Ufmylation regulates granulosa cell apoptosis via ER stress but not oxidative stress during goat follicular atresia

Zhang, Xinyan; Yu, Tong; Guo, Xinyan; Zhang, Ruixue; Jia, Yanni; Shang, Chunmei; Wang, Aihua; Jin, Yaping; Lin, Peng

doi:10.1016/j.theriogenology.2021.04.009

Cited by 14 publications

(7 citation statements)

References 26 publications

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“…This phenomenon is the second factor that mediates PCOS follicular dysplasia in this study. In addition, apoptosis of GCs is considered the main mechanism of follicular atresia [ 39 ]. Upregulation of PCOS FF-derived exosomal miR-143-3p expression and downregulation of miR-155-5p expression caused apoptosis of GCs by antagonizing glycolysis, which finally mediated PCOS-related follicular dysplasia in this study.…”

Section: Discussionmentioning

confidence: 99%

Follicular fluid-derived exosomal miR-143-3p/miR-155-5p regulate follicular dysplasia by modulating glycolysis in granulosa cells in polycystic ovary syndrome

et al. 2022

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Objective Polycystic ovary syndrome (PCOS) is characterized by follicular dysplasia. An insufficient glycolysis-derived energy supply of granulosa cells (GCs) is an important cause of follicular dysplasia in PCOS. Follicular fluid (FF) exosomal microRNAs (miRNAs) have been proven to regulate the function of GCs. In this study, exosomes extracted from clinical FF samples were used for transcriptome sequencing (RNA-seq) analysis, and a human ovarian granulocyte tumour cell line (KGN cells) was used for in vitro mechanistic studies. Methods and results In FF exosomal RNA-seq analysis, a decrease in glycolysis-related pathways was identified as an important feature of the PCOS group, and the differentially expressed miR-143-3p and miR-155-5p may be regulatory factors of glycolysis. By determining the effects of miR-143-3p and miR-155-5p on hexokinase (HK) 2, pyruvate kinase muscle isozyme M2 (PKM2), lactate dehydrogenase A (LDHA), pyruvate, lactate and apoptosis in KGN cells, we found that upregulated miR-143-3p expression in exosomes from the PCOS group inhibited glycolysis in KGN cells; knockdown of miR-143-3p significantly alleviated the decrease in glycolysis in KGN cells in PCOS. MiR-155-5p silencing attenuated glycolytic activation in KGN cells; overexpression of miR-155-5p significantly promoted glycolysis in KGN cells in PCOS. In this study, HK2 was found to be the mediator of miR-143-3p and miR-155-5p in FF-derived exosome-mediated regulation of glycolysis in KGN cells. Reduced glycolysis accelerated apoptosis of KGN cells, which mediated follicular dysplasia through ATP, lactate and apoptotic pathways. Conclusions In conclusion, these results indicate that miR-143-3p and miR-155-5p in FF-derived exosomes antagonistically regulate glycolytic-mediated follicular dysplasia of GCs in PCOS.

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Section: Discussionmentioning

confidence: 99%

Follicular fluid-derived exosomal miR-143-3p/miR-155-5p regulate follicular dysplasia by modulating glycolysis in granulosa cells in polycystic ovary syndrome

et al. 2022

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“…The fGCs are instrumental in determining follicular fate and coordinate the follicular development cycle through apoptosis-induced follicular atresia [ 13 , 49 , 50 ]. However, the excessive apoptosis of fGCs can cause abnormal follicular atresia, thus affecting follicular utilization and reducing fertility [ 51 ]. Herein, we detected an increase in the apoptotic rate of fGCs as well as pro-apoptotic-related proteins with increasing BHBA concentrations.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 regulation: a target to alleviate β-hydroxybutyric acid-induced mitochondrial dysfunction in bovine granulosa cells

