FSH protects mouse granulosa cells from oxidative damage by repressing mitophagy

Shen, Ming; Jiang, Yi; Guan, Zhiqiang; Cao, Yan; Sun, Shao‐Chen; Liu, Honglin

doi:10.1038/srep38090

Cited by 58 publications

(47 citation statements)

References 55 publications

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“…Moreover, no significant induction of CASP3 was observed in the early stages of H 2 O 2 -induced cell death. 57 These results thus suggested the involvement of apoptosis-independent autophagic PCD in FSH-mediated GC survival upon acute oxidative stress. Since autophagosome formation requires the participation of several autophagy-related genes such as Becn1 and Atg7, 58,59 we then tested whether blocking autophagy with small interfering RNA Figure 3.…”

Section: Fsh Reduces Oxidative Injury In Cultured Gcs Via Inhibitingmentioning

confidence: 82%

Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy

et al. 2017

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Oxidative stress-induced granulosa cell (GCs) death represents a common reason for follicular atresia. Follicle-stimulating hormone (FSH) has been shown to prevent GCs from oxidative injury, although the underlying mechanism remains to be elucidated. Here we first report that the suppression of autophagic cell death via some novel signaling effectors is engaged in FSH-mediated GCs protection against oxidative damage. The decline in GCs viability caused by oxidant injury was remarkably reduced following FSH treatment, along with impaired macroautophagic/autophagic flux under conditions of oxidative stress both in vivo and in vitro. Blocking of autophagy displayed similar levels of suppression in oxidant-induced cell death compared with FSH treatment, but FSH did not further improve survival of GCs pretreated with autophagy inhibitors. Further investigations revealed that activation of the phosphoinositide 3-kinase (PI3K)-AKT-MTOR (mechanistic target of rapamycin [serine/threonine kinase]) signaling pathway was required for FSH-mediated GCs survival from oxidative stress-induced autophagy. Additionally, the FSH-PI3K-AKT axis also downregulated the autophagic response by targeting FOXO1, whereas constitutive activation of FOXO1 in GCs not only abolished the protection from FSH, but also emancipated the autophagic process, from the protein level of MAP1LC3B-II to autophagic gene expression. Furthermore, FSH inhibited the production of acetylated FOXO1 and its interaction with Atg proteins, followed by a decreased level of autophagic cell death upon oxidative stress. Taken together, our findings suggest a new mechanism involving FSH-FOXO1 signaling in defense against oxidative damage to GCs by restraining autophagy, which may be a potential avenue for the clinical treatment of anovulatory disorders.

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Section: Fsh Reduces Oxidative Injury In Cultured Gcs Via Inhibitingmentioning

confidence: 82%

Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy

et al. 2017

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“…Other studies also show that BMP6 has an inhibitory role during in-vivo folliculogenesis, i.e., AMH inhibits GC proliferation and later ultimately reduces aromatase expression [38,48]. FSH decreases the cell cycle and suppresses mitophagy via the PINK1-Parkin (PTEN-induced kinase 1) cascade to promote GC survival [58,59]. Initially, Cell viability increased with the concentration of FSH, but significantly decreased at high doses (50 ng/mL FSH).…”

Section: Discussionmentioning

confidence: 99%

Regulation of AMH, AMHR-II, and BMPs (2,6) Genes of Bovine Granulosa Cells Treated with Exogenous FSH and Their Association with Protein Hormones

