Follicle-Stimulating Hormone Alleviates Ovarian Aging by Modulating Mitophagy- and Glycophagy-Based Energy Metabolism in Hens

Abstract

As a predominant hormone in the reproductive axis, follicle-stimulating hormone (FSH) is known as the primary surviving factor for follicular growth. In this study, the alleviating effect of FSH on aging chicken granulosa cells (GCs) was investigated. Results showed that FSH activated mitophagy and relieved mitochondrial edema in D-gal-induced senescent GCs, which was evidenced by an increased number of mitophagosomes as well as increased mitochondria-light chain 3 (LC3) colocalization. Mitophagy activation was accompanied by the activation of the AMP-activated protein kinase (AMPK) signaling pathway. Furthermore, upregulated glycophagy was demonstrated by an increased interaction of starch-binding domain protein 1 (STBD1) with GABA type A receptor-associated protein-like 1 (GABARAPL1) in D-gal-induced senescent GCs. FSH treatment further promoted glycophagy, accompanied by PI3K/AKT activation. PI3K inhibitor LY294002 and AKT inhibitor GSK690693 attenuated the effect of FSH on glycophagy and glycolysis. The inhibition of FSH-mediated autophagy attenuated the protective effect of FSH on naturally aging GC proliferation and glycolysis. The simultaneous blockage of PI3K/AKT and AMPK signaling also abolished the positive effect of FSH on naturally senescent ovarian energy regulation. These data reveal that FSH prevents chicken ovarian aging by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/AKT and AMPK pathways.

MFN2 regulates progesterone biosynthesis and proliferation of granulosa cells during follicle selection in hens

“…Ma et al (2020) reported that the proliferation of granulosa cells in chicken prehierarchical follicles increased significantly after treated with 100 mIU/mL FSH for 72 h. In mice, increased mitochondrial activity, elevated ATP level and mtDNA copy numbers of granulosa cells were detected during the FSH‐stimulated follicle development process (Hoque et al, 2021). Similarly, in Hyline white hens, treatment of FSH (0.01 IU/mL) promoted proliferation and ATP production, and delayed cell senescence in D‐gal‐induced senescent granulosa cells (Dong et al, 2022). In the present study, treatment with FSH (80 ng/mL) for 72 h markedly promoted P4 biosynthesis in the F5G, but did not promote the P4 production of SYFG in vitro.…”

Nobiletin Ameliorates Aging of Chicken Ovarian Prehierarchical Follicles by Suppressing Oxidative Stress and Promoting Autophagy

“…In addition, it was demonstrated that Nob had a specific anti-aging effect on naturally aging follicles. Previous evidence has indicated that after the addition of FSH, the proportion of β-galactosidase-positive cells decreased by 45% compared to the D-gal group [ 18 ]. Lycopene supplementation could restore the proliferation of D-gal-induced senescent cells by 73% and reduce the apoptosis rate by 67% [ 3 ].…”

“…D-galactose (D-gal) is a well-known reducing sugar that has been used in aging models. D-gal was shown to induce the excessive accumulation of advanced glycation products in oxidative metabolism, leading to cell and tissue senescence [ 18 ]. Previous studies have demonstrated that in-vitro-cultured ovarian tissues treated with D-gal exhibit significant aging changes in chickens, such as increased levels of oxidative stress and apoptosis [ 4 , 19 ].…”

The follicle-stimulating hormone triggers rapid changes in mitochondrial structure and function in porcine cumulus cells

“…In bovine oocytes, mitochondrial distribution and ATP synthesis are modulated in response to FSH 63 , while FSH stimulates mitochondrial biogenesis and reduces mitochondrial mitophagy under oxidative stress conditions in porcine granulosa cells 64 , 65 . Furthermore, it has been demonstrated that FSH attenuates mitochondrial damage by inhibiting mitophagy induced by oxidative stress during aging in mouse granulosa cells 66 . Interestingly, FSH regulates the expression of mitochondrial apoptotic genes in cumulus cells, reduces apoptosis, and improves oocyte developmental competence 67 .…”