The role of mitochondrial dynamics in oocyte and early embryo development.

Mitochondrial dysfunction is widely implicated in various human diseases, through mechanisms that go beyond mitochondria's well-established role in energy generation. These dynamic organelles exert vital control over numerous cellular processes, including calcium regulation, phospholipid synthesis, innate immunity, and apoptosis. While mitochondria's importance is acknowledged in all cell types, research has revealed the exceptionally dynamic nature of the mitochondrial network in oocytes and embryos, finely tuned to meet unique needs during gamete and pre-implantation embryo development. Within oocytes, both the quantity and morphology of mitochondria can significantly change during maturation and post-fertilization. These changes are orchestrated by fusion and fission processes (collectively known as mitochondrial dynamics), crucial for energy production, content exchange, and quality control as mitochondria adjust to the shifting energy demands of oocytes and embryos. The roles of proteins that regulate mitochondrial dynamics in reproductive processes have been primarily elucidated through targeted deletion studies in animal models. Notably, impaired mitochondrial dynamics have been linked to female reproductive health, affecting oocyte quality, fertilization, and embryo development. Dysfunctional mitochondria can lead to fertility problems and can have an impact on the success of pregnancy, particularly in older reproductive age women.

Addition of rapamycin or co-culture with cumulus cells from younger reproductive age women does not improve rescue in vitro oocyte maturation or euploidy rates in older reproductive age women.

Both spontaneously conceived pregnancies and those achieved using assisted reproduction decline with advancing maternal age. In this study, we tested if rapamycin and/or cumulus cells (CCs) from young donors could improve oocyte maturation and euploidy rates of germinal vesicle (GV) stage oocytes obtained from older women of reproductive age. A total of 498 GVs from 201 women >38 years (40.6 ± 1.8, mean ± SD) were included. GVs were randomly assigned into five groups for rescue IVM: control (with no CCs and no rapamycin); with autologous CCs; with autologous CCs and rapamycin; with CCs from young women (<35 years); and with CCs from young women and rapamycin. After 24 h of culture, the first polar body (PB) was biopsied in metaphase II oocytes, and the cytogenetic constitution was assessed using next-generation sequencing for both oocytes and PBs. Comparable maturation rates were found (56.2%, 60.0%, 46.5%, 51.7%, and 48.5% for groups 1-5, respectively; P = 0.30). Similarly, comparable euploidy rates were observed in the five groups (41.5%, 37.8%, 47.2%, 43.6%, and 47.8% for Groups 1-5, respectively; P = 0.87). Our findings indicate that rescue IVM is effective for obtaining mature euploid oocytes in older women of reproductive age, and that incubation with rapamycin or CCs obtained from young donors does not improve the maturation or euploidy rate.

Mitochondria as determinants of reproductive senescence and competence: implications for diagnosis of embryo competence in assisted reproduction.

Mitochondria are commonly recognized as the powerhouses of the cell, primarily responsible for energy production through oxidative phosphorylation. Alongside this vital function, they also play crucial roles in regulating calcium signaling, maintaining membrane potential, and modulating apoptosis. Their involvement in various cellular pathways becomes particularly evident during oogenesis and embryogenesis, where mitochondrial quantity, morphology, and distribution are tightly controlled. The efficiency of the mitochondrial network is maintained through multiple quality control mechanisms that are essential for reproductive success. These include mitochondrial unfolded protein response, mitochondrial dynamics, and mitophagy. Not surprisingly, mitochondrial dysfunction has been implicated in infertility and ovarian aging, prompting investigation into mitochondria as diagnostic and therapeutic targets in assisted reproduction. To date, mitochondrial DNA copy number in oocytes, cumulus cells, and trophectoderm biopsies, and fluorescent lifetime imaging microscopy-based assessment of NADH and flavin adenine dinucleotide content have been explored as potential predictors of embryo competence, yielding limited success. Despite challenges in the clinical application of mitochondrial diagnostic strategies, these enigmatic organelles have a significant impact on reproduction, and their potential role as diagnostic targets in assisted reproduction is likely to remain an active area of investigation in the foreseeable future.

Mitochondria as therapeutic targets in assisted reproduction.

Mitochondria are essential organelles with specialized functions, which play crucial roles in energy production, calcium homeostasis, and programmed cell death. In oocytes, mitochondrial populations are inherited maternally and are vital for developmental competence. Dysfunction in mitochondrial quality control mechanisms can lead to reproductive failure. Due to their central role in oocyte and embryo development, mitochondria have been investigated as potential diagnostic and therapeutic targets in assisted reproduction. Pharmacological agents that target mitochondrial function and show promise in improving assisted reproduction outcomes include antioxidant coenzyme Q10 and mitoquinone, mammalian target of rapamycin signaling pathway inhibitor rapamycin, and nicotinamide mononucleotide. Mitochondrial replacement therapies (MRTs) offer solutions for infertility and mitochondrial disorders. Autologous germline mitochondrial energy transfer initially showed promise but failed to demonstrate significant benefits in clinical trials. Maternal spindle transfer (MST) and pronuclear transfer hold potential for preventing mitochondrial disease transmission and improving oocyte quality. Clinical trials of MST have shown promising outcomes, but larger studies are needed to confirm safety and efficacy. However, ethical and legislative challenges complicate the widespread implementation of MRTs.

Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility.

Mitochondrial unfolded protein stress response (mtUPR) plays a critical role in regulating cellular and metabolic stress response and helps maintain protein homeostasis. Caseinolytic peptidase P (CLPP) is one of the key regulators of mtUPR and promotes unfolded protein degradation. Previous studies demonstrated that global deletion of Clpp resulted in female infertility, whereas no impairment was found in the mouse model with targeted deletion of Clpp in cumulus/granulosa cells. These results suggest the need to delineate the function of Clpp in oocytes. In this study, we aimed to further explore the role of mtUPR in female reproductive competence and senescence using a mouse model. Oocyte-specific targeted deletion of Clpp in mice resulted in female subfertility associated with metabolic and functional abnormalities in oocytes, thus highlighting the importance of CLPP-mediated protein homeostasis in oocyte competence and reproductive function.

Mitochondrial Dysfunction, Mitophagy and Their Correlation with Perinatal Complications: Preeclampsia and Low Birth Weight.

Mitochondria are essential organelles and crucial for cellular survival. Mitochondrial biogenesis and mitophagy are dynamic features that are essential for both maintaining the health of the mitochondrial network and cellular demands. The accumulation of damaged mitochondria has been shown to be related to a wide range of pathologies ranging from neurological to musculoskeletal. Mitophagy is the selective autophagy of mitochondria, eliminating dysfunctional mitochondria in cells by engulfment within double-membraned vesicles. Preeclampsia and low birth weight constitute prenatal complications during pregnancy and are leading causes of maternal and fetal mortality and morbidity. Both placental implantation and fetal growth require a large amount of energy, and a defect in the mitochondrial quality control mechanism may be responsible for the pathophysiology of these diseases. In this review, we compiled current studies investigating the role of BNIP3, DRAM1, and FUNDC1, mediators of receptor-mediated mitophagy, in the progression of preeclampsia and the role of mitophagy pathways in the pathophysiology of low birth weight. Recent studies have indicated that mitochondrial dysfunction and accumulation of reactive oxygen species are related to preeclampsia and low birth weight. However, due to the lack of studies in this field, the results are controversial. Therefore, mitophagy-related pathways associated with these pathologies still need to be elucidated. Mitophagy-related pathways are among the promising study targets that can reveal the pathophysiology behind preeclampsia and low birth weight.