Germ cell formation and embryonic development require ATP synthesized by mitochondria. The dynamic system of the mitochondria, and in particular, the fusion of mitochondria, are essential for the generation of energy. Mitofusin1 and mitofusin2, the homologues of Fuzzy onions in yeast and Drosophila, are critical regulators of mitochondrial fusion in mammalian cells. Since their discovery mitofusins (Mfns) have been the source of significant interest as key influencers of mitochondrial dynamics, including membrane fusion, mitochondrial distribution, and the interaction with other organelles. Emerging evidence has revealed significant insight into the role of Mfns in germ cell formation and embryonic development, as well as the high incidence of reproductive diseases such as asthenospermia, polycystic ovary syndrome, and gestational diabetes mellitus. Here, we describe the key mechanisms of Mfns in mitochondrial dynamics, focusing particularly on the role of Mfns in the regulation of mammalian fertility, including spermatogenesis, oocyte maturation, and embryonic development. We also highlight the role of Mfns in certain diseases associated with the reproductive system and their potential as therapeutic targets. 

/pdf/mitofusins-from-mitochondria-to-fertility-282owm0n.pdf

Mitofusins: from mitochondria to fertility

Background Hyperandrogenemia in an obese polycystic ovary syndrome (PCOS) mouse model results in altered glucose/insulin metabolism and mitochondrial structure and function in the oocytes, in part explaining adverse outcomes and inheritance patterns seen in PCOS. Objective To study the oocyte quality by means of mitochondrial structure and function in a well-established classic PCOS mouse model. Design Animal study using an obese PCOS mouse model compared with control. Setting Animal research facility in a tertiary care university hospital setting. Animals C57/B6J mice. Intervention(s) Three-week-old mice had subdermal implants of dihydrotestosterone controlled release pellet or placebo for 90 days. Main Outcome Measure(s) The mouse model was validated by performing glucose tolerance test and glycated hemoglobin level, body weight, and estrous cycle analyses. Oocytes were subsequently isolated and were used to investigate mitochondrial membrane potential, oxidative stress, lipid peroxidation, adenosine triphosphate production, mitochondrial DNA copy number, transcript abundance, histology, and mitochondrial ultrastructure. Result(s) Results showed glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of the oocytes indicated impaired inner mitochondrial membrane function, increased adenosine triphosphate production and mitochondrial DNA copy number, altered RNA transcript abundance, and aberrant ovarian histology. Electron microscopy of the oocytes revealed severely impaired mitochondrial ultrastructure. Conclusion(s) The obese PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial function.

Hyperandrogenemia alters mitochondrial structure and function in the oocytes of obese mouse with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease, all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under the transcriptional regulation of both the nuclear and mitochondrial genome to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, as well as the dynamics that regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted, the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function, causing disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs, including the ovary (oocytes and granulosa cells), uterus, placenta, and circulation, causing reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in the transgenerational transmission of PCOS and metabolic disorders.

Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology.

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy associated with subfertility/infertility and pregnancy complications. Most PCOS women opt for assisted reproductive technologies (ART) for successful conception; however, optimization of the relative doses of the gonadotropins [follicle-stimulating hormone (FSH), luteinizing hormone (LH)/human chorionic gonadotropin (hCG)] for appropriate steroidogenesis, without causing ovarian hyperstimulatory syndrome (OHSS), is challenging. Embryonic factors probably do not contribute to pregnancy loss in PCOS women, albeit hormonal imbalance impairs the metabolic microenvironment critical for oocyte maturation and endometrial receptivity. Certain clinical studies have confirmed the role of metabolic corrections in increasing the rate of pregnancy in PCOS women. This review focuses on the impact of untimely high LHCGR and/or LH levels on oocyte/embryo quality, pregnancy outcomes in ART, and exploring LHCGR as a potential drug target in PCOS women. 

Gonadotropins as pharmacological agents in assisted reproductive technology and polycystic ovary syndrome

To evaluate the feasibility of generating a center-specific embryo morphokinetic algorithm by time-lapse microscopy to predict clinical pregnancy rates.A retrospective cohort analysis.Academic fertility clinic in a tertiary hospital setting.Patients who underwent in vitro fertilization with embryos that underwent EmbryoScope time-lapse microscopy and subsequent transfer between 2014 and 2018.None.Clinical pregnancy.A supervised, random forest learning algorithm from 367 embryos successfully predicted clinical pregnancy from a training set with overall 65% sensitivity and 74% positive predictive value, with an area under the curve of 0.7 for the test set. Similar results were achieved for live birth outcomes. For the secondary analysis, embryo growth morphokinetics were grouped into five clusters using unsupervised clustering. The clusters that had the fastest morphokinetics (time to blastocyst = 97 hours) had pregnancy rates of 54%, whereas a cluster that had the slowest morphokinetics (time to blastocyst = 122 hours) had a pregnancy rate of 71%, although the differences were not statistically significant (P=.356). Other clusters had pregnancy rates of 51%-60%.This study shows the feasibility of a clinic-specific, noninvasive embryo morphokinetic simple machine learning model to predict clinical pregnancy rates. 

https://doi.org/10.1016/j.xfre.2022.04.004

Development of a dynamic machine learning algorithm to predict clinical pregnancy and live birth rate with embryo morphokinetics

Fetal programming of polycystic ovary syndrome: Effects of androgen exposure on prenatal ovarian development.

Objective To investigate if patients with polycystic ovary syndrome (PCOS) have altered embryo morphokinetics when compared with controls. Design Retrospective cohort analysis. Setting Single academic fertility clinic in a tertiary hospital setting. Patient(s) Age- and body mass index–matched patients who underwent in vitro fertilization diagnosed with PCOS using the Rotterdam criteria. A subanalysis was performed on patients with PCOS with hyperandrogenemia. Sixty-four patients with PCOS were identified with 990 embryos that were matched with 64 control patients with 628 embryos. Intervention(s) None. Main Outcome Measure(s) Time to blastulation. Result(s) Embryos from women with PCOS displayed faster growth rate at t7, t8, and t9; all other morphokinetic points were similar. Patients with PCOS also had a higher number of oocytes retrieved. No differences were seen in the fertilization rate or blastulation rate. Patients with PCOS had a higher miscarriage rate (38.1% in PCOS vs. 18.8% in controls). Patients with hyperandrogenic PCOS showed a faster growth rate at t5, t6, t7, t8, t9, and morula. Conclusion(s) Embryos from women with PCOS grew faster until 9-cell stage and women with hyperandrogenic PCOS until morula. Patients with PCOS also showed a higher miscarriage rate. The alterations in early embryo development are consistent with altered fertility and obstetric outcomes in the population with PCOS and may be due to the hyperandrogenic microenvironment in the ovarian follicle.

Embryos from polycystic ovary syndrome patients with hyperandrogenemia reach morula stage faster than controls.

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Fetal programming of polycystic ovary syndrome: Effects of androgen exposure on prenatal ovarian development.

Embryos from polycystic ovary syndrome patients with hyperandrogenemia reach morula stage faster than controls.