Zhao

Gong

Wang

et al. 2023

J Animal Sci Biotechnol

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Background During the transition period, the insufficient dry matter intake and a sharply increased in energy consumption to produce large quantities of milk, high yielding cows would enter a negative energy balance (NEB) that causes an increase in ketone bodies (KBs) and decrease in reproduction efficiency. The excess concentrations of circulating KBs, represented by β-hydroxybutyric acid (BHBA), could lead to oxidative damage, which potentially cause injury to follicular granulosa cells (fGCs) and delayed follicular development. Sirtuin 3 (Sirt3) regulates mitochondria reactive oxygen species (mitoROS) homeostasis in a beneficial manner; however, the molecular mechanisms underlying its involvement in the BHBA-induced injury of fGCs is poorly understood. The aim of this study was to explore the protection effects and underlying mechanisms of Sirt3 against BHBA overload-induced damage of fGCs. Results Our findings demonstrated that 2.4 mmol/L of BHBA stress increased the levels of mitoROS in bovine fGCs. Further investigations identified the subsequent mitochondrial dysfunction, including an increased abnormal rate of mitochondrial architecture, mitochondrial permeability transition pore (MPTP) opening, reductions in mitochondrial membrane potential (MMP) and Ca2+ release; these dysfunctions then triggered the caspase cascade reaction of apoptosis in fGCs. Notably, the overexpression of Sirt3 prior to treatment enhanced mitochondrial autophagy by increasing the expression levels of Beclin-1, thus preventing BHBA-induced mitochondrial oxidative stress and mitochondrial dysfunction in fGCs. Furthermore, our data suggested that the AMPK-mTOR-Beclin-1 pathway may be involved in the protective mechanism of Sirt3 against cellular injury triggered by BHBA stimulation. Conclusions These findings indicate that Sirt3 protects fGCs from BHBA-triggered injury by enhancing autophagy, attenuating oxidative stress and mitochondrial damage. This study provides new strategies to mitigate the fGCs injury caused by excessive BHBA stress in dairy cows with ketosis.

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“…By comparing the expression of UFL1 in mouse ovaries at different developmental stages, it was speculated that the increased expression of UFL1 during follicular development must dedicate to the maintenance of ER homeostasis in GCs, providing a stable internal environment for the maturation of follicles (95). Consistently, the expression levels of UFM1 and DDRGK1 were reported to be higher in GCs derived from antral atretic follicles than healthy ones in ovaries from ruminants (39).…”

Section: Ufmylation In Ovariesmentioning

confidence: 93%

“…Defect in this hydrophobic N-terminal region of DDRGK1 would lead UFL1 to localize in the cytoplasm, where UFL1 was found to be cleaved with unknown mechanism (30). In addition, numerous functions have been described for DDRGK1, including ER homeostasis, stress responses and cell differentiation (38)(39)(40). However, it is still undetermined whether all these functions involve UFMylation.…”

Section: Ufl1 and Its Cofactorsmentioning

confidence: 99%

“…In mammals, each follicle, the functional unit of ovary, is composed of an innermost germ cell (so called oocyte), surrounding granulosa cells (GCs), and outer layers of thecal cells (91). Controlled by endocrine and paracrine factors, the follicles develop with the proliferation of GCs through primary, secondary and antral phases, during which most follicles undergo atretic degeneration with a few of them eventually reaching the point of ovulation (39). After the secondary follicular stage, more protein synthesis and post-translational modifications are demanded in order to satisfy the accelerated GC proliferation and oocyte growth, which may create a deleterious situation for the ER (92)(93)(94).…”

Section: Ufmylation In Ovariesmentioning

confidence: 99%

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Emerging role of UFMylation in secretory cells involved in the endocrine system by maintaining ER proteostasis

et al. 2023

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Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like molecule (UBL) discovered almost two decades ago, but our knowledge about the cellular and molecular mechanisms of this novel protein post-translational modification is still very fragmentary. In this review, we first summarize the core enzymes and factors involved in the UFMylation cascade, which, similar to ubiquitin, is consecutively catalyzed by UFM1-activating enzyme 5 (UBA5), UFM1-conjugating enzyme 1 (UFC1) and UFM1-specific ligase 1 (UFL1). Inspired by the substantial implications of UFM1 machinery in the secretory pathway, we next concentrate on the puzzling role of UFMylation in maintaining ER protein homeostasis, intending to illustrate the underlying mechanisms and future perspectives. At last, given a robust ER network is a hallmark of healthy endocrine secretory cells, we emphasize the function of UFM1 modification in physiology and pathology in the context of endocrine glands pancreas and female ovaries, aiming to provide precise insight into other internal glands of the endocrine system.

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Ufmylation regulates granulosa cell apoptosis via ER stress but not oxidative stress during goat follicular atresia

Cited by 14 publications

References 26 publications

Follicular fluid-derived exosomal miR-143-3p/miR-155-5p regulate follicular dysplasia by modulating glycolysis in granulosa cells in polycystic ovary syndrome

Follicular fluid-derived exosomal miR-143-3p/miR-155-5p regulate follicular dysplasia by modulating glycolysis in granulosa cells in polycystic ovary syndrome

Sirtuin 3 regulation: a target to alleviate β-hydroxybutyric acid-induced mitochondrial dysfunction in bovine granulosa cells

Emerging role of UFMylation in secretory cells involved in the endocrine system by maintaining ER proteostasis

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