BMI1 promotes steroidogenesis through maintaining redox homeostasis in mouse MLTC-1 and primary Leydig cells

In males, aging is accompanied by decline in serum testosterone levels due to impairment of testicular Leydig cells. The polycomb protein BMI1 has recently been identified as an anti-aging factor. In our previous study, BMI1 null mice showed decreased serum testosterone and Leydig cell population, excessive oxidative stress and p16/p19 signaling activation. However, a cause-and-effect relationship between phenotypes and pathways was not investigated. Here, we used the rescue approach to study the role of oxidative stress or p16/p19 in BMI1-mediated steroidogenesis. Our results revealed that treatment with antioxidant NAC, but not down-regulation of p16/p19, largely rescued cell senescence, DNA damage and steroidogenesis in BMI1-deficient mouse MLTC-1 and primary Leydig cells. Collectively, our study demonstrates that BMI1 orchestrates steroidogenesis mainly through maintaining redox homeostasis, and thus, BMI1 may be a novel and potential therapeutic target for treatment of hypogonadism.

对于雄性个体而言，衰老进程中血清睾酮水平会出现下降，其诱因是睾丸间质细胞（Leydig cells）的功能损伤。多梳蛋白BMI1（polycomb protein BMI1）近期被鉴定为一种抗衰老因子。在本研究团队此前的工作中，BMI1基因敲除小鼠表现出血清睾酮水平降低、间质细胞数量减少、过度氧化应激以及p16/p19信号通路激活的表型。但该研究并未探究上述表型与信号通路之间的因果关联。本研究采用挽救实验策略，探究氧化应激或p16/p19信号通路在BMI1介导的类固醇生成过程中发挥的作用。研究结果显示，采用抗氧化剂N-乙酰半胱氨酸（NAC）进行干预，而非下调p16/p19的表达，可显著挽救BMI1缺陷小鼠MLTC-1细胞与原代睾丸间质细胞中的细胞衰老、DNA损伤及类固醇生成缺陷。综上，本研究证实BMI1主要通过维持氧化还原稳态来调控类固醇生成过程，因此BMI1有望成为治疗性腺功能减退症的新型潜在治疗靶点。