Relovska Sona, Wang Huafeng, Zhang Xinbo, Fernández-Tussy Pablo, Jeong Kyung Jo, Choi Jungmin, Suárez Yajaira, McDonald Jeffrey G, Fernández-Hernando Carlos, Chung Jean-Ju
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA.
Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
bioRxiv. 2024 Feb 11:2023.12.21.572851. doi: 10.1101/2023.12.21.572851.
Desmosterol and cholesterol are essential lipid components of the sperm plasma membrane. Cholesterol efflux is required for capacitation, a process through which sperm acquire fertilizing ability. In this study, using a transgenic mouse model overexpressing 24-dehydrocholesterol reductase (DHCR24), an enzyme in the sterol biosynthesis pathway responsible for the conversion of desmosterol to cholesterol, we show that disruption of sterol homeostasis during spermatogenesis led to defective sperm morphology characterized by incomplete mitochondrial packing in the midpiece, reduced sperm count and motility, and a decline in male fertility with increasing paternal age, without changes in body fat composition. Sperm depleted of desmosterol exhibit inefficiency in the acrosome reaction, metabolic dysfunction, and an inability to fertilize the egg. These findings provide molecular insights into sterol homeostasis for sperm capacitation and its impact on male fertility.
鲨烯醇和胆固醇是精子质膜的重要脂质成分。胆固醇外流是精子获能所必需的，精子通过这一过程获得受精能力。在本研究中，我们使用了一种过表达24-脱氢胆固醇还原酶（DHCR24）的转基因小鼠模型，该酶是甾醇生物合成途径中负责将鲨烯醇转化为胆固醇的一种酶。我们发现，精子发生过程中甾醇稳态的破坏导致精子形态缺陷，其特征为中段线粒体排列不完整、精子数量和活力降低，以及随着父本年龄的增加雄性生育力下降，而体脂组成没有变化。缺乏鲨烯醇的精子在顶体反应中表现出效率低下、代谢功能障碍以及无法使卵子受精。这些发现为精子获能的甾醇稳态及其对雄性生育力的影响提供了分子层面的见解。
