Mitochondrial replacement techniques to resolve mitochondrial dysfunction and ooplasmic deficiencies: where are we now?

Abstract

Mitochondria are the powerhouses of cell and play crucial roles in proper oocyte competence, fertilization, and early embryo development. Maternally inherited mitochondrial DNA (mtDNA) mutations can have serious implications for individuals, leading to life-threatening disorders and contribute to ovarian ageing and female infertility due to poor oocyte quality. Mitochondrial replacement techniques (MRTs) have emerged as a promising approach not only to replace defective maternal mitochondria in patients carrying mtDNA mutations, but also to enhance oocyte quality and optimize IVF outcomes for individuals experiencing infertility. There are two main categories of MRT based on the source of mitochondria. In the heterologous approach, mitochondria from a healthy donor are transferred to the recipient's oocyte. This approach includes several methodologies such as germinal vesicle, pronuclear, maternal spindle, and polar body transfer. However, ethical concerns have been raised regarding the potential inheritance of third-party genetic material and the development of heteroplasmy. An alternative approach to avoid these issues is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. However, the efficacy of AUGMENT has been debated following the results of a randomized clinical trial (RCT) that demonstrated no significant benefit over conventional IVF. Recent developments have focused on novel approaches based on autologous, non-invasively derived stem cells to address infertility. While these techniques show promising results, further RCTs are necessary to establish their effectiveness and safety for clinical use. Only after robust evidence becomes available could MRT potentially become a viable treatment option for overcoming infertility and enabling patients to have genetically related embryos. This review aims to provide an overview of the current state of MRTs in addressing low oocyte quality due to mitochondrial dysfunction.

Keywords: female infertility; mitochondria; mitochondrial DNA; mitochondrial dysfunction; mitochondrial replacement; oocyte quality.