Umer

Sammad

Zou

et al. 2019

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Anti-Mullerian hormone (AMH) is an important reproductive marker of ovarian reserve produced by granulosa cells (GCs) of pre-antral and early-antral ovarian follicles in several species, including cattle. This hormone plays a vital role during the recruitment of primordial follicles and follicle stimulating hormone (FSH)-dependent follicular growth. However, the regulatory mechanism of AMH expression in follicles is still unclear. In this study, we compared the expression of AMH, AMHR-II, BMP2, BMP6, FSHR, and LHCGR genes during follicular development. In-vitro expression study was performed with and without FSH for AMH, AMHR-II, BMP2, and BMP6 genes in bovine GCs which were isolated from 3-8 mm follicles. Association among the mRNA expression and hormone level was estimated. GCs were collected from small (3-8 mm), medium (9-12 mm) and large size (13 to 24 mm) follicles before, during onset, and after deviation, respectively. Further, mRNA expression, hormones (AMH, FSH, and LH), apoptosis of GCs, and cell viability were detected by qRT-PCR, ELISA, flow cytometry, and spectrophotometry. AMH, AMHR-II, BMP2, and FSHR genes were highly expressed in small and medium follicles as compared to large ones. In addition, the highest level of AMH protein (84.14 ± 5.41 ng/mL) was found in medium-size follicles. Lower doses of FSH increased the viability of bovine GCs while higher doses repressed them. In-vitro cultured GCs treated with FSH significantly increased the AMH, AMHR-II, and BMP2 expression levels at lower doses, while expression levels decreased at higher doses. We found an optimum level of FSH (25 ng/mL) which can significantly enhance AMH and BMP2 abundance (p < 0.05). In summary, AMH, AMHR-II, and BMP2 genes showed a higher expression in follicles developed in the presence of FSH. However, lower doses of FSH demonstrated a stimulatory effect on AMH and BMP2 expression, while expression started to decline at the maximum dose. In this study, we have provided a better understanding of the mechanisms regulating AMH, AMHR II, and BMP2 signaling in GCs during folliculogenesis, which would improve the outcomes of conventional assisted reproductive technologies (ARTs), such as superovulation and oestrus synchronization in bovines.

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“…This implies that death of these cells will consequently warrant atresia of the developing follicles in which they are found. Follicle stimulating hormone is needed to sustain the viability of the granulosa cells, but vitamin D defi ciency causes AMH-induced inhibition of FSH in the developing follicles, leading to cellular degeneration and detectable late stage DNA fragments [35]. The detection of DNA damage in the oocyte is usually delayed and seldom measurable above background, hence the oocytes did not pick the TUNEL staining [33].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Detection of Vasa Antigen and Apoptosis-Related DNA Fragmentation in Ovaries of Sheep Fetuses Prenatally Exposed to Vitamin D Deficiency

2019

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The primordial germ cells (PGCs) in female animals are comprised of diplotene oocytes arrested in the first meiotic prophase. Expression of Vasa is one of the key factors required for subsequent resumption of development and recruitment of PGCs into the growing follicle class. Since vitamin D regulates recruitment of PGCs and developmental competence of ovarian follicles, this study was designed to investigate the expression of Vasa and rate of apoptosis in foetal ovaries prenatally restricted from dietary vitamin D. Nineteen sexually mature Welsh mountain ewes were randomly assigned to vitamin D deficient (VDD) and vitamin D control (VDC) diets from 17d before mating, up to 125d of gestation, when fetal ovaries were collected and fixed in formalin for immunohistochemistry and TUNEL assay. VDD ovaries had fewer healthy oocytes that could stain positive for Vasa as well as a lower integrated density value for DAB staining intensity. Conversely, TUNNEL staining in VDD animals showed a higher integrated density value and percentage of affected area (P<0.05). The present findings indicate that Vasa expression is decreased, while the rate of apoptosis increased in VDD fetal ovaries, and this may adversely affect resumption of growth and development of PGCs reserve.

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FSH protects mouse granulosa cells from oxidative damage by repressing mitophagy

Cited by 58 publications

References 55 publications

Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy

Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy

Regulation of AMH, AMHR-II, and BMPs (2,6) Genes of Bovine Granulosa Cells Treated with Exogenous FSH and Their Association with Protein Hormones

Immunohistochemical Detection of Vasa Antigen and Apoptosis-Related DNA Fragmentation in Ovaries of Sheep Fetuses Prenatally Exposed to Vitamin D Deficiency

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