Mohanty Aradhana, Kumari Anjali, Kumar S Lava, Kumar Ajith, Birajdar Pravin, Beniwal Rohit, Athar Mohd, Kumar P Kiran, Rao H B D Prasada
BRIC-National Institute of Animal Biotechnology, Hyderabad, Telangana, India.
Graduate Studies, Regional Center for Biotechnology, Faridabad, India.
Aging Cell. 2025 Apr 28:e70066. doi: 10.1111/acel.70066.
The quality and quantity of the ovarian reserve are meticulously regulated through various cell death pathways to guarantee the availability of high-quality oocytes for fertilization. While apoptosis is recognized for contributing to maintaining ovarian reserve, the involvement of other cell death pathways remains unclear. Employing chemical genetics and proteomics, this study reveals the crucial involvement of Cathepsin B in maintaining the ovarian reserve. Results indicate that apoptosis and autophagy play pivotal roles, and inhibiting these pathways significantly increases follicle numbers. Proteomics reveals a dynamic shift from apoptosis to autophagy during follicular development, with Cathepsin B emerging as a key player in this transition. Inhibiting Cathepsin B not only mimics the augmented oocyte reserve observed with autophagy inhibition but also upregulated IGF1R and AKT-mTOR pathways without compromising fertility in pre- and postpubertal mice. Further, IGF1R inhibition partially compromised the protective effects of Cathepsin B inhibition on oocyte reserves, suggesting their interdependence. This association is further supported by the finding that Cathepsin B can degrade IGF1R in vitro. Moreover, the increased IGF1R levels enhance the oocyte mitochondrial membrane potential via transcriptional regulation of mitochondrial biogenesis and mitophagy genes. Remarkably, this Cathepsin B-dependent ovarian reserve maintenance mechanism is conserved in higher-order vertebrates. Cumulatively, our study sheds valuable light on the intricate interplay of autophagy, Cathepsin B, and growth factors in ovarian reserve maintenance, offering potential therapeutic strategies to delay ovarian aging and preserve fertility.
卵巢储备的质量和数量通过各种细胞死亡途径受到精细调控，以确保有高质量的卵母细胞用于受精。虽然细胞凋亡被认为有助于维持卵巢储备，但其他细胞死亡途径的作用仍不清楚。本研究采用化学遗传学和蛋白质组学方法，揭示了组织蛋白酶B在维持卵巢储备中的关键作用。结果表明，细胞凋亡和自噬起着关键作用，抑制这些途径可显著增加卵泡数量。蛋白质组学揭示了卵泡发育过程中从细胞凋亡到自噬的动态转变，组织蛋白酶B是这一转变的关键参与者。抑制组织蛋白酶B不仅模拟了自噬抑制时观察到的卵母细胞储备增加，还上调了IGF1R和AKT-mTOR途径，且不影响青春期前和青春期后小鼠的生育能力。此外，抑制IGF1R部分削弱了组织蛋白酶B抑制对卵母细胞储备的保护作用，表明它们之间相互依赖。组织蛋白酶B可在体外降解IGF1R这一发现进一步支持了这种关联。此外，IGF1R水平的升高通过对线粒体生物发生和线粒体自噬基因的转录调控增强了卵母细胞的线粒体膜电位。值得注意的是，这种依赖组织蛋白酶B的卵巢储备维持机制在高等脊椎动物中是保守的。总之，我们的研究揭示了自噬、组织蛋白酶B和生长因子在维持卵巢储备中的复杂相互作用，为延缓卵巢衰老和保持生育能力提供了潜在的治疗策略。
