Effect of mitophagy in oocytes and granulosa cells on oocyte quality†

2020 ◽  
Author(s):  
Qiuzi Shen ◽  
Yu Liu ◽  
Honggang Li ◽  
Ling Zhang
Keyword(s):  
Cell Survival ◽  
Granulosa Cells ◽  
Mitochondrial Function ◽  
Oocyte Quality ◽  
Reproductive Technology ◽  
Developmental Competence ◽  
Mitochondrial Homeostasis ◽  
New Directions ◽  
Developmental Capacity ◽  
Assisted Reproductive Technology Treatment

Abstract Mitophagy is the process by which cells selectively remove supernumerary or damaged mitochondria through autophagy, and is crucial for mitochondrial homeostasis and cell survival. Mitochondria play vital roles in determining the developmental competence of oocytes. During the early stages of oogenesis, aberrant mitochondria can be removed by mitophagy. After oocyte formation, mitophagy is not actively initiated to clear damaged mitochondria despite the presence of mitophagy regulators in oocytes, which leads to the transmission of dysfunctional mitochondria from the oocyte to the embryo. However, granulosa cells around oocytes can improve mitochondrial function through mitophagy, thereby improving oocyte developmental capacity. Furthermore, this review discusses recent work on the substances and environmental conditions that affect mitophagy in oocytes and granulosa cells, thus providing new directions for improving oocyte quality during assisted reproductive technology treatment.

scholarly journals Mitochondrial Function in Modulating Human Granulosa Cell Steroidogenesis and Female Fertility

2020 ◽  
Vol 21 (10) ◽  
pp. 3592
Author(s):  
Dilip Bhargava Sreerangaraja Urs ◽  
Wen-Han Wu ◽  
Katerina Komrskova ◽  
Pavla Postlerova ◽  
Yung-Feng Lin ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Granulosa Cells ◽  
Mitochondrial Function ◽  
Oocyte Quality ◽  
Fertilization Rate ◽  
Mitochondrial Mass ◽  
Ovarian Endometrioma ◽  
The Relationship ◽  
Estradiol Levels ◽  
Follicular Fluids

Ovarian follicle steroidogenesis associated with embryo quality results in a successful pregnancy. Each follicle consists of an oocyte surrounded by granulosa cells, which secrete several steroid and peptide hormones. Follicles harvested from women who conceived after assisted reproductive therapy (ART) had significantly higher estradiol levels in follicular fluids than the follicles from women who failed to conceive after ART. The higher follicular estradiol levels correlate well with successful fertilization following ART. Mitochondria are the central sites for steroid hormone biosynthesis. The first and rate-limiting step in the biosynthesis of steroid hormones occurs in the mitochondria of granulosa cells. In the present study, we hypothesized that the mitochondria in granulosa cells are critical for maintaining oocyte quality and fertility capacity. This study aims to clarify the relationship between mitochondrial function and granulosa cell steroidogenesis, and the relationship between hormone levels and fertility capacity. Sera, follicular fluids and granulosa cells were obtained from individuals undergoing IVF-ET treatment. The oocyte numbers, oocyte quality, fertilization rate, and pregnancy rate were also recorded. The patients who provided the granulosa cells were further classified into four groups: endometriosis, ovarian endometrioma, endometriosis without ovarian endometrioma, and polycystic ovary syndrome (PCOS); patients with other female factor infertility and male factor infertility were used as controls. We measured the levels of estradiol (E2) by radioimmunoassay. Concurrently, we analyzed the mitochondrial mass and membrane potential, and apoptosis by flow cytometry using nonyl acridine orange, TMRE, Annexin V-FITC and PI. Mitochondrial morphology was visualized by transfection with pLV-mitoDsRed. In addition, we assessed the protein levels of steroidogenic enzymes, steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) by Western blot. The results showed significantly decreased serum E2 and follicular E2 levels, and decreased IVF outcomes, in the patients with endometriosis. Reduced mitochondrial mass and decreased mitochondrial membrane potential were correlated with lower E2. Furthermore, a significant decrease in StAR and 3β-HSD was found in patients with ovarian endometrioma. The enzyme levels of StAR and 3β-HSD were highly correlated with E2 levels. Finally, elevated cumulus cell apoptosis was found in the patient group with ovarian endometrioma and PCOS. In conclusion, mitochondrial dysfunction of human granulosa cells may contribute to the decline of steroidogenesis, decreased fertilization rate, oocyte maturation rate, and oocyte quality, and it can ultimately jeopardize fertility.

