Song Shuaifei, Yang Mingzhi, Li Jiayue, Li Yaru, Wang Lei, Yao Shiyi, Wang Zihan, Li Qiuyan, Han Yanguo, Xu Dejun, Zhao Zhongquan
Chongqing Key Laboratory of Herbivore Science, College of Animal Science and Technology, Southwest University, Chongqing, 400715, China.
J Anim Sci Biotechnol. 2025 Jul 17;16(1):101. doi: 10.1186/s40104-025-01231-8.
Reproductive efficiency in goats is closely linked to the healthy development of follicles, with the proliferation of ovarian granulosa cells (GCs) playing a crucial role in this process. Sirtuin 3 (SIRT3), an enzyme that catalyzes post-translational modifications (PTMs) of proteins, is known to regulate a variety of mitochondrial metabolic pathways, thereby affecting cell fate. However, the specific effect of SIRT3 on the follicular development process remains unclear. Therefore, this study aimed to investigate the regulatory role of SIRT3 in the mitochondrial function and proliferation of goat GCs, as well as the underlying mechanisms involved.
In this study, GCs from small follicles in goat ovaries presented increased proliferative potential and elevated SIRT3 expression levels compared with those from large follicles. In vitro, SIRT3 overexpression enhanced mitochondrial function, promoted proliferation and inhibited apoptosis in GCs. Correspondingly, the inhibition of SIRT3 led to the opposite effects. Notably, SIRT3 interacted with carnitine palmitoyl transferase 2 (CPT2) and stabilized the CPT2 protein by mediating delactylation, which prolonged the half-life of CPT2 and prevented its degradation. Further investigation revealed that CPT2 overexpression enhanced fatty acid β-oxidation and mitochondrial function in GCs. Additionally, CPT2 promoted the proliferation of GCs by increasing the protein levels of β-catenin and its downstream target, cyclin D1 (CCND1). However, this effect was reversed by 3-TYP (a SIRT3 inhibitor).
SIRT3 stabilizes CPT2 protein expression through delactylation, thereby enhancing mitochondrial function and the proliferative capacity of GCs in goats. This study provides novel insights into the molecular mechanisms and regulatory pathways involved in mammalian follicular development.
山羊的繁殖效率与卵泡的健康发育密切相关，卵巢颗粒细胞（GCs）的增殖在此过程中起着关键作用。沉默调节蛋白3（SIRT3）是一种催化蛋白质翻译后修饰（PTMs）的酶，已知其可调节多种线粒体代谢途径，从而影响细胞命运。然而，SIRT3对卵泡发育过程的具体作用仍不清楚。因此，本研究旨在探讨SIRT3在山羊GCs线粒体功能和增殖中的调节作用及其潜在机制。
在本研究中，与来自大卵泡的GCs相比，来自山羊卵巢小卵泡的GCs具有更高的增殖潜力和更高的SIRT3表达水平。在体外，SIRT3过表达增强了线粒体功能，促进了GCs的增殖并抑制了其凋亡。相应地，抑制SIRT3则产生相反的效果。值得注意的是，SIRT3与肉碱棕榈酰转移酶2（CPT2）相互作用，并通过介导去乳酸化使CPT2蛋白稳定，从而延长了CPT2的半衰期并防止其降解。进一步研究表明，CPT2过表达增强了GCs中的脂肪酸β-氧化和线粒体功能。此外，CPT2通过增加β-连环蛋白及其下游靶点细胞周期蛋白D1（CCND1）的蛋白水平促进了GCs的增殖。然而，3-TYP（一种SIRT3抑制剂）可逆转这种作用。
SIRT3通过去乳酸化稳定CPT2蛋白表达，从而增强山羊GCs的线粒体功能和增殖能力。本研究为哺乳动物卵泡发育所涉及的分子机制和调节途径提供了新的见解。
