FSH prevents porcine granulosa cells from hypoxia-induced apoptosis via activating mitophagy through the HIF-1α-PINK1-Parkin pathway
FSH prevents porcine granulosa cells from hypoxia-induced apoptosis via activating mitophagy through the HIF-1α-PINK1-Parkin pathway
复制标题
FSH 通过 HIF-1α-PINK1-Parkin 通路激活线粒体自噬，防止猪颗粒细胞缺氧诱导的细胞凋亡
DOI：
10.1096/fj.201901808rrr
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发表时间：
2020-01-20
期刊：
影响因子：
4.8
通讯作者：
Liu, Honglin
中科院分区：
文献类型：
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作者：
Li, Chengyu;Zhou, Jiaqi;Liu, Honglin
在发育中的卵泡中，由于缺乏血液供应，颗粒细胞(GC)生活在低氧环境中。据报道，在低氧条件下，几种类型的哺乳动物细胞会发生凋亡。卵泡刺激素(FSH)通过抑制GCs的凋亡被认为是有腔卵泡的主要生存因子。有丝分裂吞噬是一种细胞器特异性的自噬，它移除受损或应激的线粒体以维持细胞健康。本研究首次提出了FSH介导的有丝分裂噬细胞保护猪GCs免受缺氧诱导的细胞凋亡的证据。我们的研究结果表明，FSH处理后，缺氧应激下线粒体途径引起的GCs细胞凋亡明显减弱，这与激活线粒体吞噬作用有关。有趣的是，FSH还刺激了线粒体的生物发生，这表明在低氧暴露期间线粒体转录因子A和核呼吸因子1的表达增加。值得注意的是，经FSH处理后，缺氧GCs中缺氧诱导因子-1α(HIF-1α)的蛋白水平显著增加，同时伴随着丝裂原活性的增强和凋亡信号的抑制。阻断HIF-1α抑制有丝分裂并恢复低氧诱导的细胞凋亡，尽管FSH治疗。重要的是，FSH通过HIF-1α依赖的方式促进低氧应激时PTEN诱导的丝氨酸/苏氨酸激酶1(PINK1)和E3连接酶Parkin的表达。这诱导了受损线粒体的有丝分裂清除，从而通过减少细胞色素c的释放来抑制细胞凋亡。用抑制剂或RNAi抑制HIF-1α和/或PINK1进一步证实了FSH-HIF-1α-PINK1-Parkin-mitphagy轴在低氧条件下抑制胃癌细胞凋亡中的作用。这些发现突显了FSH的一个新功能，即通过激活HIF-1α-PINK1-Parkin介导的有丝分裂来保护GCs在缺氧损伤中的生存能力。
In developing follicles, the granulosa cells (GCs) live in a hypoxic environment due to the devoid of blood supply. Upon hypoxic conditions, several types of mammalian cells have been reported to undergo apoptosis. Follicle-stimulating hormone (FSH) is known as the primary survival factor for antral follicles by preventing GCs apoptosis. Mitophagy is a type of organelle-specific autophagy that removes damaged or stressed mitochondria to maintain cellular health. This study provides the first evidence suggesting that FSH-mediated mitophagy protected porcine GCs from hypoxia-induced apoptosis. Our data showed that the GCs apoptosis caused by mitochondrial pathway upon hypoxia stress was markedly attenuated after FSH treatment, which was correlated with enhanced activation of mitophagy. Interestingly, FSH also stimulated mitochondrial biogenesis as suggested by increased expression of mitochondrial transcription factor A and nuclear respiratory factor 1 during hypoxia exposure. Notably, the protein level of hypoxia inducible factor-1 alpha (HIF-1 alpha) was significantly increased in hypoxic GCs following FSH treatment, accompanied by elevated mitophagic activity and dampened apoptotic signaling. Blocking HIF-1 alpha inhibited mitophagy and restored hypoxia-induced apoptosis despite FSH treatment. Importantly, FSH promoted the expression of serine/threonine kinase PTEN induced putative kinase 1 (PINK1) and the E3 ligase Parkin during hypoxia stress through a HIF-1 alpha dependent manner. This induced the mitophagic clearance of damaged mitochondria, hence inhibiting apoptosis by reducing cytochrome c releasing. The inhibition of HIF-1 alpha and/or PINK1 using inhibitor or RNAi further confirmed the role of the FSH-HIF-1 alpha-PINK1-Parkin-mitophagy axis in suppressing GC apoptosis under hypoxic conditions. These findings highlight a novel function of FSH in preserving GCs viability against hypoxic damage by activating HIF-1 alpha-PINK1-Parkin-mediated mitophagy.