ABSTRACT

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.

摘要

在男性中，由于睾丸 Leydig 细胞受损，衰老伴随着血清睾酮水平的下降。多梳蛋白 BMI1 最近被确定为抗衰老因子。在我们之前的研究中，BMI1 缺失小鼠的血清睾酮和 Leydig 细胞数量减少、氧化应激过度和 p16/p19 信号激活。然而，没有研究表型和途径之间的因果关系。在这里，我们使用救援方法来研究氧化应激或 p16/p19 在 BMI1 介导的类固醇生成中的作用。我们的结果表明，用抗氧化剂 NAC 处理，但不是 p16/p19 的下调，在很大程度上挽救了 BMI1 缺陷小鼠 MLTC-1 和原代 Leydig 细胞的细胞衰老、DNA 损伤和类固醇生成。总的来说，