151. LIPOTOXICITY MEDIATED ENDOPLASMIC RETICULUM STRESS, MITOCHONDRIAL DYSFUNCTION AND APOPTOSIS CONTRIBUTE IMPAIRED OOCYTE QUALITY IN RESPONSE TO OBESITY

2009 ◽  
Vol 21 (9) ◽  
pp. 69
Author(s):  
L. L. Y. Wu ◽  
X. Yang ◽  
K. R. Dunning ◽  
R. J. Norman ◽  
R. L. Robker
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Potential ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Granulosa Cells ◽  
Oocyte Quality ◽  
Developmental Competence ◽  
Tunel Staining ◽  
Marker Genes ◽  
Er Homeostasis

In obesity, accumulation of lipid in non-adipose tissues, a process termed lipotoxicity, is associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction and ultimately apoptosis . We have previously shown that diet-induced obesity in mice causes impaired oocyte developmental competence, but whether this is due to activation of lipotoxicity pathways in the ovary is not known. The present study examined the hypothesis that diet-induced lipid accumulation in the cumulus oocyte complex (COC) disrupts ER homeostasis and mitochondrial membrane potential which leads to apoptosis. COCs and mural granulosa cells were collected from ovaries of adult mice fed a high fat (HFD) or control diet for 4 weeks. ER homeostasis was assessed by measuring expression of known ER stress marker genes, GRP78, ATF4 and CHOP. COCs from mice fed HFD showed significantly increased expression of GRP78 and ATF4. There was a similar trend towards increased expression in granulosa cells. Mitochondrial function was assessed by measuring membrane potential using the dual emission probe JC-1. In COCs from mice fed HFD there were reduced numbers of active mitochondria but instead large aggregated clusters of inactive mitochondria. Apoptosis in granulosa cells was determined by DNA laddering assay which showed significantly increased DNA fragmentation in cells from mice fed HFD. Apoptosis was also assessed by TUNEL staining of paraffin embedded ovaries from identical treatment groups. Ovaries from HFD mice appeared to have increased TUNEL positivity in both granulosa and cumulus cells. Our results demonstrate that the ER stress, mitochondrial dysfunction and apoptosis are markedly increased in granulosa cells and COCs from mice fed HFD, suggesting that lipotoxicity contributes to the impaired oocyte quality and reduced fertility observed in response to obesity.

scholarly journals The Function of Cumulus Cells in Oocyte Growth and Maturation and in Subsequent Ovulation and Fertilization

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2292
Author(s):  
Bongkoch Turathum ◽  
Er-Meng Gao ◽  
Ri-Cheng Chian
Keyword(s):  
Granulosa Cells ◽  
Follicular Development ◽  
Cumulus Cells ◽  
Oocyte Quality ◽  
Early Embryo ◽  
Developmental Competence ◽  
Meiotic Maturation ◽  
Supporting Cells ◽  
Oocyte Growth ◽  
Oocyte Meiotic Maturation

Cumulus cells (CCs) originating from undifferentiated granulosa cells (GCs) differentiate in mural granulosa cells (MGCs) and CCs during antrum formation in the follicle by the distribution of location. CCs are supporting cells of the oocyte that protect the oocyte from the microenvironment, which helps oocyte growth and maturation in the follicles. Bi-directional communications between an oocyte and CCs are necessary for the oocyte for the acquisition of maturation and early embryonic developmental competence following fertilization. Follicle-stimulation hormone (FSH) and luteinizing hormone (LH) surges lead to the synthesis of an extracellular matrix in CCs, and CCs undergo expansion to assist meiotic resumption of the oocyte. The function of CCs is involved in the completion of oocyte meiotic maturation and ovulation, fertilization, and subsequent early embryo development. Therefore, understanding the function of CCs during follicular development may be helpful for predicting oocyte quality and subsequent embryonic development competence, as well as pregnancy outcomes in the field of reproductive medicine and assisted reproductive technology (ART) for infertility treatment.

scholarly journals Changes in granulosa cells' gene expression associated with increased oocyte competence in bovine

Reproduction ◽  
2013 ◽  
Vol 145 (6) ◽  
pp. 555-565 ◽  
Author(s):  
Anne-Laure Nivet ◽  
Christian Vigneault ◽  
Patrick Blondin ◽  
Marc-André Sirard
Keyword(s):  
Gene Expression ◽  
Granulosa Cells ◽  
Principal Component ◽  
Oocyte Quality ◽  
Developmental Competence ◽  
Follicle Growth ◽  
Oocyte Competence ◽  
Functional Changes ◽  
Extracellular Molecules ◽  
Apoptosis And Inflammation

