Mitochondrial DNA segregation and replication during early mouse embryogenesis

Van de Putte Lieselot, 2023
Mitochondrial disorders, caused by mutations in mitochondrial (mt)DNA, affect 1 in 4,300 individuals and can cause severe symptoms such as muscle pain, developmental delays, and vision problems. MtDNA disorders are maternally inherited, meaning that mtDNA mutations are passed from a mother to all her children. There are some options for women carrying these disorders to have healthy children. Preimplantation genetic testing (PGT) selects embryos with low mutation loads for uterine transfer. However, for patients who only produce embryos with high mutation loads or for homoplasmic mtDNA mutations, PGT is not an option. To address this, a technique known as nuclear transfer (NT) was developed. NT involves transferring nuclear DNA from the affected mother to an enucleated donor egg containing healthy mitochondria. However, a small number of mutated mitochondria, known as carryover, are always transferred along. These few mutated mtDNA copies can outcompete the healthy ones, thereby inducing the development of the disease phenotype, known as mitochondrial reversion. Techniques developed to destroy (mutated) mitochondria can be used in addition to PNT to eliminate the carryover, including forced mitophagy or mitochondria-targeted nucleases such as restriction endonucleases, zinc finger nucleases, or TALENs. The development of an effective carryover destruction technique, together with the knowledge of mtDNA segregation and replication patterns, may pave the way for safer applications of PGT and NT. Overall, improvement of these public health applications for mtDNA patients can also give patients with limited treatment options the chance to have their own healthy children, ultimately leading to an improved quality of life for all mtDNA patients.

Promotor Björn Heindryckx
Opleiding Biomedische Wetenschappen
Domein Tissue Engineering and Regenerative Medicine