Zhang Rui, Cui Yan, Pan Yangyang, Wang Meng, Yu Sijiu, Xu Ruihua, Ma Wenbin, Wang Junqian, Zhong Donglan, Jiao Zhengxing
College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730000, China.
Gansu Livestock Embryo Engineering Technology Innovation Center, Lanzhou 730000, China.
Biomolecules. 2025 May 24;15(6):759. doi: 10.3390/biom15060759.
Cold-inducible RNA-binding protein (CIRBP) has been reported to be involved in various cellular functions by regulating programmed cell death (PCD). However, the specific mechanism and function of CIRBP in regulating mitochondrial autophagy are still unclear. In this study, we found that CIRBP induced mitophagy through the AMPK/mTOR pathway to improve the function of yak cumulus cells (YCCs). We observed that low temperatures (32 °C) activated autophagy, increased E2 and P4 secretion, and up-regulated CIRBP expression. CIRBP overexpression activated mitophagy in YCCs, promoted cumulus diffusion, enhanced E2 and P4 synthesis and secretion, and inhibited apoptosis. CIRBP overexpression significantly attenuated the dysfunction of YCCs induced by the inhibition of mitophagy, whereas the activation of mitophagy exerted the same effect as CIRBP overexpression. DOX HCL is an AMPK/mTOR pathway inhibitor. CIRBP overexpression can successfully alleviate the inhibition of mitophagy caused by DOX HCL inhibiting the AMPK/mTOR pathway and can significantly enhance the mitophagy induced by AMPK/mTOR pathway activation in YCCs. Furthermore, we found that the increased expression of CIRBP protein alleviated the apoptosis caused by AKT pathway activation. In summary, CIRBP promoted mitophagy by activating AMPK/mTOR pathway, thereby promoting the synthesis and secretion of steroid hormones and cumulus diffusion in YCCs and enhancing YCCs survival through activating autophagy and AKT signaling pathway, and then improve the function of YCCs. Our research provided new perspectives on CIRBP's regulation of cell death and highlighted its potential role in female reproductive systems.
据报道，冷诱导RNA结合蛋白（CIRBP）通过调节程序性细胞死亡（PCD）参与多种细胞功能。然而，CIRBP在调节线粒体自噬中的具体机制和功能仍不清楚。在本研究中，我们发现CIRBP通过AMPK/mTOR途径诱导线粒体自噬，以改善牦牛卵丘细胞（YCCs）的功能。我们观察到低温（32°C）激活自噬，增加E2和P4分泌，并上调CIRBP表达。CIRBP过表达激活YCCs中的线粒体自噬，促进卵丘扩散，增强E2和P4的合成与分泌，并抑制细胞凋亡。CIRBP过表达显著减轻了线粒体自噬抑制诱导的YCCs功能障碍，而激活线粒体自噬产生了与CIRBP过表达相同的效果。盐酸多柔比星是一种AMPK/mTOR途径抑制剂。CIRBP过表达可以成功缓解盐酸多柔比星抑制AMPK/mTOR途径所导致的线粒体自噬抑制，并能显著增强YCCs中AMPK/mTOR途径激活诱导的线粒体自噬。此外，我们发现CIRBP蛋白表达增加减轻了AKT途径激活引起的细胞凋亡。总之，CIRBP通过激活AMPK/mTOR途径促进线粒体自噬，从而促进YCCs中类固醇激素的合成与分泌以及卵丘扩散，并通过激活自噬和AKT信号通路增强YCCs的存活，进而改善YCCs的功能。我们的研究为CIRBP对细胞死亡的调节提供了新的视角，并突出了其在女性生殖系统中的潜在作用。