One of the challenges in mammalian reproduction is to understand the basic physiology of oocyte quality. It is believed that the follicle status is linked to developmental competence of the enclosed oocyte. To explore the link between follicles and competence in cows, previous research at our laboratory has developed an ovarian stimulation protocol that increases and then decreases oocyte quality according to the timing of oocyte recovery post-FSH withdrawal (coasting). Using this protocol, we have obtained the granulosa cells associated with oocytes of different qualities at selected times of coasting. Transcriptome analysis was done with Embryogene microarray slides and validation was performed by real-time PCR. Results show that the major changes in gene expression occurred from 20 to 44 h of coasting, when oocyte quality increases. Secondly, among upregulated genes (20–44 h), 25% were extracellular molecules, highlighting potential granulosa signaling cascades. Principal component analysis identified two patterns: one resembling the competence profile and another associated with follicle growth and atresia. Additionally, three major functional changes were identified: i) the end of follicle growth (BMPR1B,IGF2, andRELN), involving interactions with the extracellular matrix (TFPI2); angiogenesis (NRP1), including early hypoxia, and potentially oxidative stress (GFPT2,TF, andVNN1) and ii) apoptosis (KCNJ8) followed by iii) inflammation (ANKRD1). This unique window of analysis indicates a progressive hypoxia during coasting mixed with an increase in apoptosis and inflammation. Potential signaling pathways leading to competence have been identified and will require downstream testing. This preliminary analysis supports the potential role of the follicular differentiation in oocyte quality both during competence increase and decrease phases.

scholarly journals Constitutive Expression of TERT Enhances β-Klotho Expression and Improves Age-Related Deterioration in Early Bovine Embryos

2021 ◽  
Vol 22 (10) ◽  
pp. 5327
Author(s):  
Lianguang Xu ◽  
Muhammad Idrees ◽  
Myeong-Don Joo ◽  
Tabinda Sidrat ◽  
Yiran Wei ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Constitutive Expression ◽  
Growth Factor Receptor ◽  
Oocyte Quality ◽  
Low Fertility ◽  
Treatment Groups ◽  
Age Related ◽  
Early Embryos ◽  
Plasmid Injection ◽  
Telomere Lengthening

Age-associated decline in oocyte quality is one of the dominant factors of low fertility. Aging alters several key processes, such as telomere lengthening, cell senescence, and cellular longevity of granulosa cells surrounding oocyte. To investigate the age-dependent molecular changes, we examined the expression, localization, and correlation of telomerase reverse transcriptase (TERT) and β-Klotho (KLB) in bovine granulosa cells, oocytes, and early embryos during the aging process. Herein, cumulus-oocyte complexes (COCs) obtained from aged cows (>120 months) via ovum pick-up (OPU) showed reduced expression of β-Klotho and its co-receptor fibroblast growth factor receptor 1 (FGFR1). TERT plasmid injection into pronuclear zygotes not only markedly enhanced day-8 blastocysts’ development competence (39.1 ± 0.8%) compared to the control (31.1 ± 0.5%) and D-galactose (17.9 ± 1.0%) treatment groups but also enhanced KLB and FGFR1 expression. In addition, plasmid-injected zygotes displayed a considerable enhancement in blastocyst quality and implantation potential. Cycloastragenol (CAG), an extract of saponins, stimulates telomerase enzymes and enhances KLB expression and alleviates age-related deterioration in cultured primary bovine granulosa cells. In conclusion, telomerase activation or constitutive expression will increase KLB expression and activate the FGFR1/β-Klotho pathway in bovine granulosa cells and early embryos, inhibiting age-related malfunctioning.

scholarly journals Glycine ameliorates mitochondrial dysfunction caused by ABT-199 in porcine oocytes

2021 ◽  
Author(s):  
Sicong Yu ◽  
Lepeng Gao ◽  
Yang Song ◽  
Xin Ma ◽  
Shuang Liang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Oocyte Maturation ◽  
Mitochondrial Function ◽  
Protective Action ◽  
Damage Model ◽  
Developmental Competence ◽  
Free Calcium ◽  
Maturation In Vitro

