Aghazadeh Yasaman, Martinez-Arguelles Daniel B, Fan Jinjiang, Culty Martine, Papadopoulos Vassilios
1] The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Medicine, McGill University, Montreal, Quebec, Canada.
1] The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Medicine, McGill University, Montreal, Quebec, Canada [3] Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Mol Ther. 2014 Oct;22(10):1779-91. doi: 10.1038/mt.2014.116. Epub 2014 Jun 20.
Low testosterone (T), a major cause of male hypogonadism and infertility, is linked to mood changes, fatigue, osteoporosis, reduced bone-mass index, and aging. The treatment of choice, T replacement therapy, has been linked with increased risk for prostate cancer and luteinizing hormone (LH) suppression, and shown to lead to infertility, cardiovascular diseases, and obesity. Alternate methods to induce T with lower side effects are desirable. In search of the mechanisms regulating T synthesis in the testes, we identified the 14-3-3ɛ protein adaptor as a negative regulator of steroidogenesis. Steroidogenesis begins in mitochondria. 14-3-3ɛ interacts with the outer mitochondrial membrane voltage-dependent anion channel (VDAC1) protein, forming a scaffold that limits the availability of cholesterol for steroidogenesis. We report the development of a tool able to induce endogenous T formation. Peptides able to penetrate testes conjugated to 14-3-3ɛ site of interaction with VDAC1 blocked 14-3-3ɛ-VDAC1 interactions while at the same time increased VDAC1-translocator protein (18 kDa) interactions that induced steroid formation in rat testes, leading to increased serum T levels. These peptides rescued intratesticular and serum T formation in adult male rats treated with gonadotropin-releasing hormone antagonist, which dampened LH and T production.
低睾酮（T）是男性性腺功能减退和不育的主要原因，与情绪变化、疲劳、骨质疏松、骨质量指数降低及衰老有关。首选治疗方法——睾酮替代疗法，与前列腺癌风险增加及促黄体生成素（LH）抑制有关，且已证明会导致不育、心血管疾病和肥胖。因此，需要副作用较小的诱导睾酮生成的替代方法。为了探寻调节睾丸中睾酮合成的机制，我们确定了14-3-3ɛ蛋白衔接子是类固醇生成的负调节因子。类固醇生成始于线粒体。14-3-3ɛ与线粒体外膜电压依赖性阴离子通道（VDAC1）蛋白相互作用，形成一个支架，限制了用于类固醇生成的胆固醇的可用性。我们报告了一种能够诱导内源性睾酮生成的工具的研发情况。与14-3-3ɛ与VDAC1的相互作用位点结合的能够穿透睾丸的肽，阻断了14-3-3ɛ-VDAC1的相互作用，同时增加了VDAC1-转位蛋白（18 kDa）的相互作用，从而诱导大鼠睾丸中的类固醇生成，导致血清睾酮水平升高。这些肽挽救了用促性腺激素释放激素拮抗剂处理的成年雄性大鼠的睾丸内和血清睾酮生成，该拮抗剂会抑制LH和睾酮的产生。
