HIF-1α/BNIP3-Mediated Autophagy Contributes to the Luteinization of Granulosa Cells During the Formation of Corpus Luteum

Abstract

During the luteinization after ovulation in mammalian ovary, the containing cells undergo an energy consuming function re-determination process to differentiate into luteal cells under avascular environment. Previous evidences have delineated the contribution of autophagy to the cell differentiation and the catabolic homeostasis in various types of mammalian cells, whereas few interest had been focused on the involvement of autophagy in the luteinization of granulosa cells during the formation of early corpus luteum. Herein, the present study investigated that expression and contribution of autophagy during granulosa cell luteinization and early luteal development through in vivo and in vitro experiments. The results clearly demonstrated that HIF-1α/BNIP3-mediated autophagy plays a vital role in the luteinization of granulosa cells during the early luteal formation in vivo and in vitro. In the neonatal corpus luteum, HIF-1α up-regulated BNIP3 expressions, which contributed to the autophagic initiation by disrupting beclin1 from Bcl-2/beclin1 complex and protected cells from apoptosis by curbing the skew of mitochondria balance under avascular niche. Notably, Inhibition of HIF-1α activity by echinomycin enhanced the levels of cytoplasmic cytochrome c and cell apoptosis in the nascent corpus luteum. These findings revealed that HIF-1α/BNIP3-mediated autophagy enabled the process of granulosa cell luteinization and protected the granulosa-lutein cells from further apoptosis under hypoxia niche. To our knowledge, the present study firstly clarified that HIF-1α/BNIP3-mediated autophagy contributes to the luteinization of granulosa cells during the formation of pregnant corpus luteum, which will help us further understanding the luteal biology and provide us new clues for the treatment of luteal insufficiency.

Luteinizing Hormone Regulation of Inter-Organelle Communication and Fate of the Corpus Luteum

“…In the ovary, autophagy has been associated with follicle development and atresia as well as luteal formation and regression [ 174 , 176 , 214 , 215 , 216 , 217 , 218 , 219 ]. Recently, Tang et al (2020) found that HIF1α enhances autophagy in the rat luteinized granulosa cells [ 217 ].…”

“…In the ovary, autophagy has been associated with follicle development and atresia as well as luteal formation and regression [ 174 , 176 , 214 , 215 , 216 , 217 , 218 , 219 ]. Recently, Tang et al (2020) found that HIF1α enhances autophagy in the rat luteinized granulosa cells [ 217 ]. HIF1α is highly expressed in the granulosa cells of preovulatory follicles in various species [ 220 ].…”

“…HIF1α is highly expressed in the granulosa cells of preovulatory follicles in various species [ 220 ]. HIF1α upregulated BNIP3 (BCL2 interacting protein 3) expression in rat luteinized granulosa cells, which contributed to autophagy initiation by displacing Beclin1 from the Bcl2/Beclin complex and at the same time protecting cells from apoptosis [ 217 ]. In the rat corpus luteum, expression of autophagy related proteins increases simultaneously with decreases in Akt/MTOR signaling [ 218 ].…”

Overexpression of HIF‐1α enhances the protective effect of mitophagy on steroid‐induced osteocytes apoptosis

“…HIF‐1α, furthermore, is also an inductor for mitophagy 15 . The cells have been undergone hypoxia in the mitochondria; HIF‐1α can be activated and/or promotes cell death through its downstream elements Bcl‐2/E1B interacting protein 3 (BNIP3) or BNIP3L (NIX), disturbing the interaction between Beclin‐1 and Bcl2 16 …”

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“…In the ovary, autophagy has been associated with follicle development and atresia as well as luteal formation and regression (Escobar et al, 2008;Choi et al, 2011;Aboelenain et al, 2015;Grzesiak et al, 2018;Meng et al, 2018;Zhang et al, 2018;Tang et al, 2019;Tang et al, 2020;Wen et al, 2020). However, the signaling pathways responsible for regulation of autophagy in luteal cells have received little attention.…”