern. This is particularly true regarding donor-recipient mtDNA mismatch (mtDNA–mtDNA), mtDNA-nuclear DNA (nDNA) mismatch caused by mixing recipient nDNA with donor mtDNA, and mtDNA replicative segregation. These conditions can lead to mtDNA genetic drift and reversion to the original genotype. In this review, we address the current state of knowledge regarding nuclear transplantation for preventing the inheritance of mitochondrial diseases.

Non-Interventional and High-Precision Temperature Measurement Biochips for Long-Term Monitoring the Temperature Fluctuations of Individual Cells

“…Among these, the measuring ends of 1Au2 and 1Au7 are far from the nuclei of the corresponding HeLa cells, while the ends of 1Cu8 and 1Cd2 are located in the core areas of the HeLa cells. The nucleus and mitochondria located in the cellular core area are the main heat sources in normal cell metabolism [31][32][33], and that is why the cell temperatures collected from 1Cu8 and 1Cd2 are higher than those from 1Au2 and 1Au7. The temperature fluctuations of HeLa cells-measured here using the developed chips-have been widely reported, mostly from the use of semi-contact fluorescence probes.…”

Prospects of Germline Nuclear Transfer in Women With Diminished Ovarian Reserve

“…Nevertheless, PGT might have diagnostic limitations, as embryonic mitochondria may shift their heteroplasmy levels during cell division, and mitochondrial mutations may be favored in response to environmental influences over wild type copies. In addition, patients carrying homoplasmic DNA mutations cannot be helped by PGT ( 65 ).…”

Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy

“…The most important problem is the risk of mitochondrial genetic drift. 19 , 20 , 21 , 22 , 23 In embryonic stem (ES) cells isolated from human MR reconstructed embryos, even though the initial mtDNA carryover rate is only ∼1% and most cell lines still maintain a relatively low stable level, the mitochondrial carryover level of particular cell lines may rise sharply to 80% within several generations and then completely replace donor mitochondria in subsequent passages. 21 , 24 In mice, even if there are only 5% pathogenic mitochondria in the zygotic stage, it may reach 22% at birth, 30% before weaning, and 78% in their lifetime.…”