Mitochondrial enrichment in infertile patients: a review of different mitochondrial replacement therapies

Abstract

Poor ovarian responders exhibit a quantitative reduction in their follicular pool, and most cases are also associated with poor oocyte quality due to patient’s age, which leads to impaired in vitro fertilisation outcomes. In particular, poor oocyte quality has been related to mitochondrial dysfunction and/or low mitochondrial count as these organelles are crucial in many essential oocyte processes. Therefore, mitochondrial enrichment has been proposed as a potential therapy option in infertile patients to improve oocyte quality and subsequent in vitro fertilisation outcomes. Nowadays, different options are available for mitochondrial enrichment treatments that are encompassed in two main approaches: heterologous and autologous. In the heterologous approach, mitochondria come from an external source, which is an oocyte donor. These techniques include transferring either a portion of the donor’s oocyte cytoplasm to the recipient oocyte or nuclear material from the patient to the donor’s oocyte. In any case, this approach entails many ethical and safety concerns that mainly arise from the uncertain degree of mitochondrial heteroplasmy deriving from it. Thus the autologous approach is considered a suitable potential tool to improve oocyte quality by overcoming the heteroplasmy issue. Autologous mitochondrial transfer, however, has not yielded as many beneficial outcomes as initially expected. Proposed mitochondrial autologous sources include immature oocytes, granulosa cells, germline stem cells, and adipose-derived stem cells. Presently, it would seem that these autologous techniques do not improve clinical outcomes in human infertile patients. However, further trials still need to be performed to confirm these results. Besides these two main categories, new strategies have arisen for oocyte rejuvenation by improving patient’s own mitochondrial function and avoiding the unknown consequences of third-party genetic material. This is the case of antioxidants, which may enhance mitochondrial activity by counteracting and/or preventing oxidative stress damage. Among others, coenzyme-Q10 and melatonin have shown promising results in low-prognosis infertile patients, although further randomised clinical trials are still necessary.

Role of Mitochondria Transfer in Infertility: A Commentary

“…To accomplish this, a fraction of the donor’s oocyte cytoplasm is transferred into the patient’s gamete in the ooplasmic transfer or cytotransfer, enriching it in healthy mitochondria [ 13 ]. On the other hand, the patient’s genetic material is transferred into an enucleated donor’s oocyte in the nuclear transfer, replacing the whole mitochondria content and trying to reduce to a minimum the amount of the patient’s own organelles left behind [ 1 ]. Nevertheless, in both scenarios, other cytoplasm components are transferred along with mitochondria during the procedure.…”

“…Yet, ooplasmic transfer always involves the interaction of three different DNAs. A summary of the technical properties, advantages and disadvantages of all these techniques can be found in Rodríguez-Varela et al 2021 [ 1 ]. The main human studies using these techniques will be further discussed in the following lines, and a summary of them is present in Table 1 .…”

“…Nuclear transfer techniques can be divided into the cell stage in which the mitochondria replacement takes place. Human studies have been performed using germinal vesicle, spindle, pronuclear and polar body transfer, while blastomere transfer has only been conducted in the animal model [ 1 ].…”

“…Mitochondria transfer involves a range of several techniques in which mitochondria from a donor (heterologous transfer) or from the patient (autologous transfer) are transferred into the patient’s cells. In the reproductive field, the main target cell is the female gamete: the oocyte [ 1 ].…”

Building Pluripotency Identity in the Early Embryo and Derived Stem Cells

“…Specifically, they target the CDK inhibitors p21, Rbl2 and Lats2 in both mESCs [281] and hESCs [282], and in the latter, this family also regulates Cyclins D1 and D2 [283]. Additionally, in hESCs, miR-302 family, miR-145 and miR-296 have a periodic expression along the cell cycle, with an induction at G1/S boundary and high expression levels at S phase [284]. The miR-302 cluster have also a central role in expediting the G1/S transition and promoting cellular proliferation [285].…”