Induction of Androgen Formation in the Male by a TAT-VDAC1 Fusion Peptide Blocking 14-3-3ε Protein Adaptor and Mitochondrial VDAC1 Interactions

被引:35
作者
Aghazadeh, Yasaman [1 ,2 ]
Martinez-Arguelles, Daniel B. [1 ,2 ]
Fan, Jinjiang [1 ,2 ]
Culty, Martine [1 ,3 ]
Papadopoulos, Vassilios [1 ,4 ]
机构
[1] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H3G 1A4, Canada
[2] McGill Univ, Dept Med, Montreal, PQ H3G 1A4, Canada
[3] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1A4, Canada
[4] McGill Univ, Dept Pathol, Montreal, PQ H3G 1A4, Canada
基金
加拿大健康研究院;
关键词
ACUTE REGULATORY PROTEIN; LATE-ONSET HYPOGONADISM; RAT LEYDIG-CELLS; BENZODIAZEPINE-RECEPTOR; CHOLESTEROL TRANSPORT; TESTOSTERONE THERAPY; STEROID-BIOSYNTHESIS; STEROIDOGENESIS; MEN; SEQUENCE;
D O I
10.1038/mt.2014.116
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 [微生物学]; 090105 [作物生产系统与生态工程];
摘要
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 14-3-3 epsilon protein adaptor as a negative regulator of steroidogenesis. Steroidogenesis begins in mitochondria. 14-3-3 epsilon 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 14-3-3 epsilon site of interaction with VDAC1 blocked 14-3-3 epsilon-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.
引用
收藏
页码:1779 / 1791
页数:13
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