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Induction of androgen formation in the male by a TAT-VDAC1 fusion peptide blocking 14-3-3? protein adaptor and mitochondrial VDAC1 interactions.


ABSTRACT: 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? protein adaptor as a negative regulator of steroidogenesis. Steroidogenesis begins in mitochondria. 14-3-3? 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? site of interaction with VDAC1 blocked 14-3-3?-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.

SUBMITTER: Aghazadeh Y 

PROVIDER: S-EPMC4428399 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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