Abstract Mitochondria play an important role in controlling oocyte developmental competence. Our previous studies showed that glycine can regulate mitochondrial function and improve oocyte maturation in vitro. However, the mechanisms by which glycine affects mitochondrial function during oocyte maturation in vitro have not been fully investigated. In this study, we induced a mitochondrial damage model in oocytes with the Bcl-2-specific antagonist ABT-199. We investigated whether glycine could reverse the mitochondrial dysfunction induced by ABT-199 exposure and whether it is related to calcium regulation. Our results showed that ABT-199 inhibited cumulus expansion, decreased the oocyte maturation rate and the intracellular glutathione (GSH) level, caused mitochondrial dysfunction, induced oxidative stress, which was confirmed by decreased mitochondrial membrane potential (Δ⍦m) and the expression of mitochondrial function-related genes (PGC-1α), and increased reactive oxygen species (ROS) levels and the expression of apoptosis-associated genes (Bax, caspase-3, CytC). More importantly, ABT-199-treated oocytes showed an increase in the intracellular free calcium concentration ([Ca 2+]i) and had impaired cortical type 1 inositol 1,4,5-trisphosphate receptors (IP3R1) distribution. Nevertheless, treatment with glycine significantly ameliorated mitochondrial dysfunction, oxidative stress and apoptosis, glycine also regulated [Ca 2+]i levels and IP3R1 cellular distribution, which further protects oocyte maturation in ABT-199-induced porcine oocytes. Taken together, our results indicate that glycine has a protective action against ABT-199-induced mitochondrial dysfunction in porcine oocytes.

Supplementation of c-type natriuretic peptide during in vitro growth period benefits the development of murine preantral follicles

Zygote ◽  
2020 ◽  
pp. 1-5
Author(s):  
Li Ang ◽  
Cao Haixia ◽  
Li Hongxia ◽  
Li Ruijiao ◽  
Guo Xingping ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Granulosa Cells ◽  
Culture System ◽  
Early Stage ◽  
Developmental Competence ◽  
Control Group ◽  
Follicle Development ◽  
Control Groups ◽  
Preantral Follicles

Summary The present study investigated the effects of c-type natriuretic peptide (CNP) on the development of murine preantral follicles during in vitro growth (IVG). Preantral follicles isolated from ovaries of Kunming mice were cultured in vitro. In the culture system, CNP was supplemented in the experimental groups and omitted in the control groups. In Experiment 1, CNP was only supplemented at the early stage and follicle development was evaluated. In Experiments 2 and 3, CNP was supplemented during the whole period of in vitro culture. In Experiment 2, follicle development and oocyte maturity were evaluated. In Experiment 3, follicle development and embryo cleavage after in vitro fertilization (IVF) were assessed. The results showed that in the control groups in all three experiments, granulosa cells migrated from within the follicle and the follicles could not reach the antral stage. In the experimental groups in all three experiments, no migration of granulosa cells was observed and follicle development was assessed as attaining the antral stage, which was significantly superior to that of the control group (P < 0.0001). Oocyte meiotic arrest was effectively maintained, hence giving good developmental competence. In conclusion, CNP supplementation in the culture system during IVG benefited the development of murine preantral follicles.

scholarly journals Nicotinamide Supplementation Improves Oocyte Quality and Offspring Development by Modulating Mitochondrial Function in an Aged Caenorhabditis elegans Model

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 519
Author(s):  
Hyemin Min ◽  
Mijin Lee ◽  
Kyoung Sang Cho ◽  
Hyunjung Jade Lim ◽  
Yhong-Hee Shim
Keyword(s):  
Caenorhabditis Elegans ◽  
Mitochondrial Function ◽  
Stress Responses ◽  
Oocyte Quality ◽  
Embryonic Lethality ◽  
Reproductive Aging ◽  
Control Female ◽  
Offspring Development ◽  
Developmental Growth ◽  
Ros Accumulation

Aging is associated with a decline in the quality of biological functions. Among the aging processes, reproductive aging is a critical process because of its intergenerational effects. However, the mechanisms underlying reproductive aging remain largely unknown. Female reproductive aging is the primary reason for limited fertility in mammals. Therefore, we attempted to investigate a modulator that can control female reproductive aging using a Caenorhabditis elegans model. In the present study, we examined the role of nicotinamide (NAM) in oocyte quality and offspring development. The levels of reactive oxygen species (ROS) and oxidative stress responses in aged oocytes, embryonic lethality, and developmental growth of the offspring were examined with maternal NAM supplementation. Supplementation with NAM improved oocyte quality, decreased embryonic lethality, and promoted germ cell apoptosis. Furthermore, NAM supplementation in aged mothers reduced ROS accumulation and improved mitochondrial function in oocytes. Consequently, the developmental growth and motility of offspring were improved. These findings suggest that NAM supplementation improves the health of the offspring produced by aged mothers through improved mitochondrial function. Taken together, our results imply that NAM supplementation in the aged mother improves oocyte quality and protects offspring by modulating mitochondrial function.

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