Lv Jinxing, Wu Tiantian, Xue Jiajia, Shen Cong, Gao Wenxin, Chen Xia, Guo Yueshuai, Liu Mingxi, Yu Jun, Huang Xiaoyan, Zheng Bo
Center for Reproduction, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, 215124, China.
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
Redox Biol. 2025 Feb;79:103484. doi: 10.1016/j.redox.2024.103484. Epub 2024 Dec 27.
Male infertility, frequently driven by oxidative stress, impacts half of infertile couples globally. Despite its significance, the precise mechanisms governing this process remain elusive. In this study, we demonstrate that ASB1, the substrate recognition subunit of a ubiquitin ligase, is highly expressed in the mouse testis. Mice lacking the Asb1 gene exhibit severe fertility impairment, characterized by oligoasthenoteratozoospermia. Subsequent investigations unveiled that Asb1 knockout (Asb1-KO) mice encountered excessive oxidative stress and decreased hydrogen sulfide (HS) levels in their testes, and severe sperm DNA damage. Notably, the compromised fertility and sperm quality in Asb1-KO mice was significantly ameliorated by administering NaHS, a HS donor. Mechanistically, ASB1 interacts with ELOB to induce the instability of sulfide-quinone oxidoreductase (SQOR) by enhancing its K48-linked ubiquitination on residues K207 and K344, consequently triggering proteasomal degradation. This process is crucial for preserving HS homeostasis and redox balance. Overall, our findings offer valuable insights into the role of ASB1 during spermiogenesis and propose HS supplementation as a promising therapeutic approach for oxidative stress-related male infertility.
男性不育症在全球范围内影响着半数不育夫妇，其病因常与氧化应激有关。尽管其意义重大，但调控这一过程的精确机制仍不清楚。在本研究中，我们证明泛素连接酶的底物识别亚基ASB1在小鼠睾丸中高表达。缺乏Asb1基因的小鼠表现出严重的生育能力受损，特征为少弱畸精子症。随后的研究发现，Asb1基因敲除（Asb1-KO）小鼠的睾丸中遭遇了过度的氧化应激，硫化氢（HS）水平降低，且精子DNA严重受损。值得注意的是，通过给予HS供体NaHS，Asb1-KO小鼠受损的生育能力和精子质量得到了显著改善。从机制上来说，ASB1与ELOB相互作用，通过增强硫化物醌氧化还原酶（SQOR）在K207和K344位点的K48连接的泛素化来诱导其不稳定，从而触发蛋白酶体降解。这一过程对于维持HS稳态和氧化还原平衡至关重要。总体而言，我们的研究结果为ASB1在精子发生过程中的作用提供了有价值的见解，并提出补充HS作为氧化应激相关男性不育症的一种有前景的治疗方法。
